Grants

NHLBI - National Heart Lung and Blood Institute

ABSTRACT/SUMMARY: Fanconi Anemia (FA) is the leading cause of inherited bone marrow failure (BMF) affecting thousands of patients worldwide. While allogenic (allo)-hematopoietic stem cell transplantation (HSCT) outcomes have been improving for FA patients, these treatments currently cause significant morbidity and mortality in part due to the non-specific and genotoxic chemotherapy and/or irradiation conditioning traditionally used pre-transplant. This is especially problematic in FA patients due to their exquisite sensitivity to DNA damage which results in DNA interstrand crosslinks (ICLs) and heightened risk of malignancies in all patients. Our long-term goal is to develop alternative non-toxic FA therapies using cell and gene therapy. Towards this goal, we have generated HSC-targeted conditioning approaches using monoclonal antibodies (mAbs) and mAb-drug-conjugates against the CD117 HSC cell-surface protein that clear host HSCs without non-specific tissue damage. However, from this research we have found that host HSC depletion is not critical in the FA setting. This has been further observed in the setting of autologous FANCA lentiviral gene therapy and somatic mosaicism, which have both shown that a small number of initial functional hematopoietic stem and progenitor cells (HSPCs) can stabilize hematopoiesis in FA patients. The overall objective of this work is to leverage distinctive strategies that elude the immune system to safely establish functional HSPCs in the bone marrow that can maintain hematopoiesis in the FA setting. The preliminary data supports a central hypothesis that stable hematopoiesis with ability to repair DNA ICLs can be established in FA without the use of genotoxic chemotherapy or irradiation due to the competitive advantage of functional HSPCs over failing FA HSPCs. This hypothesis will be tested through three specific aims in FA mice: 1) Achieving and optimizing haploidentical in utero HSCT without use of any conditioning, 2) Evaluating post-natal HSCT with immune conditioning alone, and 3) Developing HSC and systemic CRISPR-based base editing correction methods using engineered virus-like-particles (eVLPs) to stabilize host FA cells. The proposed research is both innovative and significant because it will identify multiple strategies that safely enable stabilization of hematopoiesis in the FA setting that will subsequently be translated into non-genotoxic therapies for FA patients. These novel approaches that enable functional HSC correction using both cell and gene therapy strategies are aimed at treatment of FA at different stages of hematopoietic disease, with the additional capacity to uniquely correct FA mutations in non-hematopoietic tissues. This work will have a major impact on improving treatment for FA patients and findings from this research will subsequently be utilized to improve the treatment of millions of people worldwide that suffer from diverse hematopoietic and genetic diseases.

NSF

This project aims to serve the national interest by improving curricula in mining technician education to align training with innovations in the mining industry. The College of Western Idaho will establish a mining technician Associate of Science (MINE A.S.) degree program to prepare graduates to fill technical career openings in the high-demand mining and geosciences industries. With the re-emergence of domestic critical mineral mining to support the nation’s shifting industrial landscape, there is a growing need to train students to use state-of-the art mining and surveying tools and equipment, such as ground penetrating radar (GPR), lidar, UAVs (uncrewed aerial vehicles), and various surveying, drilling, and water testing tools. The project will serve the NSF mission and public interest by advancing understanding about how to effectively prepare community college students for the technical demands of the mining industry through coursework, fieldwork, and faculty development. The project will support regional economic development by re-introducing mining technician training in partnership with local and regional employers, nurturing relationships between academia and industry to equip A.S. graduates with the scientific, technical, and professional skills mining employers seek. The industry-aligned project will offer direct pathways into mining industry technician-level jobs leading to industry certifications that prepare all students to enter well-paying jobs. The project's goal is to establish a MINE.A.S. program. Objectives are to (1) enroll three cohorts of students (50 to 60 over the project period); (2) train faculty in the uses and course integration of industry-standard mining and surveying equipment; and (3) build partnerships with Idaho mining employers to provide all MINE.A.S. students with significant hands-on training experiences. Key activities will include purchasing and integrating industry-aligned mining and surveying equipment into several geological sciences, environmental sciences, and engineering courses; developing two new MINE.A.S. courses (Mining Capstone and Survey Engineering); implementing a MINE.A.S. outreach and recruitment strategy; providing a yearly faculty development series led by industry experts; establishing a new MINE.A.S. Industry Advisory Technical Advisory Committee; and adding employer-paid summer internships. All graduates will complete the requirements to obtain Mine Safety and Health Administration (MSHA) certification and enter mining careers. Project evaluation will assess, inform, and disseminate learning about the essential components of course curricula and fieldwork to prepare the technician-level mining and geological sciences workforce. This project is funded by the Advanced Technological Education program that focuses on the education of technicians for the advanced-technology fields that drive the nation's economy. 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.

