Grants

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.

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.

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.

NIAAA - National Institute on Alcohol Abuse and Alcoholism

Abstract Problematic alcohol use (PAU), a complex phenotype that combines alcohol use disorder (AUD) and alcohol- related problems identified by a survey (AUDIT-P), is a major public health issue that arises from intricate interactions between genetic and environmental mechanisms. Genome-wide association studies (GWAS) have identified genomic regions associated with PAU, but it is difficult to determine which genomic variants functionally contribute to the development of PAU, largely because many of these variants are located in the noncoding genome. Recent advances in high-throughput sequencing technologies now permit the functional characterization of thousands of noncoding, disease-associated variants simultaneously with massively parallel reporter assays (MPRA). However, MPRA studies have traditionally been conducted in vitro which limits our ability to identify tissue- and sex-specific variant effects. Because the regulatory genome is sensitive to factors like cell state, tissue type, and environmental perturbation, it is crucial to study the regulatory function of noncoding variants within the intact physiological context. The goal of this project is to identify which PAU risk variants alter transcriptional regulatory capacity in the intact brain and liver under natural physiological conditions and to determine whether this modulation will differ in response to ethanol exposure. To determine the regulatory activity of variants in a tissue- and sex-specific manner, I will perform in vivo MPRA via intracerebroventricular and systemic tail vein injections (Aim 1). I will then perturb the animals with acute or chronic ethanol administration via intraperitoneal injection which may induce variant regulatory activity that is not present in the homeostatic state (Aim 2). The results of this work will pinpoint the putatively causal PAU-associated variants in a tissue- and sex-specific manner as well as which variants exhibit functional regulatory activity only in the environmentally perturbed state. Successful completion of this project will positively contribute to the neurogenetics field by determining which variants should be pursued for further study within their natural genomic context, thus elucidating the underlying molecular mechanisms of genetic predisposition for PAU.

NICHD - Eunice Kennedy Shriver National Institute of Child Health and Human Development

Project Summary / Abstract Early caregiver-child language interactions strongly influence child language development and numerous short- and long-term child outcomes, including increased success in literacy and academic achievement. Because of the public health significance, substantial research has documented evidence-based approaches that enhance early language interactions in the home and improve child outcomes, yet measurement of the home language environment and caregiver-child language interactions lags, particularly with respect to culturally and linguistically responsive measures. There is a critical need for validated tools that specifically measure language interaction behaviors across English and Spanish and Hispanic cultures to inform and evaluate interventions for Spanish-English bilingual children in the United States. Currently, tools for measuring early language interactions are costly, resource-intensive, and have not undergone significant development with members of Hispanic cultures, limiting equitable measurement and usability in both research and practice. Further, these tools are difficult to use when implementing interventions at scale. To solve this problem, our team developed the Caregiver Report of Early Language Interactions (CRELI), a brief, self-report survey about primary caregivers’ language interaction behaviors with children ages 0-36 months, which no other questionnaire uniquely captures. Our team has completed initial measurement development steps (expert reviews, revisions, and initial piloting in English) in preparation for a systematic, simultaneous development and validation in English and Spanish. Validation of the CRELI in both languages will provide researchers and providers with a free, scalable, accessible, and culturally relevant tool to measure and monitor progress of caregiver language interaction behaviors. The purpose of this measurement development project is to develop the Spanish CRELI, refine the English CRELI, and validate both versions for use in research and practice focused on caregivers of children ages 0-36 months. We will do this through the following aims: (1) Develop the Spanish CRELI and refine the English CRELI through focus groups and cognitive interviews with caregivers and providers; (2) assess the factor structure and psychometric properties of the English and Spanish CRELI; and (3) evaluate demographic factors that affect performance on the CRELI. The proposed research will result in a free, validated, culturally responsive measure to assess English and Spanish language interaction behaviors in a user-friendly and cost-effective manner. This will be invaluable to researchers and providers as a measure of intervention effectiveness and as a progress monitoring tool. Ultimately, this tool will help guide improvements in caregivers’ language interactions in English and Spanish in the United States, which may lead to short- and long-term improvements in academic, health, and economic outcomes for children, potentially reducing disparities for those in underserved and diverse families across community contexts.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary For the more than 140,000 people waiting for a kidney transplant (KT), there is a profound loss of function due to aging, numerous comorbid conditions, and dialysis. Five years after addition to the KT waitlist, only 56% of candidates receive a KT and 15% die waiting. Given the adverse physiologic changes associated with dialysis, the long wait times for KT, and high waitlist mortality, interventions to enhance KT candidates' physiologic reserve are desperately needed. Prehabilitation refers to a myriad set of interventions seeking to enhance functional capacity to tolerate upcoming surgery's physiologic stresses. Prehabilitation's rationale—especially in KT candidates—is sound. In a single-arm pilot study of 24 patients, our group previously demonstrated a 64% increase in physical activity over 8 weeks with no adverse events; however, prehabilitation studies are plagued by significant heterogeneity, low enrollment, and poor adherence. Our pilot study was no exception. Major barriers to broad implementation are that these heterogeneous programs are often developed with a conjectural approach—based on individual investigators' conception of what such a program should be, rather than an empiric approach that incorporates key stakeholder input. Indeed, there is no consensus definition as to what defines “prehabilitation” or what components are needed. With potential for faster recovery, shorter length of stay, fewer readmissions, and earlier return to functionality, there may be a strong case for prehabilitation; however, a robust, empiric-based prehabilitation program must be developed before it can become a routine clinical practice. We first aim to elicit expert opinion to identify KT-specific prehabilitation constituent components and strategies to enhance enrollment and adherence through the conduct of 2 scoping reviews and a Delphi study of experts in nephrology, transplantation, renal nutrition, gerontology, and physical medicine and rehabilitation. Next, using novel applications of marketing research methodology, as well as in-depth patient interviews, we will identify KT candidates' preferred component combination(s) to design an empirically designed, maximally implementable, KT-specific prehabilitation intervention that incorporates the aspects valued by experts and patients alike and is most likely to be embraced by patients. Finally, we will perform a randomized controlled pilot trial of this KT-specific intervention. Prehabilitation has the potential to improve outcomes for the 42,000 people in the US added to the KT waitlist each year. We will perform the foundational work necessary to define the “optimal,” maximally implementable, KT-specific prehabilitation program. If successful, the knowledge gained will provide compelling data that will inform the need for a multicenter clinical trial to test prehabilitation in KT candidates. This proposal will provide novel data essential to design and plan that trial.

