Grants

NHLBI - National Heart Lung and Blood Institute

The goal of this proposal is to investigate the contributors to infrared medical device errors and to develop correction algorithms to improve the accuracy of pulse oximeters and temporal thermometers in patients with acute respiratory failure. Over one million adults are admitted to intensive care units (ICUs) in the US every year for acute respiratory failure requiring mechanical ventilation. In these patients, it is essential to have accurate oxygen saturation and temperature measurements. Pulse oximeters and temporal thermometers, which measure oxygen saturation and body temperature, are the two most ubiquitous infrared devices in the ICU. However, these devices are significantly less accurate in Black patients, leading to delays in recognition and treatment of life-threatening hypoxemia and infection. There remains a gap in knowledge about the factors that contribute to racial disparities in infrared device accuracy. While it is hypothesized that infrared devices perform differently across racial groups due to differences in skin melanin, this hypothesis has not been rigorously tested in prior studies. Further, there are clinical factors such as anemia and chronic lung disease that could also affect the accuracy of these devices. There are known racial disparities in comorbidities such as anemia and chronic lung disease, which could then mediate the inaccuracy observed in infrared devices. In this proposal, we will quantify the role of melanin in association with infrared device errors in a multi-center, racially diverse cohort of critically ill patients with acute respiratory failure (Aim 1); we will use structural equation modeling to develop innovative correction algorithms that incorporate melanin, bilirubin, dyshemoglobins, age, sex, perfusion, and comorbidities to correct device errors (Aim 2); we will validate the correction algorithms and evaluate the clinical impact of the algorithms in accurately identifying clinically significant measurements (Aim 3). Through this proposal, we will develop an innovative publicly available de-identified dataset of critically ill patients enrolled across 9 ICUs in 3 hospitals with quantified melanin levels integrated with electronic health record (EHR) data that will enable researchers to investigate inaccuracies in other medical devices. Successful completion of this grant will significantly enhance our scientific knowledge of how individual patient factors influence the accuracy of infrared medical devices in real-world clinical settings. Although device development is often seen as the primary solution to addressing infrared device errors, it takes decades, is expensive, and may not comprehensively correct for all the complexities of physiology in critical illness. The ultimate public health impact of this work is developing EHR-based correction algorithms (Device+) as a complementary solution to device development. The Device+ solution will significantly impact clinical practice by improving the accuracy of vital sign measurements, which will lead to improved population-level as well as individual-level outcomes in critically ill patients.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

Objective assessment of image quality (IQ) using task-based performance metrics is important for developing deep-learning image reconstruction and post processing algorithms, and for translating the champion algorithms to the clinics. Ideally, task performance evaluation should use human observers. But human observer studies are time consuming and expensive, therefore cannot be realistically applied to evaluating and optimizing algorithms during early-stage development. Computer-based human-performance mimicking model observers (MO) can substitute for human observers and hold great potential as a tool for IQ evaluation. However, MO studies are not often used for DL algorithm evaluation. One possible reason could be due to the weaknesses of MOs for task performance evaluation. Diagnostic tasks are complicated due to imperfect data acquisition, e.g., quantum noise, and the large patient anatomical variation. Historically, the patient anatomical variation is quantitatively intractable, while the quantum noise can be handled well by the known data acquisition model. In this context, the current paradigm of MOs circumvents our inability to quantify patient anatomical variation, but relies on multiple realizations of quantum noise to define a patient population. This approach leads to the intertwined weaknesses of (1) simplified task definitions and (2) burdensome data requirement, which may attribute to the absence of MOs in DL algorithm evaluation. The challenge of characterizing patient anatomical variation can now be overcome, thanks to the advent of score-based probabilistic diffusion models (DMs). Score-based DMs, in addition to generating image samples as in all generative models, have the unique capability of calculating the exact log-density (or log-likelihood) of image samples. This capability can be exploited to calculate (log-)likelihood ratio type test statistics and allows us to define a new paradigm of MOs for realistic clinical tasks with free-form, essentially unlimited signal and background variability, here “unlimited” means “to the extent of variation that the DM training data are curated for.” At the same time, relying on anatomical variation reduces the burdensome, multiple noise, data requirement, so that our new MOs are also data-efficient and applicable to patient data that do not come with multiple noise realizations. Our specific aims focus on (1) developing the computational framework of such diffusion-model enabled MOs, (2) validating MO performance using clinical detection and localization tasks. Our MOs break free from the historical confines that have hindered their adoption for routine task-performance evaluation of diagnostic image quality. They hold great potential for identifying promising early-stage algorithms, for offering a performance predictor that correlates well with diagnostic task performance, and for eventually translating the champion algorithms to clinical deployment for improved patient care.

NINDS - National Institute of Neurological Disorders and Stroke

ABSTRACT Friedreich's ataxia (FRDA), the most common inherited ataxia, leads to severe neurodegeneration, cardiac dysfunction, and often results in death by age 35. Despite the availability of omaveloxolone, the first FDA- approved treatment, its effectiveness is limited, and it is associated with several side effects. AnekaBio, in partnership with the University of Florida, is developing an innovative multi-targeted therapy called QTE therapy that addresses the complex molecular mechanisms underlying FRDA. Our preclinical studies demonstrate that QTE therapy significantly outperforms omaveloxolone, enhancing critical FRDA target proteins, improving cardiac function, reducing iron overload, and dramatically increasing survival rates in FRDAkd mice. A therapeutic alternative that is effective, safe, and which can outperform the existing treatment could significantly shift the treatment paradigm. The proposed Phase I STTR project focuses on identifying and validating efficacy biomarkers—specific biological indicators in blood and muscle—that reliably measure the effectiveness of QTE therapy. Utilizing advanced proteomic and transcriptomic technologies, we will conduct in-depth analyses in FRDAkd mouse model to discover biomarkers that can be used to monitor QTE's therapeutic impact. These biomarkers are essential for future clinical trials, as they will provide a reliable means of assessing treatment efficacy and safety in humans. During the Phase II STTR, we will validate these biomarkers across different species, including primates, and initiate human testing in collaboration with industry partners. This phase will also focus on refining QTE therapy for clinical application, guiding us toward IND submission and the initiation of clinical trials. Our ultimate goal is to transition QTE therapy from preclinical studies to clinical trials, establishing it as a safer and more effective treatment option for FRDA. Through the identification of robust efficacy biomarkers and collaboration with experts in drug development, we aim to transform the treatment landscape for FRDA, offering new hope to patients affected by this devastating disorder.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