NSF

Understanding animal movement is imperative for the conservation and management of highly threatened species. However, frameworks that leverage existing data sets are currently lacking and needed to improve our knowledge of how animals move across the landscape, and to understand what factors most impact these movements. For example, there is an increasing need to better understand the effect of weather patterns and habitat conditions on annual movements of migratory species. This knowledge is often limited because it requires an understanding of patterns of movement and linkages of populations across large spatial scales for a large number of individuals. Currently, there is ever-increasing data available for wildlife populations, such as long-term, fine-scale GPS-tracking data of individual animals, as well as large-scale observation networks that capture the distribution of wildlife populations. Fine-scale information is usually obtained by fitting individual animals with GPS-units that allow for near continuous location-tracking throughout the year. Citizen science networks include observations collected by members of the public on species that they detect when engaging in various activities (e.g., hiking, birding), which can be used to map the distribution of the species through time. This work is focused on the development of statistical models that will allow, for the first time, the integration of individual movement and species distribution data to learn about large-scale species-level movement behavior. The methods and tools developed will advance society's ability to learn about difficult to observe processes that shape the distribution of migratory populations in space and time. Despite extensive work on methods for integrating multiple data sources, previous attempts to integrate tracking data with citizen-science data fail to leverage the statistical advances made in each individual field and fail to formally integrate the two data-sources in a robust and comprehensive framework. Tracking data provides information about individual movements but represents a small subset of the population. Distribution data provides comprehensive information about species distribution, but represents aggregate behavior of individuals that differ in their migratory routes and behavioral response to the landscape. The integrated framework proposed in this research will formally integrate these two data sources using flexible, interpretable parametric statistical models, which will allow researchers to obtain previously unavailable insights into the link between individual variation, subpopulations, and drivers of movement, while accounting for uncertainty and the spatio-temporal dynamics of species distributions. In addition, this research will develop models for the full-annual cycle of an individual, as opposed to just the migratory route, allowing for additional inference regarding migratory connectivity and seasonal behavior. Further, this work will apply the novel statistical models to understand the migratory behavior of species of both conservation and hunting concern, which will help managers understand the spatio-temporal risks to which different proportions of the population are exposed. This information can help prioritize when and where to take management actions. 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.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT Chronic Obstructive Pulmonary Disease (COPD) is the fourth leading cause of death among adults in the United States; nonetheless, we lack disease-modifying therapies. Herein, we hypothesize that lithium may be a novel disease-modifying agent for emphysema in smokers. Lithium is an abundant naturally occurring element that is ubiquitous in soil and groundwater from where it enters our food chain and drinking water supply. Once ingested, lithium is distributed across total body water as it diffuses freely across cell membranes. Lithium can be quite toxic when used in the high doses needed to treat mood disorders. In contrast, natural low-level lithium intake from food and water is associated with multiple beneficial effects, including a lower risk of suicide, depression, Parkinson’s and Alzheimer’s diseases, and improved longevity in independent studies. Therefore, low-dose lithium supplements are available over the counter in the US. Lithium exerts biological effects by activating WNT/β-catenin signaling, which is essential for lung development and to repair damaged alveoli, such as those observed in smokers with emphysema. Our preliminary work suggests that lithium may be a novel protective agent against emphysema. These preliminary findings are based on data from animal models, human patient-derived precision-cut lung slices, users of lithium medication in independent cohorts, assessment of circulating lithium levels in nonusers of lithium medication, and analysis of environmental lithium exposure using independent environmental datasets. During this award, we will assess circulating lithium levels in smokers enrolled in two COPD research cohorts and determine if they are associated with emphysema progression, use extensive proteomic and genomic data from both cohorts to identify the subset of smokers most likely to experience less emphysema progression by augmenting circulating lithium levels, and assess the dose-response relationship between lithium and WNT/β-catenin activity in explanted COPD lung tissues. Our overall objective is to advance lithium from ex vivo and observational human studies to clinical trials as a novel disease-modifying agent for emphysema by substantiating efficacy, implementing precision medicine, and defining a dosing strategy.

European Commission - HORIZON

Developing managed aquifer recharge techniques (MAR) in a rural context. Call: Call 01 - single stage (2026). Programme: HORIZON. Keywords: Business analysis, Business governance, Business models, Catchment scale planning, Environmental engineering and geotechnics, Environmental impact assessment, Human impacts and other stressors, Hydrology (Water science), Natural resources and environmental economics, Nature-based solutions, Water management, Water recycling and re-use, Water technology. Open call from the EU Funding & Tenders Portal.

NCI - National Cancer Institute

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second-most common cause of cancer- related death in the United States. Detecting PDAC early has been challenging due to its rapid progression and late presentation. Recent collaborative efforts among NCI, PanCAN, and NIDDK have resulted in multiple studies utilizing electronic medical records (EMRs). They provide opportunities to advance the early detection of PDAC, since the approach taken in the research setting is identical to what would be used in clinical practice. Future implementation in EMRs could lead to earlier diagnostic testing or interventions, enable the rapid identification of cancer trends or risk factors, and allow for quicker action. These studies, including our own, have demonstrated that individuals with glycemically-defined New Onset Hyperglycemia and Diabetes (NOD) have a significantly higher risk of being diagnosed with PDAC within 3 years of meeting diabetes mellitus criteria. The Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) score further stratifies individuals with NOD based on their PDAC risk, considering factors such as weight changes, blood glucose levels, and age at diabetes onset. However, several challenges need to be addressed to ensure the success of PDAC early detection. Firstly, it is important to better define the at-risk population for PDAC, as NOD alone may not be sufficient. Individuals with new-onset prediabetes and those with worsening long-standing diabetes mellitus may also be viable targets for early detection of PDAC. Secondly, more effective enrichment strategies leveraging biomarkers are critical, as directly applying existing biomarkers may not yield optimal results. For example, the ENDPAC score, which was developed primarily in a predominantly white NOD population, should be adapted for other high-risk groups, such as individuals with NOPD, LSDM, and diverse demographic populations to ensure broader applicability. We will develop a comprehensive set of methods to address these challenges, aimed at identifying high-risk populations, exploring promising biomarkers using EMR data, and integrating them with advanced biomarkers in an efficient manner. Given the expertise of our team and the strength of our collaborative partnerships, the advancements in methodologies, and the potential clinical applications, we anticipate that our efforts will yield tangible clinical benefits in the near term.

