Grants

NHLBI - National Heart Lung and Blood Institute

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading cause of death in the United States, yet drivers of disease and risk markers remain poorly characterized. Although CVD is more prevalent among non-Hispanic Blacks and Hispanics compared to non-Hispanic Whites, these populations are underrepresented in existing genetic and epidemiological studies of disease. New affinity-based high-throughput proteomics platforms offer unprecedented opportunities to study disease mechanisms across diverse populations, and to search for new clinical biomarkers of disease. However, initial comparisons of the leading proteomics platforms suggest that at least one-third of protein measures correlate poorly between platforms, resulting in platform-specific or platform-discordant genetic and epidemiological associations, which may confound biological interpretation of results across studies. Genetic variants associated with circulating protein abundance measures may highlight assays with on-target affinity-probe binding, as well as assays which may be non-specific or prone to interference from protein-altering variants, which may affect affinity-probe binding and thereby alter protein measure. As frequencies of these protein-altering variants may vary between populations, they may drive differences in assay performance across populations. Here, we propose the first examination of protein measure agreement in diverse populations, using newly generated affinity-based proteomics data across four large studies of participants within the Trans-Omics for Precision Medicine (TOPMed) consortium. After quantifying the correlation of protein measures for each platform within each study, and the heterogeneity of these correlations between ancestral populations, I will identify technical and biological predictors of platform correlation. Next, I will analyze whole genome sequences for contributing individuals to identify genetic predictors of circulating protein abundances, as measured by each platform. I will characterize signals across platforms to identify protein-altering genetic variants which may drive assay interference, and synthesize these genetic associations with platform correlation coefficients to predict assay efficacy. Finally, I will model protein measures from each platform against relevant cardiometabolic phenotypes to evaluate agreement of epidemiological associations across platforms, and explore whether adjustment for protein-altering genetic variants in epidemiological models may improve the concordance of associations. The results of this analysis will disentangle reproducible protein measures and association results from those likely reflecting genetically- driven assay interference, within and across populations, and present new strategies to harmonize downstream associations for the impacted proteins across platforms.

NIAID - National Institute of Allergy and Infectious Diseases

Summary Soil transmitted helminths (STH) are parasitic nematodes that infect over 1 billion people in developing countries. Of the 3 major STH, hookworms are the most virulent, causing anemia and stunting physical and cognitive development in heavily infected people. Currently, morbidity from hookworms and other STH is controlled by mass drug administration (MDA) using the anthelmintic drug albendazole (ABZ), a member of the benzimidazole (BZ) family of drugs. While relatively effective, rapid reinfection following treatment requires annual or biannual treatment in endemic areas. The rapidity with which anthelmintic resistance (AR) developed in parasitic nematodes of livestock suggests that increasing the selective pressure on human helminths by MDA will rapidly generate resistant worm populations as well. Detection of emerging AR will be critical to avoid losing the most effective anthelmintics for treatment of hookworm. Naturally resistant hookworm isolates are required to determine the genetic mechanism of resistance and for the development of molecular tools for detection of AR in natural populations. We identified a naturally occurring isolate (BCR) of the canine hookworm Ancylostoma caninum that is resistant to drugs from the 3 major anthelmintic classes: the BZs, the macrocyclic lactones (ML), and the tetrahydropyrimidines (THP). While testing a commercial dewormer for efficacy against the BCR strain, we found that treatment with a combination of the ML moxidectin (MOX) and the THP pyrantel pamoate (PYR) increased the frequency of the allele that confers BZ resistance to BCR without exposure to any BZ drug. This cross-drug class selection suggests linkage between one or both of the drug target mutations and the genetic mutation that confers BZ resistance, and therefore may provide insight into the underlying molecular mechanisms of IVM and PYR resistance, neither of which is currently known. Furthermore, confirmed linkage of resistance genes of one or both drugs to the known BZ resistance gene would provide a genetic marker to rapidly identify likely multi-anthelmintic drug resistant (MADR) populations of hookworm before they reach phenotypic resistance and treatment failure. Finally, knowledge of cross-class selection would permit rational deworming strategies that avoid generating multi-drug-resistant hookworm populations. In this project, we will confirm cross-selection and determine which drug is responsible, determine the resistance status of selected hookworms, and generate materials for future genomic studies to determine the underlying mechanism of cross-drug class selection.