The long-term goal of this project is to develop a scalable, user-friendly, and affordable continuous glucose monitoring (CGM) system to improve diabetes management. IMS has created the world’s smallest electrochemical analyte sensing platform using an application-specific integrated circuit (ASIC) based on Complementary Metal-Oxide Semiconductor (CMOS) technology. This design offers several advantages, including extreme miniaturization, enhanced signal-to-noise ratio (SNR), multi-sensor redundancy for better accuracy, and on-chip temperature calibration for improved reliability. The system leverages scalable semiconductor and flexible hybrid electronics manufacturing methods, increasing lot sizes by over 1000x compared to current CGMs, potentially simplifying factory calibration and reducing costs. It also provides superior performance, such as improved hypoglycemia accuracy, and usability benefits with a 5x smaller and 50% lighter transmitter compared to the Libre 3 CGM, allowing for a gentler skin adhesive that reduces irritation. IMS has demonstrated the core platform's functionality in humans through a First-In-Human (FIH) feasibility study presented at ADA 2023 and a second human study at ATTD 2024, and ADA 2025 showcasing multi-day sensor operation. This shows the significance of the platform for further NIH support. Currently, retrospective data processing is used to generate glucose readings from the device data. The Objective of this grant is to optimize these data processing algorithms to generate glucose readings from the IMS CGM while eliminating noise (de-noising) and combining multi-sensor data (fusion). IMS has shown that this is feasible. Upon demonstrating in vitro feasibility in Phase I, these algorithms will be tested in pre-clinical and clinical studies in Phase II. The project team includes the original inventors from the California Institute of Technology (Dr. Nazari, Dr. Rahman, and Mr. Sencan), along with seasoned researchers and industry experts such as Bill Van Antwerp (former CSO of Medtronic MiniMed), quality and IP expert John Heithaus, commercialization expert Paul Strasma (former CEO of Capillary Biomedical), clinical expert Dr. Anne Peters (Head of USC Diabetes Clinics), and biosensor expert Dr. Natalie Wisniewski (former CTO of Profusa, Inc.). The team will mentor Ms. Narges Honarvar Nazari in her transition from academic research into medical devices industry and entrepreneurship.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY Group A Streptococcus (GAS) is among the most common infectious agents worldwide, with an estimated 700 million infections and half-million deaths per year, numbers that increase annually. These factors, in addition to the growing prevalence of antimicrobial-resistant strains, it is vital to investigate new and innovative approaches for GAS infection treatment or prevention. Developing a universal vaccine is a promising long-term solution for improving the global burden of GAS. Unfortunately, attempts to develop a vaccine have been largely unsuccessful. For instance, the risk of molecular-mimicry based autoimmunity precludes the native forms of the gold standard GAS antigen, M protein, from being further developed in its native form. Additionally, sequencing efforts have identified many M protein serotypes, making universal coverage highly unlikely. Our published data indicates a promising new candidate for a GAS vaccine, S protein. We revealed S protein is a required GAS virulence factor in vitro and in vivo. New unpublished data shows recombinant S protein-immunized animals display a robust reduction in GAS colony-forming units compared to naïve animals in a skin infection model. Strikingly, we also demonstrate the ability of S protein to immunize mice surpasses that of M protein. Importantly, unlike M protein, S protein sequences are nearly identical among various GAS serotypes and contain no cross- reactive human sequences. We further determined that anti-S protein antibodies bind the surface of multiple GAS serotypes and verified them to be cross-reactive. These preclinical data underscore S protein is a viable GAS vaccine candidate but also highlight a novel area of further investigation. The overall goal of this R21 application is to further validate S protein as a novel protective vaccine against GAS, a human pathogen responsible for nearly 1 billion infections worldwide per year. This work is significant as our proposed study can potentially reduce the health burden of over 1 billion humans infected with GAS. Our studies are innovative, as they will provide pharmacokinetic insight into a novel vaccine antigen for GAS treatment. Our team, composed of clinicians and researchers, has expertise in GAS pathogenesis and immunity, vaccination studies, animal models, and the most powerful proteomics instrument currently on market. Therefore, our team is well-positioned to study GAS vaccine development in innovative fashions.

OD - NIH Office of the Director

Project Summary Accidental exposure to ionizing radiation (IR) poses a significant risk for cardiovascular morbidity, a leading cause of mortality among irradiated populations. However, the mechanisms driving long-term cardiovascular risks remain poorly understood. IR disrupts immune homeostasis, exacerbating chronic inflammation and accelerating pathological remodeling. The current multi-PI U01 proposal seeks to address this knowledge gap by developing an innovative extracorporeal system composed of human stem cell derivatives to identify biomarkers and medical countermeasures (MCMs) for radiation-induced delayed cardiac remodeling (RidCR). In Milestone 1, we will establish a 3D cardiac-immune co-culture system using iPSC-derived cardiomyocytes, endothelial cells, fibroblasts, and macrophages to simulate the immune-competent 3D microenvironment. Optimized culture conditions will be validated in 3D engineered cardiac tissues (EHTs) for physiological and inflammatory responses. In Milestone 2, we will perform multi-omics analyses on irradiated EHTs and parallel animal models to identify molecular signatures of RidCR via multi-omics and functional assessments of tissue contractility. In Milestone 3, AI/ML will integrate the generated datasets to predict candidate MCMs, which will be validated in vitro and tested in vivo using a protracted irradiation mouse model. Comprehensive evaluations will assess the efficacy of the lead MCM in mitigating RidCR.