NSF

This project will contribute to the national need for well-educated scientists, mathematicians, engineers, and technicians by supporting the retention and graduation of high-achieving, low-income students with demonstrated financial need at Texas Tech University. A total of at least 36 scholars pursuing BS degrees in electrical engineering and computer engineering will receive scholarships of up to $15,000 per year for three years. Scholars will receive faculty and semiconductor industry focused mentoring, and the project will build strong scholar cohorts through experiential learning such as hands-on semiconductor manufacturing experiences. Additional activities for scholars include personalized, AI-informed career preparation support, industry-informed mentorship, laboratory training, and academic and professional mentoring. The overall goal of this Track 2 Scholarships in STEM project is to increase STEM degree completion of academically talented, low-income undergraduate students with demonstrated financial need. There is a significant national need to grow the STEM workforce and nurture key talent that will ensure economic competitiveness and provide domestic leadership across critical sectors. This project directly speaks to this need by supporting STEM student success, which will strengthen the workforce in the semiconductor industry and other key areas of need. The project will be assessed by an experienced evaluator that will help the team gain knowledge (e.g., access to academic and professional development resources, learning gains and learning gaps, industry engagement, etc.) about the specific needs of these high-achieving, low-income students, and the data generated will contribute to the knowledge base regarding effective strategies to support students in STEM. This project is funded by NSF's Scholarships in Science, Technology, Engineering, and Mathematics program, which seeks to increase the number of academically talented, low-income students with demonstrated financial need who earn degrees in STEM fields. It also aims to improve the education of future STEM workers, and to generate knowledge about academic success, retention, transfer, graduation, and academic/career pathways of low-income students. 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.

NIDA - National Institute on Drug Abuse

Project Summary/Abstract Many drugs of abuse target G protein coupled receptors (GPCRs), including the opioids which have fueled the ongoing opioid abuse epidemic. Many of these compounds have substantial room for improving their therapeutic window by precisely tuning their signaling profiles. However, rational design of such compounds is difficult due to a lack of understanding of how these compounds alter the structure and dynamics of receptors to relay their pharmacological profile intracellularly to their signaling partners. Here we propose to generate chemical biology tools to facilitate the determination of molecular movies of GPCRs interacting with their signaling partners with time-resolved cryogenic electron microscopy. This will be complemented by the development of a new computational method to drive simulations from time-resolved cryogenic electron microscopy data in order to fully sample all of the transition and intermediate states involved in GPCR signaling. These methods will be applied to several ligands of various efficacies for a key receptor for drugs of abuse, and the insights used in ultra-high throughput virtual screening campaigns to identify novel allosteric modulations to stabilize specific intermediate states. Finally, allosteric compounds will be tested in rodent models of addiction to explore how modulation of these specific intermediate states attenuates the addiction liability of canonical drugs of abuse.