NSF

Open and accessible research data is essential for scientific progress, informed policy, and public benefit. Yet many researchers and communities, especially in rural states, lack the infrastructure, skills, and support needed to share and reuse data effectively. This project, led by the Vermont Research Open Source Program Office (VERSO) at the University of Vermont (UVM), addresses these gaps by strengthening open-data infrastructure and cultivating a regional culture of open science. It expands UVM’s institutional data repositories, so research outputs become more findable, accessible, and reusable (FAIR) for scholars, state agencies, nonprofits, and the public. The project also continues the annual Vermont Open Data Summit, bringing together researchers, government, industry, and civic organizations to build skills and collaborate around open data. Through partnerships with state agencies, regional planning bodies, and the Leahy Institute for Rural Partnerships, the initiative links university capabilities to real community needs. The Vermont Research Open Source Program Office (VERSO) at the University of Vermont proposes a three-year effort to build sustainable, multidisciplinary FAIR (Findable, Accessible, Interoperable, Reusable) research data management practices and open science capacity across Vermont. The project will expand UVM’s open data infrastructure by increasing Dataverse storage beyond its current one-terabyte limit, establishing standard operating procedures for data ingestion and curation, and providing researcher outreach, onboarding, and individualized data management consultations. The enhanced repository will support Digital Object Identifier assignment, metadata standards, and interoperability with external systems. VERSO will launch the annual Vermont Open Data Summit, a two-day regional event that strengthens open-data literacy and collaboration among academic institutions, government, nonprofits, and industry. The summit will feature keynotes, workshops including an adapted NASA Open Science 101 curriculum that the team has published, and a participant-driven unconference, with proceedings openly published via GitHub and Jupyter Books. VERSO will continue supporting community-driven open data projects through the Open Research Community Accelerator (ORCA), which engages interdisciplinary student teams in Agile-managed open data and open-source software projects with public-sector and community partners. Project outcomes will be tracked using repository metrics and summit metrics. Together, these efforts provide a replicable model for advancing FAIR data practices at rural land-grant institutions nationwide. 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

Current processes of scientific communication limit researchers’ ability to share findings with the general public and other researchers, slowing the progress of science. This project addresses the issues by removing financial barriers to participation for authors and readers; building community-based, post-publication review processes; and developing open, values-enacted research assessment metrics. Seven community testbeds are implementing a Publish-Review-Curate-Assess workflow; documenting the work with these communities establishes reproducible models that bring scientific communication into alignment with the goals of open science. Open Science requires building a Publish-Review-Curate-Assess workflow within integrated systems. PUBLISH: By establishing community-based platforms for hosting and disseminating scientific research, the project can eliminate restrictions imposed by proprietary systems in the form of publishing fees and subscription costs. This enables new work to be made public immediately via preprint servers or disciplinary repositories, moving the endorsement phase of the communication process to post-publication. REVIEW: By transforming review from a publisher-controlled process to one designed and overseen by the research community, review processes can become part of the scientific conversation, allowing reviewers to be credited with their insights and researchers to participate in the engagement with their work. CURATE: By leveraging a multi-institutional, open-source publishing platform, the project enables research communities to select and endorse the best current research. ASSESS: Full attention to impact requires better analytics for research assessment to be made more openly available. By leveraging a multi-institutional, open-source publishing platform, the project can aggregate information to measure the impact of research, returning control of analytics to research institutions. 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

Scientific research across domains is increasingly driven by large-scale, complex datasets produced by simulations, experiments, and observations. While the volume and variety of data continue to grow, researchers still face major challenges in discovering, understanding, and accessing the data most relevant to their work. This project aims to establish a new data curation infrastructure by integrating Large Language Models (LLMs) and vector indexing into the data life cycle: improving metadata, enhancing discoverability, and optimizing data storage. Existing data management systems primarily depend on structural metadata and keyword-based search, which often fail to capture the scientific meaning, analytical context, or intended use of a dataset. This disconnect significantly hampers data reuse, cross-disciplinary collaboration, and the broader goals of open and reproducible science. This project addresses these limitations by building a new class of data management infrastructure that integrates large language models (LLMs) and vector indexing into the scientific data lifecycle. The framework will introduce an intent-aware semantic layer that enables users to interact with data through natural language, discover relevant datasets based on scientific goals, and guide storage systems in organizing data based on expected use. This work directly advances the FAIR (Findable, Accessible, Interoperable, and Reusable) principles and responds to the priorities outlined in the NSF FAIROS solicitation, which emphasizes sustainable, socio-technical innovations for research data management. 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.

