Vanderbilt University

NIH Research Projects · FY 2025 · 2024-08

Project Summary A fundamental question in cell biology is how this crowded space can be organized to enable the control of biochemical processes and reactions in space and time. Biomolecular condensates have emerged as a potential universal solution to how activities and functions are organized within cells. Condensates by nature are formed via collective interactions between biomolecules which together form concentrated assemblies. These collective biochemical interactions govern both condensate regulation and function within cells. The interface of the condensate with the cytosol (interfacial surface) has emerged as a critical molecular determinant for condensate regulation, and function. Biological Pickering agents absorb the interfacial surface of condensates and offer a versatile solution for how cellular functions can be compartmentalized. As interest in biomolecular condensates as an organizing principle in the cell has increased, so have the criticisms of the quality of evidence supporting the biological significance of condensates in native cells. To overcome these valid criticisms a key challenge moving forward for the field is the development of technical approaches to measure and manipulate the collective interactions within these assemblies in native cells. The molecular mechanics that underpin condensate regulation, dynamics, and function in native cells is not well understood. During C. elegans embryogenesis, RNA granules called P granules undergo a dramatic stereotyped polarization within the zygote. Using P granule as a model condensate this proposal aims to define the core biochemical principles that underpin the spatial and temporal regulation of P granule polarization. The goals of this proposal are to 1) identify key biochemical determinants that facilitate P granule assembly 2) define the molecular mechanism by which DYRK kinase regulate P granule disassembly 3) define the biochemical mechanism by P granule assembly and disassembly is spatially regulated 4) determine the biochemical mechanism by which biological Pickering agents are removed from the interfacial surface of P granule 5) define the molecular mechanics that underpin the kinetic arrest of P granules. To accomplish these goals, we will use a multifaceted approach that includes biochemistry, cell biology, and genetics. Leveraging our unique in vivo and in vitro assays we will define the collective biochemical grammar that facilitates the regulated assembly and disassembly of P granules.

NSF Awards · FY 2024 · 2024-08

The mismatch hypothesis states that past lifestyles selected for genes that are now, in modern urbanized groups, detrimental to human health. The presence of these past-selected genes in modern human populations account for the current surge of non-communicable diseases such as obesity, type-II diabetes, and cardiovascular disease. To date, most studies that test this idea are limited because they compare genetically distinct groups. This dissertation project addresses this issue by focusing on a group of individuals that share a similar genetic background but live in environments that are a “match” (subsistence-level) or a “mismatch” (urban) to their previous lifestyle. The study informs genome-environment interactions in humans, human adaptation, and health, as well as the tempo of evolution in modern human populations. The study involves the participating community through multiple strategies and uses community-driven techniques in the production of public information. The study provides training opportunities for graduate and undergraduate students of diverse backgrounds and deepens the interaction and communication among researchers interested in this topic. A total of ~700 participants, with approximately even sex-ratios, are included in the study. A composite continuous lifestyle index (traditional-to-non-traditional) is calculated for each individual based on data collected through structured interviews. Putatively beneficial genomic sites are identified using whole genome sequencing (WGS). Signatures of past-selection are recognized using selection statistics that examine patterns of allele frequency and/or haplotype homozygosity. These analyses include population branch statistics (PBS), integrated haplotype score (iHS), and cross population extended haplotype homozygosity score (XP-EHH). Two outgroups are used to calculate allele-frequency-changes in each single nucleotide polymorphism (SNP). RNA extracted from the participants is analyzed with mRNA-seq analyses. The expression of the identified previously-selected genes will be assessed to characterize genotype-environment interactions and evaluated in relation to lifestyle-associated diseases. 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.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT Many inflammatory diseases and cancer are driven by dysregulation of CD4 T helper cells (Th cells). Our group has shown that different T cell subsets utilize distinct metabolic programs. Proinflammatory Th1 and Th17 T cells utilize aerobic glycolysis and increase lipid synthesis, while anti-inflammatory T regulatory cells (Tregs) utilize fatty acid oxidation and oxidative phosphorylation (OXPHOS). Importantly, the lab has shown that manipulation of metabolic pathways can affect Th cell differentiation, thus offering new approaches to modify immune-related diseases. Fatty acid and mitochondrial metabolism are critical processes that may be targeted to alter CD4 T cell fate. Utilizing established in vivo CRISPR screens in models of inflammatory bowel disease and lung inflammation, I identified several metabolic genes involved in lipid metabolism for this potential purpose. These screens found mitochondrial fatty acid synthesis (mtFAS) and the mtFAS enzyme Mitochondrial trans-2-enoyl- coenzyme A reductase (Mecr) to be important in T cell-mediated inflammation. mtFAS is a pathway parallel to cytosolic fatty acid synthesis that creates acyl-ACP and lipoic acid or longer fatty acid chains crucial for electron transport chain assembly and OXPHOS. Mecr is the final mtFAS enzyme and humans with MECR loss-of- function mutations develop a rare neurometabolic disorder. Mechanistically, Mecr-deficient skeletal myoblasts have reduced OXPHOS and Mecr-knockout in patient fibroblasts and drosophila cause increased levels of iron and impaired iron-sulfur (Fe-S) cluster biogenesis. Despite cytosolic fatty acid synthesis being well-characterized in T cells, it is currently unclear what effect Mecr and mtFAS play in immune cells. Therefore, I proposed studying the effects of Mecr and mitochondrial fatty acid synthesis on T cell function and metabolism. In a Th17 model of transfer inflammatory bowel disease, Mecr-knockout cells were depleted compared to non-targeting control cells in the spleens, mesenteric lymph nodes, lamina propria, and intra-epithelial lymphocytes. Mecr-knockout cells had lower Tbet expression and reduced IFNγ+ T cells, showing reduced Th1 function. In addition, Mecr-knockout cells had reduced proliferation, increased rates of cell death by apoptosis, and an increase in intracellular iron. These preliminary data demonstrate that Mecr plays a key role in inflammatory T cells as a rate limiting step in mtFAS. I hypothesize that mtFAS and Mecr activity supports TCA cycle flux and are required for the mitochondrial metabolism of Th1 CD4+ T cells. I will utilize control and Mecrfl/fl; Cd4cre conditional knockout mice that I generated and validated for my experiments in which Mecr will be knocked out specifically in T cells. I have also developed and utilized single-guide CRISPR/Cas9 knockouts for Mecr and have validated their functionality. I will: (1) Test the requirement of Mecr expression in the differentiation and function of CD4+ T cells in Th1/Th17-driven IBD; and (2) Define the role of Mecr in T cell mitochondrial fatty acid synthesis and iron metabolism. Ultimately, these studies will advance our understanding of mtFAS in T cells and the potential opportunities to modify this pathway to decrease T cell-mediated inflammation in IBD.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Within the small intestinal epithelium, tuft cells are a rare chemosensory cell type (less than 1% of cells), defined by their unique morphology consisting of large apical protrusions that extend over 2 μm into the lumen. Tuft cells have been implicated in sensing intestinal parasites and activating an immune response and are therefore recognized for their importance in maintaining the health of the intestinal epithelium. Tuft cell morphology is defined by a unique cytoskeletal structure consisting of giant bundles of actin filaments, which support an array of large apical membrane protrusions (a “tuft”) while extending over 6 μm down into the cell’s perinuclear region. Despite their role in activating an immune response against intestinal parasites, tuft cells remain understudied due to their rarity in the intestinal epithelium. As a result, there is a gap in our understanding of how the unique cytoskeletal architecture found in tuft cells contributes to the physiological function of this cell type. My preliminary research identified LIM domain and actin binding 1 (LIMA1) as a tuft cell enriched factor that localizes specifically to the basal ends of core actin bundles that extend deep into the sub-apical cytoplasm. Previous studies indicate that LIMA1 can cross-link actin, inhibit actin depolymerization, and inhibit actin branching in vitro, which are all molecular activates that tuft cells could use to promote the formation of giant actin bundles. Based on my preliminary data and previous studies in the literature, I hypothesize that LIMA1 drives the formation of the giant actin bundles found in tuft cells. Under Aim 1, I will test this hypothesis by establishing how LIMA1 expression impacts the formation of actin bundles in an intestinal cell culture model. In addition, I will use live cell imaging and Fluorescence Recovery After Photobleaching (FRAP) to characterize LIMA1 dynamics on actin bundles and determine if LIMA1 expression impacts the dynamics of actin turnover in decorated bundles. In Aim 2, I will determine whether LIMA1 expression is required for tuft cell actin bundle formation. Because tuft cells are not represented in intestinal epithelial cell culture models, I will instead use a LIMA1 knockout mouse model and visualize de novo tuft cell development in the context of intestinal organoids derived from these animals. This research seeks to develop a fundamental understanding of the molecular machinery underpinning the unique morphology of tuft cell. The insights derived from this project will additionally help us understand how tuft cells contribute to gastrointestinal physiology, immune sensing, and human health issues caused by intestinal parasites and for inflammatory illnesses such as Crohn’s Disease.