NIGMS - National Institute of General Medical Sciences

Continuous bioprocessing that brings with it the advantages of lower ultimate cost, a smaller equipment footprint and energy efficiency, is beginning to be embraced by the biopharmaceutical industry. Long term continuous fermentation requires a high level of genetic and metabolic stability. Scarab Genomics proprietary reduced genome E. coli strains provide the requisite genetic and metabolic stability for such long term continuous fermentations. Scarab Genomics proposes to develop the first fully continuous platform for the production and purification of recombinant proteins and plasmid DNA (pDNA) by replacing homogenization of bacteria with a custom autolysis system controlled by a temperature sensitive promoter. Distinctive features of Scarab’s Clean Genome bacteria such as the absence of all cryptic prophage make it uniquely suited for tightly regulated lysis. Having attained proof-of-concept in small scale culture, this application proposes to optimize this lysis system in high density (>200 OD600) continuous fermentation (C-Flow). To further facilitate the development of a continuous system, the lysis operon will also drive the exonuclease bensonase so that as lysis occurs, the large amount of nucleic acid that hinders downstream processing will be removed. To enable a lysis system for plasmid DNA (pDNA) purification, bensonase in the lysis operon will be replaced by the lambda exonuclease which digests genomic DNA but not pDNA thereby providing an alternate system for the production of pDNA. Once optimized, this lysis and nucleic acid digestion system will be used to express two commercially relevant test proteins. The first will be insulin because Scarab sees the possibility of C-Flow as a vehicle for the production of less expensive insulin and insulin related compounds to meet the objectives of the US government and the WHO. The second will be a single chain antibody (scFv) given the numerous applications in diagnostics and therapeutics for single chain antibodies and antibody fragments. To prepare C-Flow for market, the application also proposes to develop upgrades to the current system including oxygen infusion of medium using microbubble delivery and a microbubble separation chamber for the removal of cell debris. These innovations will result in the first continuous fermentation platform in E. coli for the production of biopharmaceuticals.

NIMH - National Institute of Mental Health

PROJECT SUMMARY In the United States, racial-ethnic disparities in mental health treatment engagement and consequently rates of unmet mental health needs have increased over the past two decades. Although drivers of these disparities are multifaceted, key contributors include the fallacy that evidence-based treatments (EBTs) are acultural as well as limited empirically supported guidance on culturally adapting EBTs. Developing a tool to help clinicians decide whether, when, and how to culturally adapt EBTs for individual Latine youth clients may enhance the cultural compatibility of EBTs and consequently improve treatment engagement and outcomes for this underserved population. The overall objective of this research is to develop and pilot a novel tool to help clinicians make personalized cultural adaptation decisions for their Latine youth clients. Our central hypothesis is that this decision support tool will help clinicians make appropriate cultural adaptations to EBTs, which will ultimately lead to improved mental health services and outcomes for Latine youths. In Aim 1, we will develop a novel tool – the Culturally Responsive Assessment, Formulation, and Treatment Tool (CRAFTT) – through four co-creation sessions with nine clinicians and researchers. These co-creation sessions will involve activities to: (1) triangulate cultural factors that may influence treatment engagement or progress to inform whether/when to culturally adapt EBTs; (2) triangulate cultural adaptations to inform how to culturally adapt EBTs; (3) match cultural factors with corresponding cultural adaptations; and (4) determine how to package this tool to facilitate effective and efficient clinician use. In Aim 2, we will refine CRAFTT through usability testing with eight clinicians. Lab-based user testing (“think aloud”) observations and quantitative usability ratings will be merged to identify and prioritize usability problems to be addressed through CRAFTT refinements. In Aim 3, we will evaluate the feasibility of the approach intended to be used in a future large-scale randomized effectiveness trial. This pilot study will include clinicians (N = 16) working with Latine youths (N = 64) with anxiety, depression, trauma, and disruptive behaviors. Clinicians will be randomized to either: (1) assess for cultural factors that may influence treatment engagement or progress using the Cultural Formulation Interview (CFI), treat psychopathology using the Modular Approach to Treatment for Children (MATCH), and make cultural adaptation decisions using CRAFTT; or (2) assess for cultural factors using the CFI, treat psychopathology using MATCH, and make cultural adaptation decisions using their best clinical judgement. Completion of this project will result in the first decision support tool for helping clinicians personalize cultural adaptation of EBTs for Latine youths. This work will also lay the foundation for a NIH R01 grant proposing to conduct a large randomized effectiveness trial testing the effect of MATCH augmented with CRAFTT on Latine youth treatment engagement and outcomes. This proposal aligns with NIMH’s priority to adapt EBTs to improve mental health services for underserved populations and promote mental health equity.

NIA - National Institute on Aging

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disease currently affecting approximately 6.2 million Americans. AD irreversibly damages the central nervous system, thereby inducing a variety of cognitive, behavioral, and psychiatric disturbances that include agitation and aggression. AD aggression occurs in approximately a third of AD patients and meaningfully reduces patient and caregiver quality of life. Currently available pharmacological treatments for AD aggression center on the use of atypical antipsychotic drugs, which have modest efficacy only after chronic administration, and are associated with sedation as well as adverse events including increased rates of upper respiratory tract infections, cardiovascular events, falls, and mortality. Given the modest efficacy and poor safety profile of these treatments, identification of novel treatments for AD aggression with improved efficacy and safety is an important unmet need. The long-term goal of this project is to bring to market a new treatment for AD aggression to improve the quality of life for people with AD and their caregivers. We have discovered a lead drug candidate, PGI-5128, that has a novel mechanism of action to produce serenic-like effects in rodent models of aggression. Phase I of this project seeks to evaluate the efficacy of PGI-5128 in reducing aggressive behaviors in male and female transgenic AD (APP/PS1) mice. Phase II seeks to initiate Investigational New Drug (IND)-enabling non-clinical safety and toxicology studies in rats and dogs conducted according to good laboratory procedures (GLP). Specifically, studies will include 28-day repeat dose toxicology studies with 14-day recovery periods in rat and dog, genotoxicology studies including in vitro bacterial reverse mutation and in vitro and in vivo micronucleus tests, and safety pharmacology studies including in vitro manual patch clamp-based measures at the human ether-à-go-go (hERG) channel, CNS and behavioral and safety pharmacology studies in rats, a respiratory safety study in rats, and a cardiovascular safety study in dogs. Completing these studies will position PGI-5128 for an IND application to allow evaluation in human subjects.