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

Neurodevelopment and school readiness are critical determinants of long-term health, educational achievement, and socioeconomic outcomes. In Sub-Saharan Africa (SSA), millions of children face suboptimal neurodevelopmental trajectories, with significant implications for their future well-being and the prosperity of their communities. One factor that clearly impairs development is exposure to infections, both in utero and after birth. While we and others have demonstrated impaired neurocognitive development in young children born HIV- exposed and uninfected (CHEU), the long-term impact of maternal HIV on child outcomes has rarely been assessed. However, CHEU may differ from those born to mothers without HIV infection (CHU) in a variety of ways that span biological, social and environmental factors. One key factor known to influence neurological development is the composition of the gut microbiota, which is thought to be altered by in utero HIV exposure. We have already enrolled and followed a cohort of infants born to mothers with and without HIV infection in Malawi and evaluated their socio-economic and nurturing environment, their post-natal health, and neurodevelopment. Here, we propose to extend the follow-up of our cohort as they reach school age. In an effort to strengthen key areas of research excellence at the Kamuzu University of Health Sciences in Blantyre Malawi, we propose establishing a core of investigators and leaders who can evaluate neurocognitive function and school readiness, lead studies of the impact of the microbiome on health, and conduct modeling to understand multifactorial health outcomes that are essential to evaluating the real-world context. While early childhood development is a key predictor of long-term health, studying older children's neurodevelopment is essential within a “life-course” perspective, which recognizes that growth, health, and development continue beyond early childhood. By considering the interconnectedness of in utero exposure, the psychosocial environment, the microbiome, and cognitive development, we can better target interventions that promote holistic development across multiple areas. The interconnectedness of these three factors makes it challenging to assess their combined and independent effects on development, particularly among older children. We will characterize these relationships in our ongoing cohort of CHEU and CHU and apply causal inference techniques to estimate the relative contributions and interactions between each of these factors. The goal of this proposal is to elucidate the role of in utero HIV exposure on the child's microbiome development and subsequent neurodevelopmental progress. We aim to identify microbiome profiles associated with both exposure to HIV in utero and neurodevelopmental outcomes. This research will be complemented by a comprehensive training component, fostering capacity building and knowledge transfer to local researchers and healthcare providers, thereby maximizing the health and well-being of this vulnerable population of children.

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

Neurodevelopment and school readiness are critical determinants of long-term health, educational achievement, and socioeconomic outcomes. In Sub-Saharan Africa (SSA), millions of children face suboptimal neurodevelopmental trajectories, with significant implications for their future well-being and the prosperity of their communities. One factor that clearly impairs development is exposure to infections, both in utero and after birth. While we and others have demonstrated impaired neurocognitive development in young children born HIV- exposed and uninfected (CHEU), the long-term impact of maternal HIV on child outcomes has rarely been assessed. However, CHEU may differ from those born to mothers without HIV infection (CHU) in a variety of ways that span biological, social and environmental factors. One key factor known to influence neurological development is the composition of the gut microbiota, which is thought to be altered by in utero HIV exposure. We have already enrolled and followed a cohort of infants born to mothers with and without HIV infection in Malawi and evaluated their socio-economic and nurturing environment, their post-natal health, and neurodevelopment. Here, we propose to extend the follow-up of our cohort as they reach school age. In an effort to strengthen key areas of research excellence at the Kamuzu University of Health Sciences in Blantyre Malawi, we propose establishing a core of investigators and leaders who can evaluate neurocognitive function and school readiness, lead studies of the impact of the microbiome on health, and conduct modeling to understand multifactorial health outcomes that are essential to evaluating the real-world context. While early childhood development is a key predictor of long-term health, studying older children's neurodevelopment is essential within a “life-course” perspective, which recognizes that growth, health, and development continue beyond early childhood. By considering the interconnectedness of in utero exposure, the psychosocial environment, the microbiome, and cognitive development, we can better target interventions that promote holistic development across multiple areas. The interconnectedness of these three factors makes it challenging to assess their combined and independent effects on development, particularly among older children. We will characterize these relationships in our ongoing cohort of CHEU and CHU and apply causal inference techniques to estimate the relative contributions and interactions between each of these factors. The goal of this proposal is to elucidate the role of in utero HIV exposure on the child's microbiome development and subsequent neurodevelopmental progress. We aim to identify microbiome profiles associated with both exposure to HIV in utero and neurodevelopmental outcomes. This research will be complemented by a comprehensive training component, fostering capacity building and knowledge transfer to local researchers and healthcare providers, thereby maximizing the health and well-being of this vulnerable population of children.

NSF

Nontechnical Description: This project will advance the understanding of nano-polaritons—waves that combine light and matter and travel within nanoscale materials. These waves can be used to control energy and information at extremely small scales, offering potential for faster optical computing, more efficient energy use, and advanced sensing technologies. The research team will explore how these waves behave when moving across materials of different shapes and sizes. These new setups for nano-polaritons could lead to more efficient ways to send and control information and energy at the nanoscale. The research will also support hands-on education and outreach for the general public on state-of-the-art optics and materials research. In addition, the project will integrate the research products into university coursework and involve K-12 participants in summer activities. Undergraduate students will receive comprehensive training in nanomaterial fabrication and optical simulations, helping prepare the next generation of researchers in optics, materials science, and engineering. Technical Description: This project will investigate cross-interface polariton nano-light in heterostructures formed by mixed-dimensional and reduced-symmetry materials. By breaking the traditional symmetric behaviors of polaritons, the research will enable the discovery of unconventional light-matter interactions and propagating nano-optical modes over quantum-confined nanostructures. The principal investigator will explore different dimension configurations to vary the polariton propagation characteristics. The project will also utilize materials with low crystal symmetry and extreme optical anisotropy to enable non-reciprocal, directional, and non-symmetric polariton nano-light. Scattering-type scanning near-field optical microscopy will be used to provide direct visualization of polariton nano-light behaviors with nanometer resolution. At the same time, finite element method simulations will be conducted to offer theoretical insights into field distributions and dispersion relations of the polaritons. Together, these methods will elucidate the mechanisms of polariton energy transfer and photonic density of states enhancement at the nanoscale interfaces. These polaritonic heterostructures are expected to yield novel optical phenomena that cannot be achieved in conventional systems or material combinations. The research outcomes will contribute to the fundamental understanding of nanoscale optical energy transport and hold promises for practical applications such as fast photonic circuits, efficient energy transport, precise biomedical treatment, effective thermal management, and quantum information and communication. This research may also expand current knowledge in physics and optics by revealing novel mechanisms of nano-light propagation and energy transfer at intriguing nano-interfaces. 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