NIH Research Projects · FY 2025 · 2024-08

Intimate partner violence (IPV) is a significant public health problem that has damaging effects at the individual and societal levels. Major health disparities exist for rates of IPV. Women experience IPV at almost twice the rate of men, and Black women are disproportionately killed by intimate partners compared to most other racial groups. Homicide is the second leading cause of death for Black female youth between the ages of 15 and 24, with more than half of the deaths perpetrated by an intimate partner. The most common method used to kill intimate partners is firearms, and firearm access as well as threat with a firearm have been identified as key precursors to firearm-related IPV fatalities. Little to no research has examined patterns of firearm-related IPV or factors associated with firearm-related IPV involvement. The goal of the proposed project is to address the limitations of previous research by investigating patterns of nonfatal firearm-related IPV involvement among individuals at different stages of development and use a social-ecological framework to examine community, interpersonal, individual, and situational modifiable risk and protective factors that characterize patterns of firearm-related IPV victimization and perpetration. This goal aligns with NICHD’s research priority to effectively inform prevention strategies to address the leading causes of traumatic injury and death among children and adolescents. These goals will be addressed through secondary data analysis from two Federally funded projects, which provide data from local samples of 496 middle and 1,177 high school youth and a nationally representative sample of 1,674 adults. The specific aims are to 1) identify distinct patterns of firearm-related IPV victimization and perpetration within the broader context of IPV, and 2) examine the demographic characteristics and modifiable risk and protective factors that characterize IPV subgroup membership. I will test whether subgroup membership differs by age group, sex at birth, and race/ethnicity in each sample. The identification of patterns of individuals who display patterns of firearm-related IPV and understanding how subgroups differ across stages of development will help to identify sensitive time periods when prevention strategies may have the greatest impact. This approach will also inform how firearm-related behaviors fit within the broader context of IPV as well as identify subgroups of individuals at the greatest risk of firearm-related IPV involvement. Lastly, the identification of modifiable risk and protective factors will inform prevention strategies by identifying targets for preventing firearm-related IPV. Moreover, the research and training outlined in this proposed application will equip me with the skills and support needed to pursue a successful career as a research scientist, including knowledge of relevant theoretical models and their application to prevention and policy efforts, competencies in advanced statistical methods, and dissemination and grant-writing skills.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Cellular responses to environmental stressors (e.g., hypoxia, metals, and oxidants) are essential to animal performance and their dysregulation is associated with blindness, cancer, and aging. These responses are mediated by protein-level mechanisms regulating cytoprotective programs essential to animal survival. However, the majority of our knowledge into these proteins stems from human and mouse systems, ignoring the rich diversity of animal specialists —such as fishes, whales, and birds—that have evolved to survive chronic hypoxia and oxidative stress. This limits our understanding of the organismal stress response, as well as our ability to modulate these pathways in novel and unanticipated ways. With hundreds of these animals now represented by high-quality genomes, my goal is to harness evolutionary adaptation to identify novel molecular mechanisms modulating the environmental stress response. I recently demonstrated the enhanced NRF2 stress response of birds, pinpointing the protein-level mechanisms responsible. Since then, I have produced strong preliminary data identifying additional novel mechanisms in avian NRF2, as well as equine NRF2 and HIF-1 stress responses—species adapted to environmental oxidants, metals and chronic hypoxemia. We have identified substantial overlap of these adaptive mechanisms with those implicated in human diseases, suggesting these animals have evolved additional compensatory mechanisms. My vision is to reverse engineer these animal systems to reveal novel strategies capable of modulating the NRF2 and HIF-1 axis in human diseases where they are dysregulated. Thus, my plan over the next five years is to dissect these systems with a range of interdisciplinary techniques. Through a research strategy that integrates diverse perspectives from evolutionary biology, biochemistry, and cell biology, my program will address major gaps in our understanding of how stress response pathways operate in natural systems. Thus, my work is well-poised to improve our understanding of human health by harnessing the molecular strategies ‘discovered’ by natural selection millions of years ago.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY Coordination between the replication and transcription process is one of the major challenges that cells face during proliferation. As both replication and transcription machinery use the same genomic DNA as a template, to avoid conflicts, spatial-temporal separation between these two processes is necessary. Cells have evolved different mechanisms to evade conflicts but several physiological contexts such as the proximity of transcription start site to replication origins or diverse, adaptive transcription programs throughout different cell types together with the vast number of replication origins in human cells make distinct demarcation between these two processes hard to achieve. Moreover, several pathological conditions such as oncogene activation during cancer onset further complicate matters by altering the replication and transcription program and inducing transcription-replication conflicts profusely. Transcription-replication conflicts are known to perturb DNA replication and induce DNA damage and genome instability. Although how these conflicts affect the other key component of the conflicts, RNA polymerase II (RNAPII), its elongation speed, or transcription in general remains completely unexplored. Moreover, RNAPII speed or transcription kinetics regulate critical co-transcriptional processes such as alternative splicing, alternative polyadenylation, and transcription termination, thus regulating the production of alternative splice variants, circular RNAs, alternatively polyadenylated transcripts, or read‐through transcripts. Hence, alteration in just RNAPII speed could lead to the expression of different isoforms of proteins with potential physiological significance. My long-term goal is to understand the regulation of multiple aspects of transcriptional and co-transcriptional processes by transcription-replication conflicts and DNA damage in general especially during tumorigenesis. Moreover, I aim to enhance our understanding of how cells use different mechanisms to deal with the conflicts at different regions of the genome and how these pathways, dedicated to resolve conflicts, are coordinated. In the next five years, my proposal, for the first time, will systematically explore the effect of transcription- replication conflicts on transcription, investigate the role and significance of RNAPII speed in maintaining cellular fitness, and characterize the mechanistic role of the Integrator complex on the conflicts. Integrator is a transcription processing machinery that I recently discovered to have the ability to mitigate the damaging effects of transcription-replication conflicts. I anticipate that these studies will act as a platform for future efforts to understand the interplay of transcription and replication in controlling cellular homeostasis. Broadly, this work is part of a larger effort by my lab to understand whether conflicts are a regulated process, triggering cellular changes of physiological significance rather than a futile accident. Furthermore, these results will form the basis for future efforts screen for small molecules with the ability to modulate RNAPII speed, which potentially be useful to treat different conditions where RNAPII speed is modulated, for example ageing and cancer.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Women are more likely to develop Alzheimer's disease and related dementias later in life. This pattern can be partially explained by sex-related biological differences and women's longer life expectancy. The remaining portion is hypothesized to reflect differences in social, economic, and policy conditions across the life course. Building on prior research, I hypothesize that women's historical patterns of employment have contributed to their greater probability of experiencing cognitive decline by diminishing their ability to cognitive enrichment through the life course and other valuable employment-related resources. The proposed Mentored Research Scientist Development Award (K01) will give me protected time and resources to undertake additional training in cognitive neuroscience, retrospective life course data measurement, and survey cognitive health assessment. Supported by a team of highly accomplished mentors in neuroscience, psychology, gerontology, and population health, I will carry out innovative and rigorous quasi-experimental studies that approach the question of women's labor force participation implications for cognitive health from a life course perspective. First, I will use the Irish TILDA cohort to examine the effects of married women's labor force participation on their cognitive outcomes later in life. Second, I will use UK's ELSA data to study the effects of the introduction of paid and protected maternity leave on British women's cognitive outcomes later in life. Finally, I will use American HRS data to evaluate the impact of women's earlier retirement on their cognitive outcomes later in life. The datasets used have been selected for their unique strengths, which combine high-quality cognitive data and rich life course histories, and, in some cases, the genetic information of respondents. I will pursue the planned research together with a rigorous training plan. The skills and expertise I will gain will put me in a strong position to make major contributions to our understanding of cognitive health, become an independent NIH-funded researcher, and lay the foundation of my new research program in employment, policy, and cognitive health.