NIDCD - National Institute on Deafness and Other Communication Disorders

Project Summary/Abstract Noise-induced hearing loss is one of the most prevalent and irreversible forms of sensorineural hearing loss, affecting approximately 40 million American adults. It significantly reduces quality of life and is associated with cognitive decline, depression, and social isolation. While hearing aids and cochlear implants partially restore auditory function, they fail to replicate natural hearing and may introduce further auditory damage. Prevention remains a promising pathway to preserving auditory health, especially for individuals exposed to occupational or therapeutic risks, such as firefighters, military personnel, and chemotherapy patients. Among the various approaches studied for hearing preservation therapeutic hypothermia (MTH) has emerged as the most clinically translatable option. However, evidence suggests current mild therapeutic hypothermia devices deliver suboptimal spatial temperature distributions and lack the precision needed to uniformly cool critical cochlear structures. A transformative approach is used in this project to enhance mild therapeutic hypothermia for hearing loss prevention. Computational modeling, experimental validation, and device development will be integrated to design a new non-invasive cooling strategy that accounts for anatomical variability and vascular heat transfer. Specifically, a multiphysics model of the cochlea and surrounding vasculature will be constructed to evaluate how blood flow affects cooling dynamics during mild therapeutic hypothermia. Using insights from simulation and cadaveric studies, an advanced cooling device will be fabricated to deliver targeted, uniform hypothermia to the cochlear region. Rapid onset, spatial uniformity, and safety will be prioritized, minimizing adverse effects such as overcooling. Comparative analysis will be conducted against existing devices using ex vivo and in vitro methods to quantify efficacy in achieving desired thermal profiles. The results are expected to define the thermodynamic parameters and spatial targets essential for optimal hypothermic neuroprotection of the cochlea. In addition to technical advancements, the project will serve as a training platform for undergraduates and graduate students, offering interdisciplinary exposure to computational modeling, experimental bioengineering, and auditory neuroscience. By addressing key limitations of current mild therapeutic hypothermia systems, this work will lay the foundation for next-generation cooling devices with the potential to significantly reduce the incidence of noise-induced hearing loss. These contributions will support future clinical investigations and provide a reproducible research model for non-invasive auditory preservation techniques. The in-silico model developed here may also serve as a virtual microscope to explore and optimize emerging hearing preservation strategies.

NINDS - National Institute of Neurological Disorders and Stroke

Project summary/Abstract Variants in the ubiquitin like modifier activating enzyme 5 (UBA5) result in an ultra-rare autosomal recessive disease with neurological presentations. UBA5 patients present with infantile spasms, failure to thrive, hypotonia, developmental delay, microcephaly, intellectual deficit, loss of motor skills and seizures. Most of the patients die in childhood. Current standard of care for UBA5 deficiency is focused on managing the clinical signs with standard anti-seizure medications or surgical procedures and physical therapies, but there is no treatment. Compound heterozygous mutations in UBA5 causes impairment in a ubiquitin-like post-translational modification pathway called Ubiquitin-fold modifier 1 (UFM1). UBA5 is an E1 activating enzyme on UFM1 pathway. The role of the UBA5 and UFM1 system in the central nervous system (CNS) has not been studied. This stems from lack of a viable mammalian model for UBA5 deficiency. Our team has identified the first viable Uba5 mouse model that carries patient mutation, exhibits an overt phenotype, and recapitulates presentations of UBA5 deficiency in patients including smaller body size, motor, cognitive and gait abnormalities. Our team has postmortem tissues of UAB5 patients, their clinical course, MRI and EEG records. The first neuropathological characterization of postmortem UBA5 patient brain indicates the shared features with Uba5 mice. To determine the top adeno associated virus (AAV) vector candidate for efficacy studies in Uba5 mouse, we developed four UBA5 expressing constructs and showed their 1) efficacy in restoration of expression and function of UBA5 in UBA5 Knockout HEK293T cells and 2) durability, safety, and cell type tropism in a one-year study in wild type mouse. The top candidate, AAV9-JeT-UBA5, restored motor, cognitive and most aspect of gait abnormalities in Uba5 mouse model treated by neonatal intracerebroventricular (ICV) treatment. However, weight of treated Uba5 mice did not get normalized. We hypothesize that gradual loss of transduced cells in liver prevented long term weight gain normalization. Since the overarching goal of this project is to develop a transformational AAV gene therapy to treat our symptomatic UBA5 patient cohort at UMass Chan, we need to address the therapeutic imperfections and develop biomarkers. We will perform CNS and periphery wide gene therapy of JeT-UBA5 in pre and post symptomatic Uba5 mouse to determine the therapeutic window and feasibility of gene therapy to rescue or modify disease course. We will use 1) AAV9 capsid for combined CSF and periphery wide gene delivery in Uba5 mouse and 2) a new blood-brain barrier penetrant capsid (BI-hTFR1; interact with human Transferrin Receptor (TFRC)) for very efficient gene delivery to CNS and periphery by systemic injection. We will perform an in-depth characterization of the Uba5 mouse model and its humanized version, expressing TFRC, with clinically relevant outcomes measure (MRI and EEG) and compare them with patient findings (Aim 1). Four gene therapy approaches will be performed in Aim 2. In Aim 3 metabolomic based biomarker discovery will be performed and the best gene therapy approach to normalize transcriptomic profile of Uba5 mouse of will be determined.

NIDCD - National Institute on Deafness and Other Communication Disorders

F.220: 7. PROJECT SUMMARY / ABSTRACT The olfactory epithelium (OE) is a pseudostratified tissue deep within the nasal cavity, near the cribriform palate. It primarily contains olfactory sensory neurons (OSNs) that are responsible for transmitting odor- detecting signals to the olfactory neural pathway, as well as basal progenitor cells and supporting cells1,2. Anosmia (the loss of the sense of smell) arises from conditions where OSN regeneration is diminished, leaving behind depleted regions without OSNs3,4. This can happen due to normal aging, neurodegenerative diseases, viral infections, congenital disorders, and exposure to external toxins3,5,6. More than half of people aged 65 or older will experience some degree of anosmia5. When a patient presents with anosmia, clinical evaluation involves a combination of the patient's medical history and functional tests. These tests have been shown to be subjective due to cultural and environmental factors5, and they do not discern whether the problem lies with OSNs and their transmission or elsewhere in the olfactory neural pathway. Biopsies are reserved for extreme cases since they carry a risk of damaging the already scarce OE tissues, offer extremely limited sampling, and require significant time and expertise5,7. There is currently no endoscopic tool that can reliably identify and image the olfactory epithelium in humans in real time with high spatial and temporal resolution. This type of imaging has been difficult to achieve due to anatomical complexity, inability to differentiate between cell types, and optical limitations. The OE is located deep within the nasal cavity, behind bony structures and cartilage, requiring careful and precise navigation to access1. Even when reached, the OE exists as scattered patches that constitute only ~10% of the nasal epithelia1. These patches have no clear macroscopic boundaries and are nearly indistinguishable from their surrounding RE without the aid of external markers1,8. Furthermore, these patches shrink with age and disease progression3,5,9,10, making identification even more difficult. In this proposal, I aim to develop a nasal endoscope tool that can reliably distinguish between OE and RE while also providing real-time imaging of the OE at high spatial and temporal resolution. This device would be designed for use by clinicians in outpatient settings to enable direct assessment of the OE in patients. The proposed tool would significantly advance both biomedical research and clinical practice. By enabling direct visualization of the spatial distribution of OSNs, this technology would allow researchers and clinicians to visually assess the size, uniformity, and patchiness of the OE. Because these features change with aging and disease, they can offer valuable insights into the underlying biology of olfactory dysfunction. This tool will enable longitudinal studies of OE regeneration and response to therapies, informing the development of targeted treatments. Clinically, this tool would provide a more objective assessment of anosmia than current smell tests, allow for the monitoring of OE changes over time, and significantly improve diagnostic accuracy.