Cocaine use disorder (CUD) is a highly prevalent in people living with HIV (PWH), and co-occurring HIV and CUD result in poorer clinical outcomes and more severe neurocognitive sequelae. Despite exacerbated risk for behavioral and cognitive deficits in PWH who use cocaine, there is limited understanding and an absence of targeted therapeutic strategies addressing the effects of CUD and HIV on the brain. Better definition of the interaction between cocaine use and HIV infection in the CNS is essential to address this knowledge gap. HIV and CUD both increase neuroinflammation via activation of inflammasomes, multiprotein complexes that regulate inflammation through production of the cytokines IL-1β and IL-18. NLRP3, the most widely studied inflammasome, is highly expressed in microglia, as well as other CNS myeloid cells. Cocaine exposure and HIV infection can both activate NLRP3. While processes regulating inflammasome activity are well-defined, the mechanisms by which HIV and cocaine affect them are not. Cocaine increases dopamine in the mesolimbic region. Increased dopamine appears to mediate the effects of cocaine effects on inflammasomes, as cocaine use upregulates NLRP3 expression and IL-1β in the mesolimbic region in vivo (when it increases dopamine levels), but not in microglia in vitro. HIV infection also disrupts dopamine reuptake and metabolism and increases inflammation in mesolimbic structures. This suggests that cocaine use and HIV infection interact via dopaminergic dysregulation, potentiating regional neuroinflammation and disrupting behaviors and cognitive processes defined by mesolimbic circuits. The mechanistic link between dopamine and inflammasomes is not clear, but mitochondrial dysregulation has been shown to regulate inflammasome activity in myeloid cells. Our preliminary data show that dopamine increases NLRP3 activity in human iPSC-derived microglia in vitro, and that in human macrophages, dopamine specifically enhances caspase expression and Gasdermin cleavage. In these human macrophages, dopamine also disrupts mitochondrial fission, and blocking the effects of dopamine on mitochondrial fission inhibits the dopamine-enhanced in inflammasome activity. We also show that HIV and cocaine interact to drive inflammation and disrupt reward-seeking behavior in vivo in EcoHIV-infected mice self- administering cocaine, which correlates with other studies showing that cocaine mediated inflammation impairs drug seeking behavior and cognitive function. Thus, we hypothesize that cocaine-mediated increases in dopamine potentiate inflammasome activation in microglia in the HIV-infected CNS by dysregulating mitochondria and enhancing neuroinflammation, which contributes to cognitive deficits and aberrant reward seeking. Our proposal addresses this hypothesis in in vitro, ex vivo and in vivo models at the single cell (Aim 1), circuit and behavioral (Aim 2) levels. This will generate of data from complementary human and rodent systems to overcome the limitations inherent in any single neuroHIV model and generate interconnected data sets correlating functional, and behavioral changes in response to HIV and cocaine use.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Damage to the nervous system results in the death of many neurons, leading to adverse outcomes such as locomotor and cognitive defects. Neural injuries may induce neuroplasticity responses in surviving neurons, where they extend their axons and dendrites and form new connections (undergo rewiring) to cope with the loss of their neighboring neurons. Neural circuits are composed of different neuronal types, each with unique intrinsic properties such as neural firing patterns, neurotransmitter identity, and synapses of different types and sizes. Whether different neuron and synapse types are equally capable of undergoing structural plasticity remains unclear. Furthermore, the role of non-neuronal cells (such as glia and muscles), intercellular signaling pathways, and cross-talk between neurons, glia, and muscles during the plasticity response are still under investigation. Addressing these knowledge gaps will help optimize therapeutic strategies, thereby maximizing the chance of the restoration of circuit function after neural injury. The objective of this proposal is to address these problems using the motor circuits underlying locomotion in Drosophila larvae. Two types of motor neurons (MNs) form neuromuscular junctions (NMJs) with larval body wall muscles: tonic-firing MNs with large NMJs and phasic firing MNs with small NMJs. These MNs receive input from excitatory and inhibitory premotor neurons (PMNs). In addition, different subtypes of glial cells in Drosophila are functionally and morphologically comparable to those found in vertebrates. The rich genetic toolkits in larvae provide an unprecedented opportunity to determine how PMN-MN-muscle circuits rewire in response to the death (or inactivation) of PMN and MN subsets and determine the role of glial and denervated muscles in mediating proper circuit rewiring. For the first time, strong preliminary data provided in this proposal demonstrate that in response to the death of MN subsets, the motor axon of a single surviving MN extensively sprouts and forms new NMJs on denervated muscles, recovering their contractility. Expanding on this experimental setup, Aim-1 will test the hypothesis that tonic-firing MNs and excitatory PMNs are more potent than phasic MNs and inhibitory PMNs to rewire and form new synapses upon loss of their neighboring neurons. Aim-2 will determine whether debris clearance and path formation by glial cells are prerequisites for sprouting and rewiring of PMN-MN-muscle circuits that survive post-injury. In parallel, Aim-2 will experimentally test a model based on which glial cells and denervated muscles release neurotrophic factors that instruct surviving MNs to form new synapses (i.e., new PMN-MN and MN-muscle connections) in proper locations. It is expected that this research will provide a deeper understanding of motor circuit recovery mechanisms mediated by synaptic plasticity that are conserved in mammals, and generate hypotheses to be tested in vertebrate locomotion.