NIH Research Projects · FY 2024 · 2024-07

Project Summary: The Vanderbilt Cell Imaging Shared Resource (CISR) requests funds to purchase a Leica ARTOS Ultramicrotome for sample preparation for Electron Microscopy (EM). CISR is an institutional, fee-for- service, advanced microscopy resource. The CISR provides researchers with access to state-of-the-art imaging equipment which includes a modern FIB-SEM and TEM. CISR provides full-service electron microscopy sample preparation including sample embedding, thick and thin sectioning, staining, and image acquisition for either SEM or TEM. These instruments and services are available to support any investigator with an appointment at Vanderbilt University or Vanderbilt University Medical Center. The CISR serves over 200 labs per year, and processes approximately 1,000 SEM and TEM samples per year. Manual serial sectioning for 3-D image reconstruction is currently an error prone, labor and time intensive process that slows down work flow. The Leica ARTOS will allow automated serial sectioning of cells and tissues for downstream array tomography and serial tomography transmission electron microscopy applications. The ARTOS can automatically cut tissue serial sections between 50-100 nm with an advanced set of features to enable collection of hundreds of sections without error. These features include automated ribbon sectioning with horizontal movements at a set number of sections, a specialized cutting knife that can hold and cut sections for an entire coverslip, a mechanism to recover all these sections without introducing wrinkles, and a vibration and acoustic isolation platform to facilitate section reproducibility. These serial sections will be used for tissue reconstructions of up to 100,000 µm3 volume at nanometer resolution. This is not currently possible with the equipment at Vanderbilt. If funded the Leica ARTOS would be incorporated into the CISR workflow run by our expert CISR staff. Dr. Evan Krystofiak manages the CISR electron microscopy staff including Maria Vinogradova. Both Evan and Maria are experts in ultramicrotomy and regularly prepare thin and thick sections on the CISR’s existing Leica ultramicrotomes, including manually prepared, short serial section ribbons. The requested Leica ARTOS would be housed in existing CISR space in RR-1207 MCN along with current CISR-EM sample preparation equipment. In summary, acquisition of the Leica ARTOS will allow for unprecedented volumetric imaging capabilities of biological samples at scales and spatial resolutions not currently available to Vanderbilt and will facilitate research on a diverse set of NIH funded research.