NSF

The global ocean oxygen inventory (total amount of oxygen stored within the entire ocean volume) has declined by over two percent over the past six decades. Although changes in the dissolved oxygen inventory appear small, they have profound and long-lasting impacts on marine organism resilience. Ocean deoxygenation has altered the viability of marine ecosystems. The ability to sustain healthy marine life and ecosystems is dependent on species-specific vulnerability to deoxygenation. The sampling density in the deep ocean (below 2000m) is significantly lower than in the upper ocean, and this presents a major obstacle to accurately monitoring dissolved oxygen fluctuations in these depths. The dearth in global ocean oxygen makes it difficult to accurately understand and predict ocean deoxygenation. Increased dissolved oxygen sampling, particularly in the deep ocean, would be instrumental in providing much needed data for assimilation into numerical models, improving model predictions, and advancing our understanding of the mechanisms affecting oceanic dissolved oxygen variability. This award will fund the development of a new dissolved oxygen sensor for integration on Deep Argo floats, with multiple benefits. The new sensor will simplify usage and improve the quality and scientific value of dissolved oxygen measurements collected in the deep ocean. This technology will help to resolve top-to-bottom regional to global ocean oxygen fluctuations at subseasonal-to-decadal time scales. The investigators will also test the capacity of machine learning algorithms to predict the vertical distribution of ocean carbon in the deep ocean using temperature, salinity and oxygen measurements. This project will support a collaboration between academia, and a US based commercial company who develops and sells oceanographic sensors and instrumentation. The team will work with teachers from NSF’s Science Teacher and Researcher (STAR) program at local charter schools to integrate an Argo-based class in their physics course. STAR directly addresses the science, technology, engineering, and math (STEM) teacher recruitment and retention crisis by creating a dual “teacher-researcher” role, immersing teachers in cutting-edge research environments. The Deep Argo Program is the deep component of the OneArgo design to extend Argo float sampling to the sea floor. While the main objectives of Deep Argo are to reduce errors in global decadal trends of deep-ocean heat content and thermal expansion, a new application under evaluation is to address ocean deoxygenation over the full-ocean depth using Deep Argo floats. All Deep Argo dissolved oxygen sensors, including operational and prototype models, have similar performance, but none of them reach the <1 µmol/kg accuracy level needed to resolve the structure and variability of deep-ocean oxygen ventilation and overturning circulation. The aim of this project is to increase the accuracy of the Deep Oxygen sensor prototype to ≤1 µmol/kg and advance stability and precision to ≤0.25 µmol/kg per 100,000 samples and ≤±0.1 µmol/kg values compatible with the accuracy objective. Deep Argo temperature and salinity profiles combined with dissolved oxygen measurements, would transform our understanding of the characteristics and history of water masses, and leading physical and biological mechanisms driving fluctuations of oxygen distribution. The use of temperature, salinity, and oxygen data collected from Deep Argo floats in neural network methodologies would provide a new means to investigate carbon dioxide uptake from the atmosphere, penetration into the deep ocean, and spatio-temporal evolution of carbon pathways and storage in the ocean reservoir. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Vision Hillman City

Vision Hillman City will publicize a proposal for creating a neighborhood council and hold a neighborhood-wide meeting to discuss the content of the proposal and seek the community's input and approval. The meeting will be on September 15, 2016 from 6:30 - 8:30 p.m. at the Rainier Avenue Church located at 5900 Rainier Avenue South.