European Commission - HORIZON

Developing methods to assess the presence, functions and sensitivity of groundwater ecosystems. Call: Call 01 - single stage (2026). Programme: HORIZON. Keywords: Biodiversity characterisation, Biodiversity indicators, Biodiversity status and trends, Biogeochemistry, biogeochemical cycles, environmental chemistry, Ecosystem management, Environment chemistry, Environment, Pollution & Climate, Environmental biology, Environmental chemistry, Environmental health, Environmental protection, Environmental sciences, Environmental stressors, Environmental toxicology at the population and ecosystems level, Fresh water biodiversity, Fresh water ecosystems, Freshwater ecology, Hydrology (Water science), Nature conservation, Open Science and FAIR Data (EOSC), Water Framework Directive, Water policy, Water quality monitoring, Water systems monitoring. Open call from the EU Funding & Tenders Portal.

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY The following proposal is a 5-year career development and training plan that will prepare Dr. Taglauer for a career as an independent clinician-scientist and leader in the field of neonatal lung disease. The chronic lung disease of prematurity, (i.e. bronchopulmonary dysplasia) causes significant impairment to the short-term and long-term health of neonates. To date, most studies on bronchopulmonary dysplasia (BPD) pathogenesis have focused on postnatal lung injury. However, the antenatal determinants predisposing infants to BPD have been less well-defined. Among these, the pregnancy disease of preeclampsia has a strong clinical association with BPD. Multiple studies have identified that premature infants born to mothers with preeclampsia have a significant risk of developing BPD postnatally. The primary source of preeclamptic disease is the placenta. In preeclampsia, placental dysregulation causes the release of anti-angiogenic and proinflammatory factors. Dr. Taglauer’s long term research goal is to characterize and address developmental lung injury caused by human preeclampsia. Dr. Taglauer has previously identified in a rodent model of experimental preeclampsia that pups born to preeclamptic mothers have changes in lung morphology and alterations in key developmental gene expression. During her K08 award period, Dr. Taglauer will expand upon these findings by evaluating the influence of human preeclampsia on fetal lung development. Dr. Taglauer will test the hypothesis that the human preeclamptic placenta releases pro-inflammatory and anti-angiogenic signaling proteins into the fetal compartment that cause specific injury to alveolar epithelium and pulmonary vasculature. Specifically, she will 1) identify human preeclampsia-specific placental proteins in the fetal circulation involved in lung developmental injury pathways; 2) develop an in vitro model to evaluate the impact of human preeclamptic placental proteins on human alveolar epithelial and pulmonary vascular endothelial cells; and 3) establish an in vivo rat pregnancy model to examine the effect of human preeclamptic placental proteins on postnatal lung development. Dr. Taglauer has 75% protected research time from the Department of Pediatrics at Boston Medical Center to accomplish these project aims under the guidance of co-mentors Dr. Darrell Kotton at the Center for Regenerative Medicine at Boston University/Boston Medical Center and Dr. Steve Abman at the University of Colorado School of Medicine. She has assembled an excellent scientific advisory committee with diverse expertise to guide her scientific research and career development. Dr. Taglauer has also created a comprehensive training plan that includes mentored research in the Kotton and Abman labs, didactic coursework, presentations at national scientific meetings, manuscript preparation and acquisition of additional grant funding leading to an R01. Dr. Taglauer has the strong commitment from her institution to accomplish these goals and transition to an independently funded physician scientist by the end of this award.

NCI - National Cancer Institute

ABSTRACT Mixed-phenotype acute leukemia (MPAL) is a high-risk leukemia subtype presenting with both myeloid (e.g. CD33) and lymphoid (e.g. CD19) surface antigens. Cure rates in children and adolescents remain lower than for most other acute lymphoblastic leukemia (ALL) subtypes treated in pediatrics, with overall survival ranging from 75-80%. Outcomes for adults are significantly worse, with overall survival ranging from 20-50% for patients over 40 years of age. Uniform approaches to therapies have been challenging to implement, in large part due to the absence of clinical trials available for these patients. Physicians variably implement therapeutic strategies for ALL or acute myeloid leukemia (AML), frequently alternating between the two approaches. The most accepted treatments employed in adults or children with a poor response to initial therapy include hematopoietic stem cell transplant (HCT) after inducing remission with either ALL or AML therapy. The fact that B-Myeloid MPAL cells frequently express both CD19 and CD33 while no non-neoplastic human cells express both targets creates an opportunity to selectively kill MPAL cells with minimal toxicity. We hypothesize that an MTE engineered to require CD19 AND CD33 expression will selectively kill MPAL cells compared to an MTE that requires CD19 OR CD33 expression. We propose to achieve this by engineering an MTE that binds both CD19 and CD33 on MPAL cells and CD3 on T cells and by tuning the affinity of the CD19 and CD33 binders so that the MTE binds poorly to single positive (SP) normal cells that express either CD19 or CD33 but binds well to double positive (DP) cancer cells that express both. For this we take advantage of both affinity and avidity, the latter of which occurs only when the CD19/CD33 MTE interacts with both CD19 and CD33 on MPAL cells. Such therapies could be used to induce deep remissions, improve outcomes when integrated with chemotherapy, and/or serve as a bridge to HCT. Bispecific T cell engaging therapies such as blinatumomab, recognize CD19, is standard of care for treatment of relapsed childhood ALL, and is being incorporated into upfront regimens for adult and childhood ALL. However, patients treated with blinatumomab require months of intravenous immunoglobulin (IVIG) replacement therapy due to the consequential depletion of healthy CD19 positive B cells, which share CD19 as a critical surface antigen with most B-cell ALL. We will show preliminary data that demonstrate our initial in vitro success in targeting CD19/CD33/CD3 antigens as well as improved specificity by generating lower affinity variants of known CD19 binders. In this proposal, we will further engineer and generate MTEs using additional affinity variants of CD19 and CD33 binders to enhance specificity, and also evaluate the toxicity of these MTEs on normal B-cells. We will further test our MTEs in pre- clinical mouse trials to assess the efficacy of MTEs targeting these common antigens expressed on MPAL cells. The future goal of this work is to advance these data into human clinical trials.