NIH Research Projects · FY 2025 · 2024-07

Project Summary Several aggressive types of breast cancer (BCa) are nutritionally reliant on glutamine metabolism, and glutamine uptake has been shown to be enhanced in BCa bone-homing clonal cell populations. This is especially significant as bone metastasis will occur in approximately 70% of women with metastatic BCa and remain clinically incurable. The enzyme glutaminase (GLS) catalyzes the conversion of glutamine to glutamate, and I have shown that its loss in bone tropic BCa cell lines results in reduced osteolysis. During outgrowth of bone metastases, bone destruction is driven by changes in bone-forming osteoblasts and bone-degrading osteoclasts, known as the “vicious cycle.” As the metabolic conversion catalyzed by GLS is also essential to osteoblast lineage commitment, a genetically modified mouse model was used to delete Gls in osteoblast progenitors. Surprisingly, loss of GLS function in osteoblast progenitors led to reduced bone destruction and osteoclast numbers. This proposal seeks to identify the mechanisms by which glutamine metabolism in the bone niche influences bone destruction and how they could be exploited therapeutically. I hypothesize that loss of functional GLS in bone- tropic BCa cells induces a senescence-like phenotype that reduces tumor burden and confers sensitivity to senolytic therapy while GLS loss in osteoblast progenitors limits release of osteoclastogenic signals, reducing bone destruction by cutting off the “vicious cycle.” In Specific Aim 1, I will follow up on data from an RNA-seq analysis, which indicated upregulation of Ypel2 (Yippee-like protein 2) in GLS KO cells, a gene that has been linked to cell cycle arrest and senescence in endothelial cells. I will use CRISPR/Cas9 to KO and overexpress Ypel2 in various GLS WT and KO breast cancer cell lines and test for cell cycle activity and detect markers of senescence. I will also test for the presence and levels of osteolytic factors such as PTHrP (in vitro) and RANKL (in vivo). Finally, I will test the effect of genetic deletion and pharmacologic inhibition of GLS (CB-839) on sensitivity of aggressive breast cancer cell lines E0771, 4T1-2, and MDA-MB-231-BoM to senolytic treatment in vitro and in vivo. In Specific Aim 2, to determine the effect of osx-driven GLS KO (GLSOBKO) on osteoblast differentiation and function, I will co-culture osteoblasts from mice with GLSOBKO with bone-tropic BCa cells ex vivo and test for osteoblast differentiation and function, including production of osteoblast-specific proteins (RUNX2, OPN, OCN, etc.). This will allow me to determine the effect of tumor cell signaling on the compromised osteoblast progenitors. To determine the effect of GLS loss in osteoblast progenitors on osteoclastogenesis and osteoclast function in tumor-bearing bones, I will perform RNA-scope analysis and Tartrate-Resistant Acid Phosphatase (TRAP) staining on tissue sections from GLSOBKO mice and wild type controls. Findings from this research have the potential to provide new information about a highly morbid, yet incurable manifestation of metastatic breast cancer and could even raise the possibility of using pre-existing cancer therapies targeting glutamine metabolism to ameliorate bone metastatic burden in breast cancer.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Bacteria-host interactions are emerging as critically important mechanisms for cancer progression but are poorly defined in precancerous colonic dysplasia. Host proteins responsible for maintaining the bacteria-resistant barrier in the colon can also function as regulators of epithelial cell differentiation and growth, such as Deleted in Malignant Brain Tumors 1 (DMBT1). DMBT1 is a secreted glycoprotein highly expressed at epithelial barrier sites in the human gastrointestinal tract. Published data show DMBT1 is upregulated in gastric metaplasia and gastric adenocarcinoma, but the expression and mechanistic role of DMBT1 in colonic precancerous lesions is unknown. Recent research suggests DMBT1 slows epithelial proliferation and may inhibit the development of colorectal cancer (CRC). My preliminary data show the DMBT1 gene is downregulated in distal colonic dysplasia. Our spatial transcriptomics data reveals downregulated DMBT1 expression in dysplastic foci compared with normal colonocytes. In mouse colon tissue, I use immunofluorescence to characterize DMBT1 protein expression. The DMBT1 staining is predominantly in mid-crypt colonocytes with cytoplasmic localization and enhanced staining near the apical border. I further show DMBT1 expression in 3 different mouse models of CRC: azoxymethane/dextran sodium sulfate, C. difficile-associated tumorigenesis in Apcmin, and Lrig1CreER/+;Apcfl/+ mice. In 100% of the dysplastic foci (n = 57 foci from 11 mice), the immunofluorescent staining of DMBT1 protein is reduced in precise correlation with upregulated β-catenin. Analysis of DMBT1 expression in human CRC samples, including tissue microarrays containing early dysplasia, shows DMBT1 protein localization and abundance correlates with disease progression. Specifically, more advanced pathologies correlate with DMBT1 loss or secretion. Based on my preliminary data and published literature, it appears DMBT1 may function as a tumor suppressor specifically acting in early CRC dysplasia. Previous studies show DMBT1 is transcriptionally regulated via canonical innate immune signaling pathways (e.g. NF-κB, STAT3) in infection and inflammatory bowel disease. However, the critical pathways mediating DMBT1 downregulation in colonic dysplasia are unknown. My hypothesis is that reduced DMBT1 expression in colonic dysplasia is transcriptionally regulated and provides a selective advantage for tumorigenesis through hyperproliferation and altered cell polarity. To test this, I will determine the timeline and mechanism of DMBT1 loss using CRC mouse models and biochemical and genetic manipulations of cellular pathways commonly dysregulated in CRC (Aim 1), and I will determine how loss of DMBT1 might be advantageous for tumor development in CRC by establishing DMBT1 knockout (DMBT1 -/- ) cells, human organoids, and a DMBT1 -/- CRC mouse model. Potentially, the loss of DMBT1 staining may aid with clinically distinguishing dysplasia from reactive changes in inflammatory bowel disease and provide a biomarker for early dysplastic transformation in human CRC.