NIH

Significance to VA: Noise has long been known to induce hearing loss (noise-induced hearing loss - NIHL) however it can have a multisensory impact. Studies from our group and others now provide evidence that noise can also induce vestibular dysfunction (noise-induced vestibular dysfunction - NIVD) (Stewart et al., 2020a for review). NIHL reduces communication and ability to react to critical auditory information. NIVD reduces balance, gait and agility. Hearing and vestibular disorders affect millions of Americans and are among the most common service-related disabilities. There is greater hearing and vestibular loss for those who have been in service compared to the general population due to service-related noise exposures (Kerber et al., 2008). Long term NIHL and NIVD decrease quality of life, employment opportunity and contribute to dementia. Developing therapies will therefore hold significant relevance for Veterans as well as the general population. Innovation and Impact: Since noise has a multisensory impact, a single pharmacotherapeutic treatment that could be easily given prior to or shortly after noise to prevent/reduce or provide recovery from both NIHL and NIVD would be of great benefit. Identification and testing of such treatment is the goal of the proposed studies, using an animal model as a first step towards future clinical application. Rapamycin has shown promise by decreasing induction of markers for several underlying mechanisms of NIHL, oxidative / nitrative stress and inflammation, while reducing NIHL, when given intra peritoneal (Yuan et al., 2015). Our NIHL pilot studies showed that oral rapamycin is also effective, significantly decreasing NIHL from impulse noise. Our NIVD pilot study found that noise exposure that causes persistent NIVD induces the same markers of oxidative/ nitrative stress / inflammatory response in vestibular sensory epithelia, as found in cochlea with NIHL. We then found oral rapamycin prior to noise can reduce measures of NIVD. Our preliminary results, however, are from separate NIHL pilot studies in mice and NIVD pilot studies in rats. It is now necessary to confirm our pilot results and test if oral rapamycin treatment provides protection from both NIHL and NIVD using the same noise exposure condition in the same subjects. We also need to test efficacy for repeated noise exposures, common during service, and efficacy for treatment beginning shortly after noise. Specific Aims: (1) Test if rapamycin can prevent / reduce both NIHL and NIVD in the same subjects. (2) Test if rapamycin can prevent / reduce the enhancement of NIHL and NIVD from repeated noise exposure. (3) Test efficacy of starting rapamycin treatment of NIHL and NIVD 1 day or 3 days after noise. Methodology: The proposed studies will assess noise exposures that can be encountered during service, examining multisensory consequences on NIHL and NIVD. Studies will assess auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and vestibular shot-latency evoked potential (VsEP), changes in static head position and stability, and measure the tilt-maculo-ocular reflex (tMOR) before and after noise exposure. Motor consequences will be assessed with balance beam crossing metrics. Studies will use these metrics to determine the potential for rapamycin to prevent, reduce or induce recovery from NIHL and NIVD when administered prior to or shortly after noise exposure. Path to Translation/Implementation: This is a basic science proposal focusing on the characterization of noise-induced vestibular loss at levels that cannot be carried out with the control, precision, and range in human subjects that is possible in rats. As we characterize the efficacy of treatment on noise induced pathology and functional changes, our work will inform clinical measurements that can be tested with available or newly developed tools in the future. Rapamycin (sirolimus) is already given orally in clinical application for other disorders and could be re-purposed for treating NIHL and NIVD.

NCATS - National Center for Advancing Translational Sciences

PROJECT SUMMARY Vascular diseases driven by endothelial dysfunction represent a major therapeutic challenge due to the lack of cell-specific delivery systems. While TGFβ-driven endothelial-to-mesenchymal transition (EndMT) has emerged as a key therapeutic target, current approaches are limited by off-target effects of systemic TGFβ inhibition. We have developed a novel HDL-mediated RNA delivery platform (C15-9- 900 LNP) that achieves unprecedented endothelial cell specificity through innovative ionizable lipid design. Our preliminary data demonstrate >90% targeting efficiency across multiple vascular beds, with exceptional manufacturing reproducibility at 2g scale, minimal inflammatory response, and established quality control parameters. This R21 ASCETTS proposal will advance platform development through two complementary aims. In Aim 1, we will establish critical quality attributes and manufacturing parameters through systematic evaluation of formulation conditions. Comprehensive particle characterization will include size, polydispersity index, and zeta potential analysis, complemented by quantitative biodistribution studies using endothelial lineage-traced mice. Advanced imaging and flow cytometry validation will confirm targeting specificity across multiple vascular beds. In Aim 2, we will demonstrate therapeutic efficacy using an established hypoxia- induced pulmonary hypertension model. We will evaluate the platform's ability to modulate TGFβ pathway signaling in pulmonary vascular endothelium, assess therapeutic outcomes through comprehensive hemodynamic and histological analyses, and establish clear translational parameters for clinical development. This platform technology represents a fundamental advance in targeted RNA therapeutics by enabling selective endothelial modification while minimizing systemic effects. Our systematic approach establishes standardized manufacturing parameters and analytical methods suitable for clinical translation. While initially focused on pulmonary hypertension, the platform creates a foundation for addressing multiple cardiovascular disorders where endothelial dysfunction plays a central role. Success in this R21 phase will accelerate therapeutic innovation through validated manufacturing processes and clear regulatory parameters.

Rochester Refugee Resettlement Services, Inc.

Engage students of refugee families to use our, �Fish Flash Card Survey� to characterize their communities� risks of eating the most harmful and toxic species of fish

Rochester Refugee Resettlement Services, Inc.

Engage students of refugee families to use our, �Fish Flash Card Survey� to characterize their communities� risks of eating the most harmful and toxic species of fish