NSF

This project aims to serve the national interest by preparing a skilled, robust engineering workforce capable of advancing U.S. energy independence, infrastructure innovation, and rural energy resilience. The project is built on three foundational learning methods: interdisciplinary design, experiential learning, and professional networks to create dynamic educational experiences that link engineering frameworks to rural energy resilience and infrastructure. Students will participate in week-long engineering intensives focused on community-based research projects in emerging energy technologies and microgrid systems within Alaska's remote and off-grid communities. Led by researchers from the Alaska Center for Energy and Power (ACEP), these intensives intend to build interdisciplinary problem-solving skills, industry-relevant stakeholder collaboration skills, and professional networks. Participants interested in continued mentorship by the instructor-researcher will apply for funding through ACEP's summer internship program, then culminate their work in their senior engineering capstone. By incentivizing a sustained inquiry pathway, the project will increase retention in engineering programs and advance the next generation of energy engineers. The goal of the project is to advance understanding of how immersive, thematic learning experiences impact student retention, engagement, and career aspirations in engineering. The scope includes designing a flexible intensive framework, delivering four week-long, place-based intensives with energy researchers tailored to Alaska's unique energy landscape, and sustaining research relationships for researchers and engineering students. At the time of graduation, participants are expected to have a rich portfolio of practical experience, research achievements, and a deep professional network, making them highly competitive members of the energy workforce or graduate programs. Project outcomes include a tested framework for thematic intensives that address critical energy security challenges, deeper integration of undergraduates into state and federally funded energy research, and a model for energy workforce pipelines. Results are projected inform future strategies for scaling experiential engineering education that drives economic growth and energy innovation across U.S. regions. The NSF IUSE: EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. 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.

NIGMS - National Institute of General Medical Sciences

ABSTRACT Within the crowded environment of the cell membrane, membrane proteins dynamically interact with both soluble and membrane-associated partners, as well as surrounding lipids, to form transient protein complexes that are central to cellular function. Growing evidence indicates that these assemblies are regulated by both specific protein-lipid interactions and the broader biophysical properties of the membrane itself. Therefore, to understand how membrane protein assemblies drive cellular responses to external stimuli, it is essential to study their functional homo and heteromeric organization directly within the lipid bilayer context. The overarching goal of this MIRA is to address these challenges over three independent projects by developing next-generation mass spectrometry (MS)-based technologies to directly analyze membrane protein complexes and their lipid environment with precise molecular resolution and nanoscale spatial resolution. Project 1 will develop a native MS platform to capture heteromeric complexes of membrane and soluble proteins directly from tunable invitro single or bridged dual lipid bilayers. Using the neuronal SNARE assembly as a model, we will detect multi-protein complexes formed at membrane contact sites and interrogate how specific lipids modulate their architecture. This will establish a versatile platform to probe transbilayer signaling assemblies with tunable membrane properties. Project 2 will build an nMS pipeline for directly detecting membrane protein complexes from native cell membranes. By integrating native vesicle purification, tandem-affinity enrichment, and native top-down and complex up fragmentation strategies, we will resolve the composition and stoichiometry of physiological MP assemblies. We will further integrate our membrane active polymer-based native nanodisc platform as an alternative avenue. Project 3 will develop a lipidomics-based method to map the nanoscale lipid domains surrounding endogenously expressed membrane proteins. Using custom polymers and ultra-sensitive nanoLC-MS, we will quantify enriched lipid classes around specific organelle-resident membrane proteins to demonstrate how within the same organellar membrane proteins are distributed in different lipid domains. Together, these projects will yield a generalizable, modular, and highly sensitive technological toolkit to interrogate membrane protein-lipid assemblies directly within complex biological membranes. The unifying goal is to bridge the molecular resolution of structural biology with the native context of cell membranes. These platforms will broadly advance our ability to decode membrane-associated signaling mechanisms and their dysregulation in human health and disease—an outcome aligned with the MIRA mission of supporting innovative, high-impact, and sustainable research programs.