NIH Research Projects · FY 2025 · 2024-07

This proposal requests support for the Medical Scientist Training Program (MSTP) at the Vanderbilt University School of Medicine. The program's primary goal is to identify, recruit, train, and mentor a talented workforce of compassionate and dedicated future physician-scientists. These Vanderbilt-trained physician-scientists will serve critical needs in all aspects of medicine, science, industry, and government to improve human health and improve society through leadership in biomedical research and clinical practice. Our joint MD-PhD program is based on rigorous training in clinical medicine and scientific inquiry. Core program elements explicitly developed for dual-degree students include a foundational biomedical course, a literature-based seminar series, the Clinical Preceptorship Program, Seminar Series, leadership workshops, the Physician- Scientist Speaker Series, extensive near-peer mentoring, a host of student-led institutional and community outreach activities to give back to the community, and an annual retreat to reinforce connections, hear about great science, and learn together. Students receive formal instruction in quantitative reasoning, responsible conduct of research, and rigor and reproducibility threaded and reinforced throughout the curriculum. An innovative advising college program offers opportunities for vertical integration of faculty members and both physician-scientists in residency and MSTP trainees. Current students play key roles in student recruitment and curriculum development. Our alumni are exceptionally accomplished which include the founding president of the Gladstone Institute, three deans, three department chairs, 26 full professors, and 18 industry leaders. More recent graduates still in training are in superb residencies and fellowships. The 109 current trainees come from 74 colleges and universities distributed across North America. The increase in applicants from across the country is due to our dedicated recruitment campaigns, which emphasize attracting students whose personal experiences uniquely qualify them to provide care for others. In the current year, 595 applications have been received, from which 15 students will be selected to enter the incoming class. The educational environment for physician-scientists at Vanderbilt University ranked #12 in NIH funding, is outstanding and built on established strengths in biomedical informatics, cancer biology, cell biology, clinical pharmacology, diabetes, neurosciences, toxicology, drug discovery, genetics, chemical and physical biology, imaging sciences, microbial pathogenesis, pharmacogenomics, and vaccine science. Newer areas of research emphasize immunobiology, inflammation and cancer, precision medicine, quantitative systems biology, and structural biology. Based on the commitment of our leadership team, the strength of our applicant pool, enhanced opportunities for physician-scientist training, a longstanding institutional commitment to the education of MSTP leaders in biomedical research, and the success of our graduates in academic medicine, this proposal requests an increase in positions to 27 for the five-year project period.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Obstacles on mRNAs cause eukaryotic ribosomes to stall. Severely stalled ribosomes collide with the upstream, translating ribosomes and form a complex of two ribosomes, referred to as “disome”, which is detected and removed by the Ribosome Quality Control (RQC) pathway. By establishing Disome-seq technique, which reveals genome-wide distribution of ribosome collisions across the transcriptome, we showed that RQC-targeted disomes frequently form on yeast mRNAs. We also found that collisions in yeast trigger the Integrated Stress Response (ISR), which reduces translation while inducing the expression of survival genes. Similarly, disomes activate ISR in humans to promote survival, but its hyperactivation leads to cell death. This indicates that cellular health is determined by disome homeostasis, which collectively refers to the disome distribution across transcripts, the overall disome abundance and the downstream response evoked by RQC/ISR. The mechanisms by which RQC and ISR detect disomes and affect collision dynamics, however, are poorly understood. The mutations of RQC and ISR components as well as dysregulated ribosome stalling have been linked to neurodevelopmental and neurodegenerative diseases. However, the contribution of disome homeostasis to neuronal differentiation and function is unclear. The objective of this proposal is to determine the mechanisms of disome homeostasis, to examine the role of disome regulation in neurons and to understand how its dysregulation leads to diseases. I hypothesize that regulation of disome homeostasis is important for neurodevelopment and neuronal health, and its dysregulation causes neuronal pathologies. In Aim 1, I will determine the mechanism of disome recognition by RQC and ISR in healthy and stressed cells by using selective Disome-seq and single-molecule fluorescence microscopy. In Aim 2, I will determine the distribution and abundance of disomes, and the role of RQC/ISR factors during the differentiation of induced pluripotent stem cells (iPSCs) into mature neurons by using fluorescence reporters, Disome-seq and neuronal assays. In Aim 3, I will delineate the link between dysregulation of disome homeostasis and neuronal diseases that were proposed to affect ribosome stalling by using Disome-seq, RNA-seq, RQC/ISR reporters and phenotypic experiments in the cells with disease mutations. I will further test the translation inhibitors as potential therapeutics to ameliorate the disease phenotypes. Overall, proposed work will illuminate crucial insights into the regulation of ribosome collisions and their role in neuronal homeostasis.

NIH Research Projects · FY 2025 · 2024-07

The application of quantitative approaches to study biology and medicine is an essential underpinning for the advancement of biomedical research. This proposal requests support for the Molecular Biophysics Training Program (MBTP) at Vanderbilt University, which was founded in 1989. The goal of our program is to train students to work at the interface between quantitative molecular approaches and key problems in biology and medicine within an environment that fosters the success of all students. The MBTP operates in a unique niche compared with typical domain-specific programs, providing both a deeper grounding in the physical sciences for trainees who have a life sciences background, and a more thorough exposure to the life sciences and medicine than is usual for students with a physical sciences, mathematics or engineering background. Although the program draws its training faculty from 9 different departments in the School of Medicine, the College of Arts & Science, and the School of Engineering, it is rooted in an established network of common research and training activities. The number of 83 current students associated with the MBTP is > 2.5 times the number (27) from 15 years ago. Together, our trainees, the 28 Training Faculty, the scientific staff, and our postdoctoral fellows make for a highly collegial and collaborative community of ~150 members. Beyond their individually tailored curriculum, trainees meet along with the entire MBTP community for a minimum of three formal research seminars and one informal gathering each month. The scope of research in the community spans the range of modern molecular biophysics, from understanding the principles of protein folding, to structural characterization of membrane proteins, to defining the action of multi-protein cellular machinery, to investigating the movement of biomolecules into, out of, and within cells. Research projects involve a broad spectrum of physical, biochemical, and computational approaches, including x-ray crystallography, NMR, EPR and fluorescence spectroscopies, small angle scattering, cryo-electron microscopy, cell imaging with a range of light microscopies and molecular/cellular simulations. Most trainees utilize several of these approaches. Trainees join the MBTP in their first year of graduate training after choosing a thesis laboratory and are typically supported for two years. This grant support is requested to cover time needed for additional specialized didactic training, the initiation of thesis research, and professional development for 10 trainees. Importantly, whether T32-funded or not, all trainees (and their preceptors) will remain active in MBTP program activities throughout the duration of their graduate training. Overall, the MBTP enriches each student’s research and training experience and is designed to foster the development of the next generation of independent biomedical scientists.