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY: In this R03 application, “Development of a Humanized IL33 Mouse” we plan to engineer and characterize a mouse strain in which the human IL33 gene sequence from ~28 kb (including the 20 kb asthma-associated region) upstream of exon 1 to ~21 kb downstream of exon 8 of human IL33 gene will be cloned into intron 1 of ROSA26 locus in the mouse. This strategy uses a bacterial artificial chromosome (BAC) to insert all of the human regulatory regions which have been associated with allergic disease into the mouse. The targeting strategy uses the PiggyBac technology to deliver a single copy of the transgene into the specific integration site. The strategy includes the upstream regulatory regions because they confer localization of the human IL33 gene expression to the bronchial epithelial cells and the endothelium. That is in contrast to the mouse Il33 gene expression which is located in the lung type 2 alveolar epithelial cell. The mouse will also have lox-p sites introduced into exon 5 which can be used to conditionally delete IL33 expression. Finally, the human IL33 locus will drive an IRES-Citrine reporter that can report on the expression of the human IL33 promoter. This mouse will be crossed to the Il33cherry mouse which is a knock-in/knock-out (mcherry reporter) so that the resulting mouse will only have human IL-33 protein (which is biologically active in mice) from the human IL33 promoter along with a human IL33 Citrine reporter and a mouse Il33 cherry reporter. This mouse will then be compared to wildtype mice in an acute lung allergen challenge model to determine how localization of expression to different lung cell types (bronchial epithelium/endothelium vs type 2 alveolar epithelium) alters the location of lung type 2 infiltrates and the degree of bronchial epithelial remodeling. This proposal will utilize novel spatial transcriptomic technologies to ask important questions about how IL-33 localization alters the architecture of lung type 2 inflammation. This mouse has great potential to advance our understanding of human genetics since the asthma-associated genetic architecture (upstream of the human IL33 gene) will be introduced into the mouse.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary Despite recent advances in diabetes treatment and technology (e.g., automated insulin delivery [AID] systems), achieving recommended glycemic targets is still difficult for people with type 1 diabetes (T1D) and, worrisomely, T1D confers substantial cardiorenal risk even when conventional glycemic targets are achieved. The sodium- glucose cotransporter inhibitors (SGLTi) are antihyperglycemic medications that have demonstrated significant cardiorenal benefits in people with and without type 2 diabetes, including reductions in kidney disease progression and hospitalization for heart failure. SGLTi medications have been tested in people with T1D and shown beneficial effects on glycemic control; however, they also contribute to an increased risk of ketoacidosis that has drastically limited their clinical utility in this population. AID systems pair continuous glucose monitors (CGM) and insulin pumps with control algorithms that automatically modulate insulin delivery in real-time. Continuous ketone monitoring (CKM) is a rapidly evolving technology with the potential to prevent ketoacidosis by tracking ketone levels, transmitting results to a dedicated smartphone or device, and providing early warnings of ketone elevations. A combined CKM/CGM biowearable sensor (Abbott Diabetes Care; Alameda, CA) is currently in clinical testing for commercial use and has the potential to be integrated into closed-loop AID systems. The current proposal will specifically address this by developing a “ketone-aware” AID system that receives dual input from the CKM/CGM sensor and subsequently optimizes glycemic control while minimizing ketosis. Our study aims are as follows: 1. We will refine and implement the Ketone-Aware Predictive Algorithm (kAPA), a ketone-aware algorithm with its roots in our recent SGLTi + AID crossover trial. Using archival data and CKM characteristics, we will model ketone elevation and measurement in our well-known simulation environment that is FDA-accepted for preclinical testing of AID systems. In parallel, we will create a kAPA model predictive AID controller and refine it in silico before implementing kAPA into our established DiAS prototyping platform. 2. We will demonstrate the feasibility and safety of kAPA in people with T1D by conducting a 36-hour supervised pilot study to demonstrate acceptable real-time ketosis control while taking sotagliflozin 200 mg; 3. We will demonstrate that kAPA improves glycemic control and minimizes ketosis by conducting a 12- week randomized, single-blind, placebo-controlled crossover clinical trial comparing kAPA + sotagliflozin to AID + placebo in people with T1D. Successful completion of this project will develop a proactive, ketone-aware AID system that can optimize glycemic control, minimize ketosis, and allow for safe administration of SGLTi medications in people with T1D.

NIAID - National Institute of Allergy and Infectious Diseases

To support the advanced development of candidate products for use following the intentional release of or in response to naturally occurring outbreaks of infectious diseases, including emerging infectious diseases. This contract may support formulation and manufacture of the individual vaccine components, as well as stability testing, nonclinical immunogenicity and efficacy testing in animal models, IND enabling GLP toxicology, submission of an IND and clinical safety and efficacy evaluation.

NCI - National Cancer Institute

Project Summary Coupling high-throughput omics technologies with machine learning and the phenotypic-based drug discovery paradigm allows for data-driven drug discovery (D4). D4 has the advantage of being unbiased, like phenotypic- based drug discovery, but the comprehensive measurements of 100s to 100,000s of biological features also enables characterizing drug perturbations and disease signatures to gain mechanistic insights. The predominant data type for D4 has been transcriptomics and more recently image-based assays. Other biomolecules (i.e., proteins and metabolites) are considered closer to the phenotype, however technical challenges in data generation and analysis, as well as the lack of standardized data analysis pipelines have limited the systematic use of these data types. Sinopia Bioscience and Omix Technologies have combined their strengths in systems biology data analysis, AI/ML, and LC-MS/MS based metabolomics to develop a unique metabolomics-based platform that has allowed for systematic metabolic characterization of a chemical library consisting of ~3,300 small molecules covering more than 1,000 drug targets. Our preliminary results demonstrate that metabolomics is more sensitive, reproducible, and predictive of the mechanism of action of these small molecules than transcriptomics. Further, we found that using metabolomics data we could predict cell line specific toxicity of cancer drugs in viability assays. Importantly, we found we could derive metabolic signatures of sensitivity and resistance and use these to identify secondary compounds that can enhance sensitivity to cancer drugs. In this Phase I proposal, we will expand on these findings and develop novel algorithms to better understand how baseline metabolic states of cancers affect their sensitivity to cancer drugs. As a development test case we will focus on sensitivity of breast cancer cell lines to docetaxel and tucatinib. First, we will perform high throughput metabolomics and analysis of 100 cancer cell lines to characterize metabolism both in a baseline state and after administration of docetaxel and tucatinib. Second, we will develop novel computational algorithms for predicting the ability of compounds to sensitize cancer cells to cancer drugs. Finally, we will experimentally validate novel compound combinations and generate metabolomics data to further improve our algorithms. Success of this Phase I proposal will lead to validated metabolomics-based methods for identifying underlying metabolic phenotypes predictive of drug sensitivity, which will then be leveraged to predict the effects of compound combinations. This allows us to further expand Sinopia’s platform’s capabilities and its application to oncology applications through partnerships with biotech/pharma and/or fundraising through outside investors. In addition, it would lead to novel use of targets and compounds to enhance the sensitivity to existing cancer treatments that we can internally develop. Phase II will focus on further development of the platform, expanding our metabolomics-based library, and advancing promising synergistic combinations into preclinical models.

NHLBI - National Heart Lung and Blood Institute

ABSTRACT Hypertension in pregnancy is highly prevalent and increasing in the United States, and 40% of maternal deaths involve women with hypertension. In adults from racial/ethnic minority groups, hypertension is two-fold more prevalent and leads to higher rates of preeclampsia and stroke, thus resulting in devastating health consequences in the infant and mother alike. The time required for frequent in-person visits, inadequate counseling, and the asymptomatic nature of hypertension are major barriers to effective blood pressure (BP) control in pregnant women. These issues can be addressed through home BP monitoring (HBPM), which holds the potential to reduce preventable and devastating clinical events while also proven to reduce racial inequities in pregnant women. Obstetric societies recommend HBPM for all pregnant women with hypertension, but our pilot work suggests that rates of HBPM counseling and uptake are low. With the increasing use of mobile health apps in pregnancy, there is an opportunity for digital health approaches with culturally appropriate storytelling to improve HBPM and allow pregnant women with hypertension to learn from others with similar lived experiences. We are requesting an administrative supplement to allow for direct caregiving for critical illness, to support the aims of the parent K23 Award proposal to develop Moms@Home, a digital health approach to support HBPM in pregnant women with hypertension. Moms@Home integrates storytelling videos with a Social Cognitive Theory-based proven approach to support behavior change and address the cultural and literacy needs of a diverse population of pregnant women. We hypothesize that incorporating storytelling with a successful digital health approach may increase the adoption of HBPM. Aim 1 has adapted the existing mobile health app MyDataHelpsTM to create Moms@Home for pregnant women with hypertension by incorporating stories from women with similar lived experiences. Aim 2 has led to refinement of the Moms@Home components with obstetric caregiver and patient interviews. Aim 3 will pilot test the Moms@Home approach in pregnant women with hypertension, enriched in those from racial/ethnic minority groups, to assess HBPM adherence, feasibility, and acceptability. Beyond the research plan, the K23 will provide Dr. Kovell with advanced research training, protected time, and mentoring to become an independent physician-scientist focused on improving outcomes for pregnant women with hypertension. This K23 award, with additional support from the administrative supplement, will set the stage for Dr. Kovell’s future R01 application examining digital behavioral health interventions on BP control for pregnant women with hypertension. This innovative and scalable proposal has tremendous potential to positively impact and support women with hypertension through healthy pregnancies.