NCI - National Cancer Institute

PROJECT SUMMARY/ABSTRACT: This proposal aims to address a critical challenge in treating anaplastic lymphoma kinase (ALK)-driven neuroblastoma (NB) and other cancers: namely the development of resistance to targeted therapies, particularly tyrosine kinase inhibitors (TKIs). ALK is a receptor-tyrosine kinase that plays a crucial role in the development of the central and peripheral nervous systems, and its dysregulation, through mutations, fusions, and overexpression, has been implicated in several cancers, most notably NB. Despite the success of TKIs in treating ALK-driven cancers, resistance mutations in ALK often emerge, leading to disease relapse and limited long-term efficacy. One promising alternative approach to bypass resistance is targeted protein degradation through PROteolysis TArgeting Chimeras (PROTACs), small molecules that harness the ubiquitin-proteasome system to degrade specific target proteins. However, the current landscape of protein degradation therapies is limited to the near-exclusive use of two E3 ubiquitin ligases – CRBN and VHL – for PROTAC development. These ligases, while effective for certain targets, may not be optimal for all targets, and the emergence of resistance to these degrader-based therapies highlights an overlap in limitations between TKIs and PROTACs that necessitates recruitment of more diverse and effective degraders. Additionally, while at least a third of the proteome transits the endoplasmic reticulum (ER) through its membrane or lumen, almost all current degraders target cytosolic proteins leaving a large swathe of the proteome unexplored. Given ALK mutant proteins in NB often mislocalize to the ER, where they become constitutively activated and contribute to oncogenic signaling, the ER presents an untapped resource for therapeutic development through targeted protein degradation. This project intends to leverage ER-associated degradation (ERAD), a posttranslational quality control system within the ER that aids in protein homeostasis by degrading misfolded and immature proteins, to target mutant ALK. The ERAD system, which consists of membrane-embedded E3 ligases and their associated cofactors, provides a unique platform and specificity to target a previously under-explored pool of disease- related proteins, including ALK mutants. The research strategy will focus on several key innovations: (1) identifying selective protein degraders that can efficiently target ALK mutants and overcome resistance mutations, (2) expanding the therapeutic landscape of targeted protein degradation through ORFeome-based screening approaches in search novel target-degrader pairs, (3) developing genetic proof-of-principle tools to rapidly test and validate these novel degradation strategies, and (4) leveraging the specificity of organellar- based degradation to selectively degrade disease-relevant proteins localized to the ER. Ultimately, this research seeks to develop a more diverse set of tools for targeted degradation therapies, offering promising new strategies for overcoming drug resistance in ALK-driven NB and improving clinical outcomes in cancer treatment as a whole.

NIA - National Institute on Aging

Project Summary/Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that affects millions of older adults worldwide, leading to cognitive decline, loss of independence, and significant healthcare burdens. Despite the emergence of monoclonal antibodies (mAbs) targeting beta amyloid, these therapies are costly, carry notable safety risks, and offer only partial clinical benefits. An urgently needed complementary approach is to stimulate the cell’s own clearance machinery for pathogenic proteins—particularly amyloid beta (Aβ) and tau—which accumulate and disrupt neuronal function. This project will advance pharmacokinetically stabilized analogs of the ambroxol – a small molecule drug with a long safety record in humans, excellent brain penetrance, and potent effect on the lysosomal waste clearance system – towards development as small molecule Alzheimer’s disease therapeutic. Our preliminary evidence shows that ambroxol can reverse AD pathology, but low stability affects its clinical performance. As a result we have now engineered two ambroxol analogs (ZW-002, ZW-010) with markedly improved metabolic stability. These compounds retain ambroxol’s lysosomal-enhancing capacity yet exhibit extended half-lives, potentially allowing safer, more efficacious dosing. This Phase I SBIR proposal seeks to: 1. Scale up manufacturing of ZW-002 and ZW-010 under non-GLP conditions (Aim 1), optimizing synthetic methods and partially validating analytical assays. 2. Conduct short-term toxicology in healthy adult mice (Aim 2) to identify any unanticipated toxicities and establish safe dosing parameters. 3. Evaluate efficacy in the 3xTg AD model under both prevention and treatment paradigms (Aim 3) to confirm whether these analogs can reduce or even reverse Aβ and tau accumulation. By the end of Phase I, we will determine which analog best balances manufacturability, safety, and disease- modifying capability, paving the way for IND-enabling studies and clinical translation. Ultimately, our approach aims to deliver a safe, orally available, and cost-effective therapy that harnesses the intrinsic power of lysosomal clearance to combat Alzheimer’s disease—potentially transforming how we treat neurodegenerative disorders characterized by toxic protein aggregates.

NIGMS - National Institute of General Medical Sciences

The proposed development of novel protein-based GABA sensor modules using PLP-dependent GabR regulators aims to facilitate the understanding of GABAergic neurotransmission. GabR, a bacterial transcription regulator, shows remarkable specificity for GABA through a reversible covalent bond with PLP, triggering conformational changes that produce (change of) fluorescence signals. In this proposal, we plan to create “genetically encoded” and chemically labeled “semisynthetic” fluorescent biosensors using GabR to detect real-time changes in GABA concentrations. GABA, a key inhibitory neurotransmitter in the central nervous system (CNS), is implicated in various mental health issues, including Depression, Schizophrenia, ADHD and Autism. Our effort first focuses on enhancing the stability and sensitivity of GabR-based biosensors by leveraging the intrinsic fluorophore in PLP and employing FRET signals from excitation of PLP. In addition, we also aim to optimize chemically labeled “semisynthetic” sensors with improved spectral tuning and kinetics for deep tissue imaging and real-time GABA sensing studies. These novel GABA sensors will be valuable tools for investigating GABAergic neurotransmission in live cells, brain slices, and in vitro assays, with potential applications in drug discovery and in vivo neurological research. Our work will significantly improve the understanding and monitoring of dynamic GABA levels in neurological systems, opening doors for further studies on mental health conditions and neuropharmacology. As an important part an R15(AREA) grant, educational and outreach efforts are designed in a cohesive structure to provide interdisciplinary trainings for graduate, undergraduate and high school students.