NIH Research Projects · FY 2026 · 2024-07

The global COVID-19 pandemic caused by the SARS-CoV-2 outbreak underscores the need for understanding viral-host interactions that impact host gene expression and antiviral responses. A critical virulence factor of coronaviruses is the nonstructural protein 1 (Nsp1). We uncovered a previously unknown mechanism of Nsp1- mediated inhibition of host antiviral responses: Nsp1 targets the cellular mRNA nuclear export pathway. Nuclear export of cellular mRNAs through the nuclear pore complex (NPC) is obligatory for eukaryotic gene expression including those genes encoding antiviral factors. By contrast, SARS-CoV-2 mRNA synthesis takes place at viral transcriptional factories in the cytoplasm. We have demonstrated that SARS-CoV-2 Nsp1 protein inhibits host mRNA nuclear export by targeting the cellular NXF1-NXT1 complex, a receptor required for mRNA translocation through the NPC to the cytoplasm. We identified mutations in Nsp1 that specifically reduce its binding to NXF1- NXT1. Importantly, a SARS-CoV-2 recombinant virus carrying a mutant Nsp1 deficient in NXF1-NXT1 binding is unable to inhibit mRNA nuclear export and is attenuated in cells and in mice. Together, our data indicate that Nsp1 is a regulator of host mRNA nuclear export via blocking NXF1 function, overcoming cellular antiviral responses. This proposal combines the synergistic expertise between the principal investigators in biochemistry, cell biology, structural biology, and viral pathogenesis to investigate in depth the molecular mechanisms of SARS-CoV-2 Nsp1 protein function as inhibitor of mRNA nuclear export and its impact on the virus life cycle and on virulence. In Aim 1, we will use biochemical, genetic, and imaging approaches to determine the interactions within the mRNA export machinery that lead to Nsp1 inhibition of mRNA export. In addition, we will use a combination of biophysical and structural biology approaches to determine the molecular basis for the recognition between Nsp1 and NXF1-NXT1. These findings will uncover new mechanisms that mediate or regulate cellular mRNA nuclear export and how they are targeted by SARS-CoV-2. In Aim 2, we will assess the functions of the Nsp1-NXF1 interaction during virus replication and pathogenesis. We will generate loss-of-function recombinant viruses carrying Nsp1 mutants defective in NXF1 binding and investigate the impact of these mutations on host mRNA export, viral replication, induction of host responses in infected cells, and on viral pathogenesis in two animal models, mice and hamsters. Additionally, Nsp1 polymorphisms associated with new variants of concern have been found. We will therefore address the functional significance of these polymorphisms for the Nsp1- NXF1 interaction and for viral pathogenesis. Moreover, we will identify the host mRNAs whose nuclear export are impacted by Nsp1 and determine their role in antiviral response. These extensive studies will likely not only define novel virulence function(s) of SARS-CoV-2 Nsp1, but also shed light on novel antiviral defense mechanisms. Since antagonizing Nsp1 function results in expression of mRNAs encoding antiviral factors, our proposed studies may uncover new strategies for designing antivirals against SARS-CoV-2.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Atherosclerotic cardiovascular disease (CVD) is the leading cause of death globally. Despite conventional lipid- lowering therapies to treat CVD, nearly 50% of patients suffer recurrent cardiac events that is attributed to excessive inflammation. Recent work from our group and others has demonstrated that failed resolution of a chronic inflammatory response is an important driver of inflammation seen in atherosclerotic plaques that result in clinical events. The resolution program is orchestrated by the efficient clearance of apoptotic cells (ACs) and the production of anti-inflammatory agonists known as specialized pro-resolving lipid mediators (SPMs). Notably, continual efferocytosis, which entails the successive uptake of ACs by individual macrophages in settings where cell death is rampant, is necessary to resolve inflammation. Advanced atherosclerotic plaques are characterized by large necrotic cores, caused by inefficient efferocytosis, and an imbalance of pro-inflammatory to pro- resolving mediators compared to early lesions, suggestive of failed resolution. Our primary aim for project is to uncover the endogenous cues that underlie dysregulated inflammation resolution seen in atherosclerosis. Intriguingly, recent publications suggest macrophages can have a memory-like response called “trained innate immunity”. In response to an inflammatory stimulus such as oxidized low density lipoproteins (oxLDL), innate immune cells undergo metabolic and epigenetic reprogramming that primes them to a ‘hyperactive’ state, where they can more rapidly mount an augmented secondary response. Hyper-responsiveness upon activation by a second innate stimuli ultimately boosts bacterial and viral immunity but may be detrimental for chronic diseases like atherosclerosis. Our preliminary data identified Ca2+/Calmodulin-Dependent Protein Kinase IV (CaMK4) as regulator of both resolution and innate immune memory. Our preliminary data suggests that CaMK4 supports the proinflammatory phenotypes seen in innate immune memory in part due to its negative regulation on efferocytosis. Based on these findings, we hypothesize that myeloid CaMK4 is a critical mediator of immune memory and that immune training impairs resolution through a CaMK4-dependent mechanism. Aim 1 will test the hypothesis that trained immunity impairs continual efferocytosis in myeloid cells, promoting atheroprogression. Aim 2 will explore the role of CaMK4 in the development of trained immunity through its negative regulation of important resolution genes.

NIH Research Projects · FY 2025 · 2024-06

Project Summary Basement membranes are strong thin sheets of extracellular matrix, and they are found throughout the human body: under epithelia, surrounding muscles and nerves and organs, and separating tissues. Their structure and function are critical for many aspects of human health, including mechanical support of tissues and muscles, embryonic morphogenesis, filtration of the blood in the kidney, blood-brain barrier function, resisting tumor metastasis, and wound healing. The most prevalent protein in basement membranes is collagen IV, which is crosslinked into a covalently-bound polymer network and gives the basement membrane its mechanical strength. Basement membranes and Collagen IV are highly conserved throughout the animal kingdom. Using Drosophila as a model, we recently found that there appear to be two fractions of collagen IV, a core fraction that appears stable and a mobile fraction that is more dynamic. In this R21 project, we will investigate the significance of these two fractions for the structure and function of basement membranes and begin to unravel the mechanisms governing their different stabilities.

NIH Research Projects · FY 2026 · 2024-06

Modified Project Summary/Abstract Section The peripartum period is a time of dramatic neurobiological change, but these changes are not well understood across time. The peripartum period is also marked with high rates of depression. As such, the proposed research project aims to characterize brain changes prospectively across pregnancy to better understand the implications of neurobiological changes on mental health. Our multidisciplinary team has the necessary expertise (developmental neuroscience, peripartum mental health, imaging science, bioethics, and maternal– fetal medicine) to safely conduct an advanced neuroimaging study with this understudied population. Our team members have worked together to administer repeated magnetic resonance imaging (MRI) scans with multiple scan modalities to examine within- and between-person alterations in brain structure and function during this period of neurobiological change. Data from our preliminary studies scanning pregnant women longitudinally provide the foundation for this innovative project. In 100 pregnant women we will use advanced multimodal MRI (structural, diffusion, and functional MRI) to study brain changes across 9 months of pregnancy using an accelerated longitudinal design with planned missingness so that each participant contributes only 4 scans across their pregnancy. First, we aim to characterize changes in brain structure and function across pregnancy, including the magnitude and pattern of change in various brain volume metrics, white matter microstructure, and functional connectivity (Aim 1). Preliminary data suggests a .41% decrease in total brain volume per week during pregnancy, as well as decreases in cortical volume, gray matter, and cortical thickness. Second, we aim to investigate hormonal changes (cortisol, estradiol, progesterone, and testosterone) underlying alterations in brain structure and function (Aim 2). Our preliminary data suggest that increases in progesterone level partially explain reductions in gray matter volume, while surges in progesterone and estradiol levels may be linked to increased white matter microstructure. Third, we aim to examine the potential functional consequences of brain changes (Aim 3). To explore the potential functional consequences of changes in brain structure and function, we will collect EEG data in response to reward and threat, assess self-reported negative affect, and evaluate cognitive function using the NIH toolbox. Participants will also report on peripartum depressive symptoms at each assessment wave and again at 8 weeks postpartum. The project's innovative planned missingness design will provide unprecedented insights into the neurobiological changes that occur across the full course of pregnancy without overburdening participants. By filling the knowledge gap regarding brain changes during pregnancy, the findings will set the foundation for translational work given the impact peripartum depression has on individuals and their families.