NIBIB - National Institute of Biomedical Imaging and Bioengineering

PROJECT SUMMARY: Background. Traditional drug development is slow, costly, and inefficient, with over 90% of drugs failing in clinical trials. Personalized medicine also faces challenges in accurately matching patients with optimal treatments. "Phase-0" microdosing, involving the delivery of tiny drug doses directly into target tissues, has the potential to transform both drug development and personalized drug selection by directly evaluating drug effects in patients without systemic toxicity and rapidly identifying the best treatment for each individual. Our team is leading the clinical translation of an implantable microdevice (IMD) that provides Phase-0 microdose readouts of multiple drugs in a single patient. IMDs are placed into diseased tissue (most commonly tumors) and subsequently release drugs into spatially discrete microscopic regions. The devices and surrounding tissue are then removed surgically and drug effects are characterized and compared using a multi-omic spatial analysis pipeline. Preclinical and first-in-human IMD trials have been highly promising with unprecedented drug insights. However, surgical resection required for IMD analysis is not feasible or safe in most deep anatomic locations. This has prevented IMD validation and use in most settings where they are needed, including neoadjuvant and aggressive metastatic cancer. A less invasive and safer approach is needed to enable broad clinical application. More specifically, there is a critical and currently unmet need for a nonsurgical interventional device to deliver drug microdoses and subsequently biopsy drug-containing tissues for Phase-0 measurements. Proposal and impact. In Aim 1, we will develop an interventional drug response assay (IDRA) device that will broadly enable biopsy-based Phase-0 measurements from any percutaneously accessible site similar to routine percutaneous biopsies, with similar outpatient workflow and low risk. In Aim 2, we will validate IDRA safety and feasibility in prostate and ovarian cancer pre-clinical models (Aim 2). This will enable clinical investigational trials in neoadjuvant and advanced metastatic prostate and ovarian cancer, two settings where oncologists have expressed a critical and urgent need. In a parallel Aim 3, we will integrate label-free optical imaging into the IDRA and evaluate feasibility to image real-time drug effects directly in tumors (Aim 3). Aim 3 will lay the groundwork for our long-term goal of dynamic in-vivo optical Phase-0 imaging, which would provide unprecedented capability to directly monitor drug response and resistance over time. In the long term, these aims have the potential to broadly transform drug development and personalized treatment selection in diseases throughout the body.

NSF

With the support of the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Jason Dwyer and his research team at the University of Rhode Island will develop new tools and approaches to better understand how to fabricate and use a powerful new class of nanopore sensors. Nanopore devices are commercially available for single-molecule DNA sensing that supports a wide range of health-related applications such as personalized medicine. They are being developed for identifying proteins to enable earlier detection of disease, alongside other medical purposes. Nanopore devices are also useful for a wide range of other functions such as desalination and high-density molecular data storage readout. Developing better understanding of how to construct and exploit nanopores will thus pay dividends across these various domains of technology and human health. The work will focus on understanding and exploiting nanopore surface coatings. It will begin with elucidating fundamental molecular-level mechanisms of how the chemical properties of the coatings affect nanopore performance. It will then extend to investigating how to more reliably and easily recognize the various chemical building blocks of proteins, as a prelude to more elaborate protein identification applications. Student training will be a vital part of this effort, with an emphasis on broadly transferable skill development spanning from fundamental research planning to technical skill development to project management. The technological implications of the work allow for workforce training opportunities that bridge academia and industry. A new apparatus and approach—a nanopore scanner—will be designed and built to streamline the in-depth assessment of the effect of nanopore surface coating on nanopore conductance—a core metric of performance, on molecular transport—a foundation of most nanopore sensing approaches, and on nanopore signal characteristics. The work will be distinguished by using a curated set of nanopore surface coatings designed to support more comprehensive, systematic, and improved mechanistic understanding of the connection between nanopore surface coatings and nanopore performance. The nanopore scanner will be central to carrying out the systematic studies designed to dissect the coating’s microscopic contributions to the nanopore-solution interface that dictate the nanopore conductance, transport, and sensing. A close examination of electroosmosis, a core mechanism to transport neutral, or locally neutral, species in nanopore sensing will be central to the proposed work because it connects molecular transport to nanopore surface coatings. Selected peptide targets will provide both molecular diversity and biological import for connecting the studies here to future applications of both broad health and technological relevance. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NEI - National Eye Institute