National Institutes of Health

Developing novel theory and methods for understanding the genetic architecture of complex human traits (R01 Clinical Trial Not Allowed)

National Institutes of Health

Developing novel theory and methods for understanding the genetic architecture of complex human traits (R21 Clinical Trial Not Allowed)

NIGMS - National Institute of General Medical Sciences

Project Summary Photoenzymes are biological catalysts that use photonic energy to drive chemical reactions. The key intermediates in these enzymes are organic free radicals, highly reactive intermediates that can be challenging to control using small molecule catalysts. In this proposal, we will use naturally occurring dark enzymes as photoenzymes to address enantio-, regio-, and chemoselectivity challenges associated with radical organic reactions. These non-natural functions will be optimized to directed evolution to enable access to chemical structures that would be challenging to access using existing synthetic methods. In this application, we will use previously identified radical initiation methods to solve new synthetic challenges. To this end, we propose to merge ‘ene’-reductase catalyzed hydroalkylations with imine reductases to prepare saturated heterocycles bearing multiple stereocenters with excellent control over the stereochemistry of the product. In a related area of research, we will develop regioselective difluoro- and trifluoromethylation of arenes to access substitution patterns that are elusive using existing C–H functionalization strategies. We will also use Baeyer-Villager Monooxygenases as potent photoreductants to convert styrenyl alkenes to the corresponding benzylic radical for various cyclization reactions to access N-heterocyclic motifs found in biologically active molecules. Concurrently, we will develop new initiation mechanisms that will expand the types of reactivity available to photoenzymes. In this context, we will use lactate monooxygenase’s ability to form alkylated flavin adducts to facilitate Csp3-Csp3 cross-coupling reactions. This work will enable asymmetric cross-coupling and strategies for preparing congested carbons. Additionally, we will engineer ‘ene’-reductases to use oxidative mechanisms for radical initiation–a challenge because of the oxidative sensitivity of these proteins. This new initiation mechanism can interface with the existing radical termination mechanism to unlock new photoenzymatic chemical transformations. Finally, we will develop energy transfer mechanisms with pyridoxal-dependent enzymes to unlock new biocatalytic transformations. Together, these methods and the goals have the potential to streamline the synthesis of biological probes and drug targets, creating a significant benefit to human health and associated biomedical sciences.

NIAID - National Institute of Allergy and Infectious Diseases

Rapid, cost-effective, and noninvasive tools to monitor host-pathogen-microbiome interactions during Chlamydia trachomatis (CT) infection are urgently needed to identify correlates of protection and predict risk for reproductive tract damage—critical for advancing vaccine development and clinical care. Chlamydia trachomatis is a globally impactful sexually transmitted bacterial pathogen for which no vaccine is available, and predictive biomarkers for adverse outcomes are lacking. Prior research and our recent study indicate that chlamydia-microbiome and microbiome-host interactions can influence establishment of infection and spread to the upper genital tract. We previously demonstrated that total RNAseq can transcriptionally profile host, pathogen and cervicovaginal microbiome activity during human genital tract infection. However, this method requires high-abundance, only moderately degraded RNA and is cost-prohibitive for large-scale use. To overcome these limitations, we developed a simple and cost-efficient, probe-based transcriptional profiling method, inspired by advancements in single-cell RNA sequencing technologies, and demonstrated its feasibility using cervical specimens from experimentally infected mice. The goals of this proposal are to: i) evaluate probe-based transcriptional profiling as an effective and cost-effective alternative to total RNAseq for characterizing human clinical cervical specimens; ii) determine if this technique can simultaneously and sensitively profile chlamydial gene expression during natural infection while iii) monitoring cervicovaginal microbiome composition. We will complete the following specific aims: (1) Compare performance of probe-based RNA sequencing with total RNAseq for cervical brush specimens collected from women at high risk for C. trachomatis infection. Using previously collected, cervical brush specimens currently undergoing total RNAseq in an R01 funded study, we will perform parallel, probe-based profiling and compare outcomes for sensitivity and robustness, particularly in the face of low RNA quality and/or abundance. (2) Profile pathogen gene expression during natural cervical infection using probes targeting the global chlamydial transcriptome. We will use probes targeting the global chlamydial transcriptome to profile gene expression during natural cervical infection, generating RNA-seq libraries from cervical brush samples with varying chlamydial loads. (3) Determine if incorporation of 16S-targeting probes will support coincident CVM characterization during chlamydial infection. Chlamydial 16S and 23S rRNAs were sensitively and robustly detected in murine genital infection samples so we will extend this approach to determine feasibility for coincidental monitoring of co-pathogen abundance and to profile resident mucosal microbiota without need for separate 16S rRNA gene amplicon library pipelines. This approach integrates emerging RNA profiling technologies into a customizable, scalable pipeline that supports unbiased studies of mucosal immunity, pathogen burden, and microbiome composition, even in low-yield or degraded clinical samples. The successful development of this platform would accelerate determination of molecular correlates of protection or immunopathogenesis in humans after infection and has significant promise for vaccine evaluation not only for chlamydia, but also for other sexually transmitted mucosal pathogens.