NSF Awards · FY 2024 · 2024-06

This study will assess how the design of transitional justice institutions in countries affected by conflict and/or authoritarianism affects public opinion, thereby shaping long-run national outcomes including regime type and conflict recurrence. Existing literature on the effects of transitional justice is inconclusive; such work is divided between micro-level, single-country studies and macro-level, cross-country studies as well as between studies of post-authoritarian and post-conflict contexts. By collecting comparable survey measures across countries that vary along several theoretically relevant dimensions and by building a cross-national dataset, this project will bridge these gaps. Further, the researchers will develop and test a novel theory about how public attitudes mediate the relationship between transitional justice institutions and long-run outcomes. Given the widespread use of transitional justice in post-conflict and post-authoritarian countries as well as democracies around the world, there is an urgent need for the field of transitional justice studies to develop a stronger base of evidence for policymaking. This project will shed light on which forms of transitional justice effectively promote peace, democracy, justice, and reconciliation as well as provide insights into how countries’ unique histories may shape the impact of transitional justice there. This project will investigate three questions. First, which kinds of transitional justice do people see as more legitimate? Second, how do people’s perceptions of the legitimacy of transitional justice institutions affect their broader political attitudes concerning the government, principles of democracy and autocracy, and out-groups? Third, do transitional justice institutions perceived as more legitimate contribute to stability following conflict? To address these questions, the research team will draw on their extensive thematic, regional, and methodological expertise to employ a mixed-methods research design which combines survey experiments, qualitative evidence collected from focus groups and elite interviews, and original cross-national data. This approach will leverage the strengths of diverse methodologies by combining (A) micro-level survey and qualitative data that will enable the investigators to assess the effects of varying transitional justice processes on individual attitudes with (B) macro-level cross-national data that will provide insight into the effects of institutions and historical context on national-level outcomes. 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 Awards · FY 2024 · 2024-06

The broader impact of this I-Corps project is the development of a highly selective electrochemical separation technology that provides users with the ability to reduce the cost and environmental footprint of metal recovery processes. Such a technology can be used in numerous natural resource extraction processes. The ability of mining operators to reduce the freshwater consumption and eliminate the consumption of toxic chemicals could expand the production of metals critical to the energy transition. In the production of lithium from hypersaline aquifers, lithium producers could utilize such a technology to improve the purity of lithium products and reduce the environmental footprint. Additionally, this highly selective separation technology could allow lithium companies to economically extract lithium from domestic resources in the United States. This I-Corps project thus has the potential to reduce dependence on fragile and complex supply chains. The increased supply of lithium and other critical metal products would enable battery manufacturers to advance the performance of their products, decreasing the costs, and increase the adoption of electric vehicles and battery-based energy storage systems. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on the development of a highly selective, low-freshwater consuming, and renewable electricity-powered electrochemical separation technology that leverages a novel electrical-switch system to operate continuously. This electrochemical separation technology has demonstrated exceptional selectivity for removing monovalent cations from complex ionic solutions while minimizing energy consumption. Further research is being conducted to investigate membrane and electrode material combinations to improve lithium selectivity, increase cycling stability, and further minimize energy consumption. Novel electrode and membrane materials are also being investigated to explore the efficacy of this novel platform for extracting other critical metals from aqueous solutions including other alkali, alkaline, or transition metals from natural resources. This project has commercial potential in the recovery of critical metals from natural resources and aqueous waste streams. 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.

NIH Research Projects · FY 2024 · 2024-06

PROJECT SUMMARY Sensory and motor dysfunctions are potential biomarkers of preclinical Alzheimer’s disease (AD) as they may precede cognitive impairments. However, how the sensory and motor dysfunctions affect the brain functional connectivity (FC) between white matter (WM) and gray matter (GM) remains uninvestigated. This is because previous functional MRI analyses have overlooked WM due to weaker signal in WM. We recently demonstrated that FC between WM and GM (i.e., WM-GM FC) is reliably detectable and sensitive to AD, confirming its potential in capturing brain function and its changes. However, three major methodological obstacles hinder accurate evaluations and analyses of WM-GM FC at multiple scales. First, the unique topology of WM-GM FC network cannot be adequately modeled by a conventional graph model. Second, the most advanced WM spatial smoothing method, which requires diffusion MRI data for guidance, is complex and impractical for standalone fMRI data. Third, the elongated shape of WM functional architecture compromises traditional group-level voxel- scale statistical analysis. Therefore, our overall goal is to develop and apply a novel family of methods to investigate multi-scale alterations in the WM-GM functional connectome resulting from sensory and motor dysfunctions in preclinical AD. This goal will be achieved through two aims. Aim 1 is to develop innovative methods to characterize, detect and analyze WM-GM FC at multiple scales, including network-, region- and voxel- scales. Specifically, we will develop a bipartite-graph model to characterize WM-GM FC networks and quantify network properties, create a 4D atlas composed of diffusion-informed smoothing kernels for all WM voxels to simplify WM smoothing for any fMRI images, and develop a functional tract-based spatial statistics (fTBSS) method to optimize group-level voxel-scale analysis. Aim 2 is to apply the developed methods to investigate changes in WM-GM FC at multiple scales resulting from motor dysfunctions in preclinical AD. Exploiting our developed methods and existing databases, we will test three hypotheses. 1) specific WM- GM FC network metrics, especially within the somatomotor-related networks, may alter in preclinical AD subjects with MD relative to elderly controls and more altered WM-GM FC metrics may be associated with more severe MD; 2) the relationship between MD and WM-GM FC metrics may be moderated by other biological factors (e.g., sex, APOE ε4 status and brain atrophy). 3) the WM-GM FC metrics may act as mediators in the relationship between amyloid deposit and MD. The outcomes of this project will fill the gaps in our knowledge of how sensory and motor dysfunctions influence WM-GM functional connectome in preclinical AD and enrich the set of biomarkers for prediction of early AD, which will eventually enhance the well-being of both the aging population and their caregivers. The released code and atlases will benefit a broad community of investigators interested in the functional connectome.

NIH Research Projects · FY 2026 · 2024-06

Project Summary 1) Background, key gaps in our understanding, and important challenges to be addressed. This project aims to address crucial gaps in our understanding of nucleotide biosynthesis and its impact on cell fate determination. While conventional research has predominantly focused on nucleotide biosynthesis in relation to proliferation, recent findings from our laboratory have unveiled its unexpected role in triggering cell fate shifts. Specifically, we have observed that inhibition of nucleotide biosynthesis drives multipotent progenitor cells to transition from adipogenesis to smooth muscle cell differentiation. Our primary objective is to decipher the underlying mechanism governing how nucleotides regulate diverse cell fate outcomes both in controlled in vitro environments and complex in vivo systems. 2) Description of recent progress by the PI. During my post- doctoral work, I systematically elucidated the initial metabolic alterations linked to adipogenesis, leveraging advanced metabolomics and metabolic flux analyses. Notably, my investigations unveiled that the reprogramming of mitochondrial branched-chain amino acid (BCAA) catabolism serves as an early trigger that precedes and facilitates the transcriptional modulation of PPARg, thereby initiating adipogenesis (Zaganjor et al., 2020). These studies have provided a conceptual advance that metabolism can be targeted to reprogram cell fate. Furthermore, in a recent breakthrough, my research team at Vanderbilt demonstrated that inhibiting nucleotide biosynthesis profoundly reshapes cell fate trajectories (Shinde and Nunn et al., 2023), with a consequential impact on the mitochondrial transcriptome. The subsequent functional assays underscored that this inhibition prompts a shift in mitochondrial fuel preference from glucose to fatty acid oxidation. This intriguing observation prompted us to postulate that nucleotide biosynthesis orchestrates cellular outcomes by modulating mitochondrial metabolism. 3) Overview of future research program. Our future studies will critically assess whether fuel switching, and nucleotide biosynthesis alter gene regulatory networks to shape cellular outcomes. We will employ an innovative and ambitious interdisciplinary research program combining biochemistry, genetics, cell biology and multi-OMICS approaches to answer fundamental questions such as: What is the mechanism by which inhibition of nucleotide biosynthesis promotes smooth muscle cell differentiation? Does blocking nucleotide biosynthesis promote angiogenesis in vivo? We plan to combine our conceptual expertise in metabolism with the state-of-the-art technology to achieve our five-year vision and generate tools and a “working blueprint” by which we can fine-tune metabolic pathways to modulate cell differentiation.