NSF

With support from the Chemical Synthesis Program in the Division of Chemistry, Professor Gojko Lalic at the University of Washington is studying the development of new reactions for the synthesis of organic molecules using organoboron compounds and transition metal catalysis. The project is advancing more efficient transformations of common starting materials into more valuable targets, complementing existing methods. These reactions are providing a new approach to forming carbon-carbon bonds, critical for constructing large organic molecules. Beyond practical applications in organic synthesis, the fundamental properties and reactivity of organoboron compounds are being investigated and expanded in these studies. An essential part of the project is its outreach initiative, which fosters connections with the local community. Dr. Lalic's team engages elementary and high school students through activities that inspire interest in science, technology, engineering, and mathematics (STEM) careers. Organoboron compounds are valuable synthetic building blocks due to their availability, stability, and versatile reactivity. Continued advances in the synthetic applications of these compounds is critically important to support the pharmaceutical industry, medicinal chemistry, the synthesis of agrochemicals, and material science. Prof. Lalic and his research team are creating more effective tools for synthesizing complex organic molecules by exploring two new classes of chemical reactions. The first is a new type of cross-coupling reaction using two nucleophilic coupling partners that leverages the ambiphilic nature of organoboron compounds and the ability of transition metal complexes to modulate their reactivity. The second focuses on innovative strategies for homologating organoboron compounds via formal insertion of C2 fragments into carbon-boron bonds. Notably, this C2 fragment insertion involves an unusuallly facile activation of carbon-carbon bonds. Integral to this work are outreach activities, which are designed in collaboration with the local community, to promote science education and engagement. 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.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Hemagglutinin (HA) antigenic changes of influenza (flu) viruses and low immunogenicity of conventional flu vaccines result in suboptimal efficacy, ranging between 10% and 60%, and much lower efficacy or no protection against pandemics. It is a high priority to design new universal flu vaccines, develop a novel vaccination strategy, and better understand the innate and adaptive immune mechanisms for vaccine- mediated effective protection. The mRNA vaccine platform would provide many advantages over conventional vaccines. In this project, we designed new mRNA vaccine constructs encoding neuraminidase (NA) conjugated to a highly conserved M2e repeat, which is based on our prior studies reporting that immunity to both NA and M2e could provide broad cross-protection against different subtypes and lineages of flu A and flu B viruses. However, non-neutralizing immunity to conserved domains would have limited efficacy despite broader protection. Lipid nanoparticles (LNP) encapsulating mRNA vaccines are known to be inflammatory. High doses of mRNA LNP vaccines would cause undesirable side effects. We hypothesize that mRNA LNP vaccine targeting conserved domains and inducing cross-protective immunity will enhance the broad cross- protection of co-administered conventional flu split vaccines at low doses of both vaccines. This hypothesis is supported by our new preliminary data demonstrating that a combination of flu A 5xM2e mRNA or B NA mRNA LNP and inactivated split virus vaccines significantly enhanced the efficacy of cross-protection against flu A and flu B viruses. Flu A (not flu B) has pandemic threats, more diverse natural hosts, and antigenic diversity, and is highly pathogenic, rendering flu A viruses more challenging to control than flu B. In Specific Aim 1, we will further test the hypothesis that the combination of new cross-protective mRNA LNP and inactivated flu A virus split vaccines will provide higher efficacy of homologous and heterologous against flu A viruses. In addition, we do not fully understand the innate and adaptive immune mechanisms of how adding an mRNA LNP vaccine to conventional inactivated split virus vaccination will enhance homologous and heterologous protection. In Specific Aim 2, we will determine whether a combination of an mRNA LNP vaccine and conventional inactivated flu split vaccines will activate a unique set of innate immune responses leading to enhanced adaptive immunity. We expect that the outcomes of this project will provide insight into innate and adaptive immune correlates with enhanced homo- and cross-protection by a combination of cross-protective mRNA and conventional vaccines, in addition to developing a new vaccination strategy inducing enhanced protection against seasonal and pandemic potential variants.