NINDS - National Institute of Neurological Disorders and Stroke

PROJECT SUMMARY Stroke commonly disrupts the corticospinal tract (CST) and impairs hand function. Transcranial magnetic stimulation (TMS) interventions that target and strengthen residual CST connections are promising candidates for improving poststroke hand function. To maximize their therapeutic effects, such interventions must repeatedly activate the residual CST and enhance its neural transmission. We and others recently showed in neurotypical adults that resting brain activity spontaneously alternates between EEG activity patterns (brain states) that predict strong and weak CST activation. TMS interventions also preferentially enhance CST transmission when delivered during strong CST states but instead diminish CST transmission when delivered during weak CST states. However, virtually all poststroke TMS interventions are uncoupled from the current brain state, such that only a fraction of TMS stimuli coincide with brain states during which the beneficial effects of TMS are likely to be strongest. To resolve this issue, poststroke TMS interventions should be delivered solely during brain states reflecting strong CST responses. Given that each stroke survivor has a unique pattern of brain damage and recovery-related brain reorganization, these brain states must be fully personalized. We recently developed a personalized machine learning framework that successfully identifies electroencephalography (EEG) activity patterns that predict strong and weak CST states in neurotypical adults. Our framework is fully personalized and is therefore unaffected by lesion-related changes in brain structure and/or function, making it ideal for application in the poststroke brain. In this project, we will use this framework to establish the mechanistic rationale and methodological foundation for future personalized brain state-dependent TMS interventions that target and strengthen the residual CST after stroke. In Aim 1, we will use our machine learning framework to identify personalized brain states that predict strong and weak residual CST activation in chronic stroke survivors; we will also evaluate relationships between our framework’s performance and functional and structural metrics of poststroke CST pathway integrity. Results of Aim 1 will establish poststroke brain state-dependency of residual CST output and the relationship of this state-dependency to CST integrity. In Aim 2, we will develop and validate a real-time EEG algorithm that accurately delivers TMS during personalized brain states reflecting strong and weak CST activation in neurotypical adults. Results from Aim 2 will demonstrate the technical feasibility of personalized, real-time brain state-dependent TMS. Overall, this project fits the scope of the NIMH/NINDS R21 mechanism because it will develop a novel neuroengineering approach that can in the future enhance residual CST transmission and promote paretic hand function in stroke survivors.

NIA - National Institute on Aging

Project Summary Anti-aging antibody research, including strategies targeting interleukins and other antigens, shows promise in rejuvenating the immune system, improving metabolic functions, and extending healthy lifespans. AI-driven platforms are revolutionizing antibody development by accelerating affinity maturation and optimizing developability properties, enabling simultaneous optimization of multiple characteristics. These advancements could lead to more effective treatments for age-related diseases and a significantly improved quality of life for the growing aging population. However, zero-shot predictions for antibody affinities using pretrained models without additional target-specific data remain challenging. In this project, we propose a new strategy to address this challenge by generating diverse antibody-antigen interactions at an unprecedented scale (Aim 1) and training new AI models using these generated data in combination with data collected from literature and public databases (Aim 2). We will rigorously evaluate the performance of the new models and benchmark against the state-of-the-art methods. We will test the generality of the new models on a diverse set of antigens and experimentally validate the prediction accuracy (Aim 3). We will apply the models to identify new antibodies against new therapeutic targets associated with ageing or age-related diseases. Once complete, the proposed research will provide a powerful tool for accelerating antibody discovery and optimization as well as new antibody candidates for anti-aging treament.

NSF

The project aims to serve the national interest by creating a collection of earth and space science laboratory investigations designed to increase the scientific literacy of undergraduate non-STEM majors. Each investigation is carefully crafted to emphasize the nature of science and progressively increase the level of scientific inquiry expected from students. Through this approach, the curriculum supports students in understanding the process of science, learning key earth and space science concepts, developing scientific skills, and gaining confidence and interest in STEM. The collection represents a significant contribution to undergraduate education by being specifically designed for two-year college students, both online and in person, without requiring specialized equipment. Importantly, the approach supports implementation across institutions regardless of available funding, resources, or instructional modality. In addition, the project strengthens undergraduate STEM education by sharing the collection and underlying approach with educators nationwide and offering training on effective implementation and adaptation. Ultimately, the project fosters the development of opportunities for students to become engaged, competent, critical consumers of scientific information. The goals of the project are to: 1) advance innovation in earth and space science courses at two-year colleges, 2) promote the success of non-STEM majors at two-year colleges by improving scientific literacy, and 3) ensure two-year college faculty have evidence-based resources to effectively engage with non-STEM majors. To meet these goals, the project seeks to create, implement, evaluate, and disseminate a collection of laboratory investigations designed for asynchronous online or in-person use. These investigations are developed and piloted at partnering institutions located on opposite coasts of the country. The design framework guides the development process and is expected to be refined throughout the project and ultimately shared with the broader geoscience education community. An advisory board supports all aspects of the project, provides regular feedback to strengthen implementation, and oversees assessment and evaluation activities that employ multiple measures to examine students' scientific literacy and understanding of scientific concepts. Dissemination efforts focus on broadly sharing the curriculum throughout a widely used repository and offering professional development that prepares faculty to implement the materials in their own context. The NSF IUSE: Innovation in Two-Year College STEM Education (ITYC) Program seeks to accelerate and advance knowledge about the impact of emerging and evidence-based practices in undergraduate STEM education at two-year colleges. 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.