NSF Awards · FY 2024 · 2024-06

This project explores a proof-of-concept and feasibility evaluation to inform the future development of a centralized data repository to support the privacy research community. The repository will enable tracking and systematic study of privacy harms. Current incident reporting systems are designed to track the occurrence of large-scale data breaches, but there is currently no centralized reporting system to effectively track other types of privacy violations (e.g., online harassment, cyber abuse) that negatively impact end-users. Without access to this information, it is difficult to quantify / qualify how and to what extent different online platforms propagate privacy breaches, as well as how to redesign such systems to be more secure and trustworthy. Therefore, this planning effort aims to (1) solicit the opinions of privacy experts on the design of the repository; (2) prototype the repository and solicit feedback from experts piloting it; and (3) build on these learnings to develop a plan to develop a centralized privacy incident repository. This will ultimately enable researchers to work together to (1) identify and prioritize privacy harms and the factors associated with the incidents; (2) understand how various populations are impacted by these harms; and (3) develop and evaluate potential interventions. This repository is envisioned to support the protection of vulnerable end-users who are disproportionately threatened and harmed by digital privacy violations, addressing the recent R&D budget priority from the White House and the Office of Science and Technology Policy focused on reducing inequities. By identifying evolving privacy risks, we also work towards two other budget priorities -- advancing trustworthy AI technology and maintaining global security and stability. 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 Awards · FY 2024 · 2024-06

This project provides support for 25 United States' (U.S.)-based graduate students to participate in the 29th ACM SIGKDD Conference on Knowledge Discovery and Data Mining (KDD 2024), to be held in Barcelona, Spain, during August 25-29, 2024. KDD is one of the premier conferences in data mining, data science, and knowledge discovery in the world. It is a prestigious interdisciplinary conference that brings together researchers and practitioners every year. KDD covers topics in the data mining lifecycle (including algorithms, software, systems, and applications), as well as artificial intelligence, machine learning, data management, and information retrieval. Students participating in the conference are exposed to the latest research developments and can attend hands-on workshops, tutorials, eye-opening keynotes, and presentations. A strong representation of U.S. students and researchers is essential in maintaining U.S. competitiveness in these important areas today and into the future. As in various STEM fields, increasing the diversity of participants in KDD research areas is an important goal. This project provides support for 25 U.S.-based graduate students to participate in the 29th ACM SIGKDD Data Mining workshop. The selection committee will select recipients of the support based on merit and need while striving for diversity in the selection process. As an interdisciplinary conference, KDD attracts researchers and practitioners from academia, industry, and governments who work on all aspects of data mining and data science problems. It includes a highly competitive technical program, with regular peer-reviewed papers in the form of oral and poster presentations, as well as panel discussions and invited talks by leading experts in academia and industry. The conference places special emphasis on supporting students through training and mentoring by offering both undergraduate and doctoral student consortiums. These will provide a comprehensive multi-facet learning experience for students at all levels. This grant aims to help U.S.-based students overcome financial barriers that may prevent them from attending the conference. The award will be advertised on different sites and social media platforms, and the results will be announced on the KDD 2024 website (https://www.kdd.org). 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 Awards · FY 2024 · 2024-06

While there has been extensive research on the barriers Black and brown students face as they strive to participate in engineering education and the workforce, there is less scholarship on solutions for addressing this complex challenge. One reason for this is because the scholarship on how change happens in engineering education tends to focus on course content and classroom instruction. Unfortunately, such findings do not easily lend themselves to value-laden, systemic issues like diversity, equity, and inclusion (DEI). Fortunately, some Colleges of Engineering (COEs) throughout the U.S. have adopted change strategies that have resulted in consistently being named among the top-ten producers of Black and brown engineers. This project is motivated by a desire to learn from and follow their example. This CAREER project will disrupt the status quo regarding who gets to be an engineer by investigating five COEs that have significantly changed the face of engineering over the last 20 years. This project will: (1) Advance our understanding of the change strategies that exemplary COEs have used to improve Black and brown students’ access to engineering education and careers; (2) Identify evidence-based models for broadening participation of underrepresented racial/ethnic groups in engineering; and (3) Set COEs on a path to parity, such that the student body demographics in COEs across the country reflect the racial/ethnic makeup of the nation. Using Kotter’s Leading Change Model and Acker’s Inequality Regimes as a framework, this multi-case study will investigate how exemplary COEs envisioned, implemented, and institutionalized changes that influenced Black and brown students’ access to engineering. The five COEs that will be investigated are: Florida International University, Morgan State University, University of Central Florida, University of Maryland-Baltimore County, and University of Maryland-College Park. Given variations in the types of universities included in the research design, comparing and contrasting insights that emerge from each case will enable the PI to understand the conditions for change. The use of a research study design that relies on both qualitative and quantitative data will produce complementary forms of evidence on what promotes and impedes progress in this context. The research outcomes will include: (1) impact narratives that document concrete examples of how to expand who gets to be an engineer; and (2) a model for broadening participation informed by a cross-case analysis of these exemplars. Furthermore, this timely work focuses on the need to leverage talent from every demographic to diversify the engineering workforce and improve the lived experiences of minoritized groups. The educational outcomes will include: an Impact Playbook that translates the research into actionable strategies; a graduate course for future engineering faculty designed around each of the cases; a townhall discussion among associate professors; sharing insights with ASEE’s Engineering Deans Council; and a partnership with Virginia Tech’s (VT) College of Engineering and College of Science to build capacity among its leaders to envision and enact sustainable changes that promote DEI on VT’s campus. This CAREER project has the potential to reshape how COEs approach their DEI efforts, and increase the likelihood of long-term success. The proposed activities are designed to foster a network of STEM leaders motivated to envision and enact sustainable, scalable changes that expand who gets to be an engineer at their institution. 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.