NIA - National Institute on Aging

ABSTRACT Across species, reproduction and immunity compete for limited physiological resources—a trade-off that becomes increasingly consequential with age, as both reproductive capacity and immune competence decline. In mammals, proteins that mediate these relationships to coordinate reproductive investment, immune regulation, and somatic maintenance are scarcely defined. This presents a critical gap in our understanding of reproductive aging and age-related disease susceptibility. This proposal investigates whether the C. elegans protein TCER-1, an established regulator of the fertility–immunity–longevity axis, has a conserved functional homolog in mammals. We previously identified TCER-1 as a pro-longevity factor that maintains fertility with age by suppressing immune and stress responses. Its homolog in Arabidopsis also promotes fertility and represses immunity, and our collaborative studies reveal a similar role for the Drosophila TCER-1 in repressing stress resistance, highlighting conserved trade-off regulation across kingdoms. TCER-1 is homologous to the mammalian transcription elongation and splicing factor, TCERG1, which has been linked to human disease in GWAS studies, though it’s in vivo function remains uncharacterized. This proposal is based on our preliminary data showing that (i) worm and mammalian TCERG1 both regulate alternative splicing of immune-related genes, and importantly (ii) mouse and human TCERG1 are enriched in germ-cells and exhibit a major age-related decline in female oocytes. In this exploratory proposal, we aim to assess whether human or mouse TCERG1 can functionally replace TCER-1 in C. elegans (Aim 1) and to define the role of mouse TCERG1 in fertility, ovarian reserve and reproductive aging by using existing and newly generated knockout models (Aim 2). By uncovering a potentially conserved molecular regulator of physiological trade-offs, this project aims to illuminate how reproductive aging shapes immune function and broader somatic aging, and to lay the groundwork for future interventions that support reproductive health in aging individuals.

NCI - National Cancer Institute

PROJECT SUMMARY There is a crucial need in the field of advanced diagnostic tool development for early detection of rare cancers such as osteosarcoma (OSA). Specifically, there is a need to develop platforms that can overcome the limitations of small sample sizes inherent in rare cancers while maintaining generalizability across patient populations for high test accuracy to improve patient outcomes. The long-term objective of this project is to develop a Raman spectroscopy-based liquid biopsy platform which uses a model trained on readily available companion animal biological samples as a basis for cross-species validation using smaller human data sets. To accomplish this objective, the research team will undertake two specific aims. First, Raman spectral signatures of canine OSA will be defined and validated as a foundation for cross-species diagnostic modeling. This will be done by using self-supervised models to train on Raman data generated from 100 canine plasma samples and subsequently using supervised classifiers to detect OSA. Biological interpretability will be validated via targeted lipidomic and metabolomic profiling. Second, the research team will develop and validate a cross-species transfer learning framework by performing Raman spectroscopy on more than 1,000 unannotated canine plasma samples and fine-tuning models on rare cancer–specific data in human patients. By accomplishing these aims, a comparative transfer learning framework will be established that enables label- efficient diagnostic development for rare cancers using abundant veterinary data. This platform has potential for broad extension to other rare cancers with canine analogs, providing a scalable path to early, noninvasive cancer detection in settings where human samples are limited.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Brain bleeding in the parenchyma, also known as intracerebral hemorrhage (ICH), represents 10 to 30 percent of strokes in distinct countries around the world. Despite its lower incidence than ischemic stroke, ICH carries higher rates of mortality and morbidity. Worse outcomes in humans with ICH have been correlated with damage to axons in areas of the brain like the thalamus or the striatum where bleeding from small, penetrating arteries (often affected by longstanding hypertension) tends to occur. Red blood cells accumulate in ICH and lyse and release toxins. These include hemoglobin (Hgb) and its breakdown product hemin . Additional understanding of how Hgb/hemin leads axons to degenerate in ICH is a strategy to fully assess and overcome disability from this condition. Excitingly, a molecular path for programmed axonal destruction has been defined involving the protein, sterile alpha and Toll/Interleukin receptor-1 (TIR) motif containing 1 (SARM1). SARM1's degenerative activities in the axon emerge from its NADase (NAD+ degrading) activity in the TIR domain. This domain's importance is highlighted by its conservation from plants to humans. In preliminary studies, we found that germline deletion of full length SARM1 prevents axonal damage in the striatum following ICH. Since previous studies from our lab have shown that hemin induces ferroptosis, an iron-dependent, caspase-independent form of programmed necrosis, following experimental ICH, we are seeking to understand the cross talk between ferroptosis and SARM1-mediated axonal destruction (sarmoptosis). Of note, we found that cortical neurons cultured from the SARM1 knockout mice are partially resistant to ferroptotic stimuli (hemin and erastin). Moreover, agents such as P7C3 that augment the cell's ability to make NAD+ protect against ferroptosis; conversely, FK866, which impedes the same NAD+ synthesizing pathway makes ferroptosis worse. From these preliminary studies we propose three aims designed to understand the interplay between ferroptosis and sarmoptosis in ICH. In the first aim, we will leverage mice that possess a germline, homozygous, single amino acid mutation (E642A) in the NADase domain of SARM1. Like the SARM1-/- mice, the neurons of these mice are resistant to axotomy in vitro and in vivo. They will be used to probe whether the NADase activity is critical for ferroptosis in vitro and ICH in vivo. In the second aim, we will address the hypothesis that hemin-induces axonal degeneration via local ferroptotic pathways that trigger SARM1 activation. We will use sensory neurons cultured in Campenot Chambers to isolate cell bodies from axons and query their possibly distinct responses to lethal concentrations of hemin. We will also probe the role of ferroptosis and sarmoptosis in the destruction of corticospinal tract axons in vivo. In the last aim, we will seek to understand whether interventions that target ferroptosis by acting in the nucleus (cell body) can be combined with SARM1 deletion (that acts primarily in axons) in mice to reduce damage and improve behavioral recovery over each agent tested alone. At the culmination of these studies, new mechanistic information will emerge regarding axonal and cell body loss following ICH with clear therapeutic implications.