NSF

This three-year project will leverage partnerships among data scientists, researchers, data science education experts and teachers to develop students' data acumen, decision making using data, and use of data tools. The project has three major goals. Goal 1: Create data sets to engage high school students in the Data Life Cycle by cultivating existing partnerships among data scientists, researchers, and data science educators. Goal 2: Co-design curricular materials with teachers and data science education experts that engage high school students in the Data Life Cycle through problem-solving with real data to develop their data acumen. Goal 3: Engage high school students, including those in rural communities, with the Data Life Cycle through problem-solving with real data to develop their data acumen in informal learning spaces. To achieve these goals, the project team will collaborate with researchers and data scientists to gather and prepare real data to design curriculum materials for 9th-12th grade learning spaces. They will co-construct materials with classroom teachers and data science educators to design and implement curricular materials and learning experiences to develop students' data acumen in data science summer camps. Researchers will also support teachers' professional learning to co-facilitate data science camps and disseminate work in their communities. Researchers on the project team will use qualitative approaches including cognitive interviews and observations to glean knowledge regarding student learning and teachers' experiences with co-creation and collaboration of data science materials. This project is co-funded by the Innovative Technology Experiences for Students and Teachers (ITEST) program, which supports projects that build understandings of practices, program elements, contexts and processes contributing to increasing students' knowledge and interest in science, technology, engineering, and mathematics (STEM) and information and communication technology (ICT) careers. 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.

NIGMS - National Institute of General Medical Sciences

Summary This project seeks to develop enabling technology for the characterization of all human proteoforms. Proteoforms are the active species in biology and include not just the genetically encoded protein sequence but any alterations including alternate splicing, post-translational modifications, spontaneous chemical modifications, etc. As such their structure cannot be readily inferred from genomic data. Identification and characterization of proteoforms is the first step towards developing a complete mechanistic understanding of the cellular processes underlying both health and disease. Proteoforms are large, complex molecules that can be difficult to disambiguate. For example, an important functional difference could result from changing the location of a single modification, creating isomers that would appear to be nearly identical in an analytical sense. However, differences in key areas would distinguish these two proteoforms, and this proposal will develop methods to target those key differences by rationally and specifically fragmenting proteoforms at desired residues inside a mass spectrometer. This approach is an improvement over existing methods where information content is dependent on random fragmentation events, which may or may not reveal the key areas that differ. To enable rational protein dissection in the gas phase, chemical modifications must first be installed to create a weak link in the backbone chain that can be specifically triggered. The proposal will develop novel photoactivated modifiers that will selectively create radicals that will facilitate selective dissociation. Both the synthetic modifications and subsequent mass spectrometry are crucial innovations that will result from this research and further advance our ability to characterize proteoforms with the end goal of populating a human proteoform atlas.

NSF

With support from the Chemical Structure and Dynamics (CSD) program in the Division of Chemistry, Professors Sean Roberts, Narayana Aluru, and Michael Cullinan of the University of Texas at Austin are combining sophisticated experimental and computational methods to study how strain affects singlet fission and energy transport in layered heterostructures. Singlet fission is a unique process wherein an energetically excited molecule shares half its energy with a neighboring molecule. This energy redistribution can enable improved systems for energy harvesting, photocatalysis, and quantum sensing, but achieving this goal requires an improved understanding of how a material’s structure impacts its ability to both undergo singlet fission and transport energy. Professors Roberts, Aluru, and Cullinan will address this challenge by developing micro-electromechanical (MEMS) devices that will be used mechanically strain molecular crystals to alter their internal structure. Computational modeling performed in concert with time-resolved microscopy measurements will identify how strain-induced changes in the structure of a crystal impacts its behavior to uncover structure-function relationships expected to guide the design of singlet fission materials for applications in energy harvesting and light detection. This project will support the training of three graduate students as well as two undergraduate student researchers from Austin Community College. Singlet fission enables individual photons to be transduced into pairs of spin-triplet excitons. However, developing technologies that utilize singlet fission to boost their performance requires singlet fission materials that direct the spatial transport of the triplet excitons they generate. To address this, a research team led by Professor Roberts will map how the structure of molecular crystals dictates their ability to undergo singlet fission and transport triplet excitons by using mechanical strain to systematically alter their intermolecular structure. By mapping how singlet fission and exciton transfer depend on a material’s structure, the research team will establish benchmarks for refining theoretical models for singlet fission and exciton transfer while simultaneously guiding the design of new compounds that can meet current challenges in energy harvesting. To achieve its objectives, the research team will employ MEMS devices to strain molecular crystals and thin film heterojunctions in concert with transient absorption microscopy experiments that will track exciton diffusion with femtosecond time resolution and tens of nanometers spatial resolution. These measurements will be modeled using electronic structure calculations that will both predict how materials deform under applied strain and how these structural changes impact a material’s ability to generate and transport triplet excitons. 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.