ABSTRACT Bacterial keratitis (BK) (corneal infection) is an aggressive disease, responsible for over 2 million cases of blindness annually. Healthcare concern is further exacerbated due to rising antibiotic resistance. Indeed, the 2023 US outbreak of extensively drug-resistant Pseudomonas aeruginosa from contaminated artificial tears was a stark reminder of the devastating consequences of drug-resistant corneal infections; out of 81 reported keratitis cases, 14 patients suffered permanent vision loss, 4 resulted in loss of the eye, and 4 patients died. Unfortunately, most large pharmaceutical companies have abandoned their antimicrobial drug discovery efforts in lieu of pursuing more lucrative, long-term medications. Moreover, the few entities developing antimicrobials are focused on systemic applications as opposed to alternative, ophthalmic formulations. As such there is a void in the ophthalmic antimicrobial pipeline, with no new classes of antimicrobials to market in nearly 15 years. To answer the critical need for new BK therapeutics, the central goal of this proposal is to advance the development of a novel, topical, ophthalmic antibiotic combination, polymyxin B/trimethoprim (PT) + rifampin. Through extensive screening of thousands of FDA-approved drug combinations we have identified PT + rifampin as a powerful, synergistic, broad-spectrum drug combination superior to currently available therapeutics. PT + rifampin displays rapid bacterial killing, potent anti-biofilm activity, and the ability to completely eradicate Staphylococcus aureus and P. aeruginosa infections in a murine model of keratitis, two of the most common causes of BK. Importantly, this drug combination has also been shown to completely eradicate contemporary, multi-drug resistant ocular clinical isolates. Of note, an ophthalmic formulation of polymyxin B/trimethoprim was approved by the FDA in 1988 for the treatment of conjunctivitis and rifampin is an FDA-approved systemic antibiotic that has been used for over 40 years in the treatment of tuberculosis. As such, all three components have decades-long established safety and efficacy in humans. Importantly, we have already achieved the key milestone of a pre-IND meeting with the FDA, during which a clear road map for further studies was established. Given the promise of PT + rifampin as a novel treatment for BK, we propose to pursue advance formulations with corresponding safety and efficacy studies during the R61 phase. Next, we propose to transition to the R33 phase to conduct IND-enabling studies in toxicology, pharmacokinetics, and define appropriate chemistry, manufacturing and controls (CMC). The development of new therapies for BK is well aligned to the NEI’s goals of supporting research to reduce visual impairment and the development of sight-saving treatments. We have compiled the necessary multi-disciplinary team of experts to support formulation development, perform necessary efficacy and safety studies, and guide regulatory and intellectual property strategies. As such this proposal is well poised for success to bring this exciting new technology from bench to bedside to treat this blinding disease.

NIAID - National Institute of Allergy and Infectious Diseases

Development of a Novel Class of Antifungal Therapy: This project aims to address the urgent need for new antifungal treatments by developing a novel class of small molecules with potent activity against drug-resistant fungal strains. Using proprietary chemical structures, SHY Therapeutics will identify and optimize compounds for clinical use, focusing on efficacy, safety, and overcoming current treatment limitations. Fungal infections affect millions of people each year, posing a significant global health burden. Existing antifungal therapies are often inadequate due to drug resistance, toxicity, and insufficient efficacy, particularly in immunocompromised populations. To tackle this challenge, SHY Therapeutics has developed a wide range of new and proprietary chemical structures, with preliminary screening identifying novel compounds active against Cryptococcus neoformans, Candida auris, Candida albicans, and Candida parapsilosis. In this Phase 1 proposal, we aim to identify novel classes of small molecules to be optimized for anti-fungal therapy through 3 aims: Aim 1 of this project is to use a Structure-Activity Relationship (SAR) approach to optimize anti-fungal activity of newly synthesized compounds, focusing on Candida auris and Cryptococcus neoformans. The most active compounds will undergo further testing against a panel of over 50 fungal strains, including drug-resistant variants, and will be evaluated for ADME/PK properties and in vivo efficacy in murine infection models. Aim 2 focuses on identifying the protein targets interacting with and inhibited by the identified small molecules using Drug Affinity Responsive Target Stability (DARTS), followed by development of cell-free assays to gain insights into the mechanism of action of the identified small molecules. Aim 3 involves conducting a proof of concept in vivo efficacy study in a murine disseminated candidiasis model, prioritizing a promising hit compound, SHY-4. SHY has a successful track record in the design, synthesis and testing of novel compounds in other therapeutic areas, resulting in 10 issued patents to date. SHY Therapeutics has already identified compounds with strong antifungal activity and minimal impact on mammalian cell viability, suggesting a potentially superior safety profile compared to current FDA-approved drugs.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Relapsing fever (RF) Borrelia are vector-borne pathogens that cause severe clinical manifestations. While RF Borrelia can be transmitted by lice and hard ticks, soft ticks transmit most RF Borrelia species. The unique biology of soft ticks causes concerns for future RF outbreaks. While soft ticks have three developmental stages, which is similar to hard ticks, they also have 2-7 instar nymphal stages and can feed multiple times as adults resulting in a 10–20-year life span. RF Borrelia are maintained in the tick through the molt to each new life stage and can be transovarially transmitted from mother to offspring creating >10 opportunities for a single tick to transmit a RF Borrelia infection. In humans, RF Borrelia repeatedly reach high densities in the blood (spirochetemia) and cause recurring febrile illness, neurologic complications, and perinatal death. Upon initiation of antibiotic treatment, 30-50% of patients experience an acute exacerbation of symptoms known as Jarisch- Herxheimer reaction (JHR). Unfortunately, due to the lack of a cost-effective animal model that mimics human RF disease, we do not understand the mechanisms leading the severe clinical manifestations caused by RF Borrelia. Mice are the most commonly used animals to study RF Borrelia infection and pathogenesis, but mice are a limited disease model because they do not become hyperthermic during RF Borrelia infection. Nonhuman primates develop fever during periods of spirochetemia, but are too expensive to routinely use for rigorous studies. In this R03 application, we propose to develop the Guinea pig model to study RF disease. A historical study described Guinea pigs as viable hosts for Borrelia hermsii and Borrelia turicatae, the two Borrelia species that cause the most RF disease in North America. Both B. hermsii and B. turicatae repeatedly reached high densities in Guinea pig blood, and Guinea pigs become hyperthermic during spirochetemic episodes. Due to a lack of follow-up studies, the RF Borrelia-Guinea pig model remains largely uncharacterized in terms of pathogenesis, disease pathology, and JHR development. We hypothesize Guinea pigs will model human RF disease by inducing hyperthermia during spirochetemic episodes, producing pro-inflammatory cytokines during infection, and developing signs of JHR following antibiotic administration. To test this, we will assess B. hermsii and B. turicatae pathogenesis in Guinea pigs through quantification of spirochetemia, asses clinical signs of RF disease by measuring weight loss and body temperature of Guinea pigs and quantify cytokine production and tissue damage caused by B. hermsii and B. turicatae infection (Aim 1). We will also evaluate the development of JHR in Guinea pigs by measuring body temperature and quantifying cytokine levels after antibiotic treatment (Aim 2). Our thorough characterization of the RF Borrelia-Guinea pig model is critical to finding a relevant animal model to perform mechanistic and intervention studies to help mitigate the severe clinical manifestations cause by RF Borrelia.