U.S. National Science Foundation

Crosscutting Activities in Materials Research

Crossett Economic Development Foundation

Crossett Economic Development Foundation is an active grantmaking foundation based in Crossett, AR. Focus: community development. Contact the foundation directly for current funding opportunities.

NIDCD - National Institute on Deafness and Other Communication Disorders

PROJECT SUMMARY Sensory loss leads to widespread adaptation across the brain areas to enhance processing of the remaining senses as exemplified by enhanced auditory functions in blind individuals. Such crossmodal compensatory plasticity is not restricted to congenitally blind individuals but is also observed after late-onset vision loss. We previously found that visual deprivation initiated in adult mice leads to widespread synaptic and circuit-level plasticity in the auditory pathway: potentiation of feedforward inputs carrying auditory information in the primary auditory cortex (A1), including recovery of thalamocortical synaptic plasticity, functional refinement of local circuitry in A1, and disinhibition of the primary auditory thalamus. These changes correlated with a reduction in the sound detection threshold and sharper tuning of A1 layer 4 (L4) neurons as well as refinement of sound representation in A1 L2/3. Here, we propose to test the hypothesis that such widespread plasticity of the auditory system following visual deprivation is functionally coordinated by the plasticity of the corticothalamic (CT) circuit. There are largely three distinct CT circuits: (1) Lemniscal CT pathway mediated by A1 L6 neurotensin receptor 1 (Ntsr1)-positive neurons, which provide cortical feedback to the primary auditory thalamus (MGBv) and the inhibitory thalamic reticular (TRN) nucleus, (2) non-lemniscal CT pathway mediated by A1 L6b neurons (Cplx3 and Drb1a-positive), which project to higher order non-lemniscal thalamic nuclei, and (3) cortico-thalamo-cortical (CTC) pathway mediated by A1 L5 neurons (Rbp4-positive), which project to higher-order auditory cortical areas via the higher-order auditory thalamic nuclei. We aim to investigate how early- and late-onset visual deprivation alters the function of these CT circuits in adult mice (Aim 1), whether it affects CT circuit regulation of feedforward auditory pathways (Aim 2), and determine how it alters the sound encoding of CT neurons (Aim 3). We will utilize optogenetics to assess the plasticity of functional circuits, multi- photon Ca2+ imaging accompanied by auditory behavioral tasks to measure neural activity changes, and pharmacogenetics for testing neural circuit elements on in vivo function and behavior. Results from our work will provide mechanistic information on how the CT circuit mediates crossmodal compensatory plasticity in early- and late-onset blind models, which would benefit the development of potential therapeutics for improving sensory function.

Crossroads College Foundation

Crossroads College Foundation is an active grantmaking foundation based in Rochester, MN. Focus: education. Contact the foundation directly for current funding opportunities.

Town of Centreville

Crossroads Community Facility

Town of Centreville

Crossroads Community Facility

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Research supports a role for reduced cholesterol efflux and lipid droplet (LD) accumulation in mitochondrial dysfunction (MD) and podocyte injury in the pathogenesis of glomerular diseases of metabolic and non-metabolic origin, including Alport Syndrome (AS). Less is known about the contribution of triglyceride (TG) accumulation in LDs to MD and podocyte injury. LDs regulate the storage and homeostasis of intracellular TGs and regulate the availability of free fatty acids (FFAs), which can be oxidized in mitochondria and used as an energy source. Proper contact of LDs with mitochondria is mediated by LD-associated proteins, such as perilipin 5 (PLIN5), and is instrumental for FA synthesis and breakdown. PLIN5 is a protein that regulates TG metabolic pathways and cellular energy homeostasis through its role in the lipolysis of TGs stored in LDs, mediates LD-mitochondrial contact formation, and serves as a substrate for chaperone-mediated autophagy (CMA). However, little is known about the function of PLIN5 in podocytes. In preliminary data, we demonstrate decreased PLIN5 expression in glomeruli of patients with AS, in kidneys of Col4a3 KO (AS mice) and AS podocytes, and in a zebrafish model of AS when compared to controls. In AS podocytes, PLIN5 deficiency is associated with increased lipolysis, FFA accumulation, and reduced LD- mitochondrial contact formation and mitochondrial membrane potential, which was restored by PLIN5 overexpression. AS podocytes have an increased autophagosome number compared to WT, often in proximity of mitochondria, suggesting increased mitophagy. PLIN5 expression is restored by Ezetimibe (EZ), a compound that we found to partially protect AS mice from the development of proteinuria. Our results suggest an important role for PLIN5 deficiency in lipotoxicity-induced MD and podocyte injury and renal disease progression in AS. The overall goal of this proposal is to investigate a novel mechanism linking PLIN5 deficiency to lipotoxicity- mediated MD, CMA and podocyte injury in AS. We hypothesize that PLIN5 deficiency in AS causes TG-rich LD accumulation due to impaired CMA, FFA accumulation due to increased TG lipolysis and impaired LD-mitochondrial contact formation, resulting in lipotoxicity-induced mitochondrial dysfunction. We propose a combined in vitro and in vivo approach to investigate the mechanism by which PLIN5 deficiency causes lipotoxicity-induced MD and podocyte injury (aim 1), and in renal failure (aim 2) in AS. If successful, this innovative study will link PLIN5 deficiency to a novel pathway of lipotoxicity-induced MD and podocyte injury and may lead to the identification of new drug targets for the treatment of patients with proteinuric kidney diseases associated with altered GBM, such as AS.

NIEHS - National Institute of Environmental Health Sciences

Project Summary Environmental and endogenous genotoxic stressors can induce DNA and RNA damage and misdeposition of the epitranscriptomic mark, N6-methyladenosine (m6A), leading to genome instability, gene dysregulation, and cancer and neurodegeneration. However, it remains unknown how DNA and RNA damage can synergize to modulate genome and epitranscriptome stability. In this project, we aim to understand the mechanisms underlying the crosstalk of RNA damage and m6A with DNA damage and repair. Our hypothesis is that environmentally-induced RNA damage, m6A, and DNA base damage and repair can interplay on R-loops to modulate RNA and DNA integrity. To test the hypothesis, we will pursue three Specific Aims. Aim 1 is to determine if environmentally-induced RNA damage can modulate RNA-guided DNA base damage repair and its fidelity on R-loops. First, we will determine if the environmental genotoxicant KBrO3 and occupational exposure level of Mn2+ can induce RNA and DNA base damage on R-loops to disrupt the expression of R-loop hotspot genes, MALAT1 and unfolded protein response regulator X-box binding protein 1 (XBP1) genes in human kidney cancer and iPSC-differentiated neural cells. Second, we will determine if RNA base damage can promote KBrO3- and Mn2+-induced DNA base damage by reducing the efficiency and fidelity of RNA-guided BER using circular RNA-mediated RNA damage systems, the artificial intelligence tool AlphaFold3, molecular dynamics simulation (MD), and steady-state enzyme kinetics. Aim 2 is to determine if m6A can modulate environmentally-induced DNA base damage repair by regulating RNA-guided DNA synthesis on R-loops. First, we will determine if KBrO3 and Mn2+ can cause the unique m6A deposition on R-loops, leading to dysregulation of the MALAT1 and XBP1 genes in kidney cancer and neural cells. Second, we will determine if m6A can disrupt DNA base damage repair induced by KBrO3 and Mn2+ on the R-loops of the MALAT1 and XBP1 genes by altering BER efficiency and fidelity using circRNA-mediated gene-targeted m6A deposition systems, AlphaFold3, MD, and enzyme kinetics. Aim 3 is to determine if environmentally-induced DNA base damage and repair can modulate m6A deposition on R-loops to disrupt RNA transcriptomic integrity. First, we will determine if KBrO3- and Mn2+-induced DNA base damage can alter m6A deposition on R-loops of the MALAT1 and XBP1 genes by disrupting the recruitment of m6A writers METTL3/METTL14 and eraser FTO and their substrate interaction on R-loops, suppressing R-loop resolution and expression of the genes in cancer and neural cells. Second, we will determine if DNA base damage can synergize with Mn2+ to cause m6A misdeposition on R-loops of the MALAT1 and XBP1 genes. Our study will create a new paradigm to reveal the crosstalk between environmentally-induced oxidative RNA damage and m6A deposition and DNA base damage and repair on R-loops in modulating genomic and transcriptomic integrity. Our results will facilitate the discovery of novel targets for RNA-based gene-targeted therapy and biomarkers for the prevention of environmentally-induced cancer and neurodegenerative diseases.

Regional Council Capital Fund - RC4

Crouse Hospital Emergency Department Capital