Vanderbilt University

NIH Research Projects · FY 2025 · 2025-01

Project Abstract Enrollment in Medicare Advantage (MA), the privatized segment of the Medicare program, has rapidly increased with roughly 50% of Medicare beneficiaries enrolling in an MA plan. Under the MA program, private plans are paid risk-adjusted capitated payments to deliver the Medicare benefit. These plans have discretion to implement utilization management tools and narrow provider networks to control costs. Beneficiaries enrolled in MA receive benefits not available in traditional Medicare (TM) including out-of-pocket maximums and supplemental benefits (e.g., vision and dental coverage). However, enrollees must remain in their plan’s network to avoid higher out-of-pocket costs. These restrictions could pose barriers to accessing care for beneficiaries who have serious illnesses. As the MA program continues to grow in popularity, a more medically complex population of beneficiaries is opting to participate in the program. The overall objective of this grant is to investigate aspects of the MA program that likely pose problems for beneficiaries with serious illness: plan networks for skilled nursing facilities (SNFs) and oncology care networks. Aim 1 describes the breadth and quality of SNFs using novel 2022 data on MA plan networks from Ideon (formerly Vericred). We hypothesize that plans will limit access to high quality SNFs and include low or average quality SNFs in network. Aim 2 uses 2019-2020 Surveillance, Epidemiology, and End Results (SEER)- Medicare data linked to Ideon data to examine the association between breadth of oncology networks and disenrollment from MA to TM or switching to a new MA plan for patients newly diagnosed with cancer. We hypothesize that being in a plan with limited access to specialized cancer centers will be associated with an increased probability of leaving one’s MA plan for TM or a new plan. Aim 3 uses a difference-in-differences study design to estimate the effect of the lengthening of the Medicare Advantage Open Enrollment period on rates of MA plan switching or exits to TM for patients newly diagnosed with cancer. We use 2016-2019 SEER- Medicare data and hypothesize that the longer enrollment periods will lead to increased rates of plan disenrollment for patients newly diagnosed with cancer. All together the results from these aims will provide added evidence on how networks contribute to poor patient experience in MA, particularly for beneficiaries with serious illnesses. We aim to contribute evidence on how restricting access to care and limiting plan enrollment choices impacts patients with serious illnesses like cancer.

NIH Research Projects · FY 2025 · 2025-01

Project Summary Building a diverse biomedical research workforce is integral to fostering scientific excellence, promoting research innovation, enhancing learning environments, reducing health disparities, meeting the needs of underserved populations, and garnering public trust in science. We propose a robust career development and mentoring program, V-ARC, to provide ARC Scholars with resources and support to successfully navigate their graduate and postdoctoral training and transition to their desired research careers, ensuring they are retained in the biomedical workforce. The V-ARC program will offer ARC Scholars stage-specific virtual professional development courses, high quality career mentoring and networking opportunities, cohort building with other ARC Scholars, and participation in in-person activities that expose them to additional skill building and a deeper understanding of the career paths they choose to pursue. In addition to enhancing the training experience of ARC-Scholars, we will take an active role in ensuring that the ARC Scholar’s research mentors are informed in principles of mentoring so they are well-prepared to support these diverse scientists. Research mentors will be offered annual mentorship skills development training, participate in a journal club focused on key literature on effective mentorship, and have opportunities to discuss ways to incorporate evidence-based strategies into their own mentoring practices. Similarly, career mentors will be offered additional support and resources to augment their mentorship skills through participation in annual mentor training and the journal club with research mentors as well as tapping into existing programming on mentoring best practices. We have carefully designed the program to leverage the expertise of the V-ARC Advisory Committee, career mentors, and the Scholar’s research mentors by including multiple touch points throughout the proposed activities. They will provide feedback on Scholar’s work outputs, serve as panelists, attend in-person events as invited guests, host Scholars at their workplaces, lead journal clubs and advise V-ARC leadership on programming. We believe strongly in the importance of fostering cultural awareness and promoting cultural responsiveness in mentorship and anticipate that access to training in these areas will benefit research and career mentors as well as their mentees for years to come. Furthermore, we are confident that participating Scholars will receive lasting benefits from the skills development and professional network they will build during their time in the V-ARC Program and that this experience will equip them with the resources necessary to make significant contributions to the biomedical research enterprise.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Impairment in visual attention and working memory is common across mental illnesses and neurological conditions. Cholinergic drugs (acetylcholine agonists and acetylcholinesterase inhibitors) can ameliorate these symptoms, though their effectiveness is limited. An alternative way of improving cholinergic function is to stimulate the endogenous source of acetylcholine in the cerebral cortex, the Nucleus Basalis of Meynert. Recent results have shown the effectiveness of the approach in improving performance in working memory and attention tasks. However, the neuronal mechanisms of action in cortical areas involved in these processes are not yet understood. This project will investigate the effects of Nucleus Basalis stimulation on the activity of neurons in the dorsolateral prefrontal and posterior parietal cortex, as monkeys are performing visual working memory tasks. Neurophysiological recordings will be performed before, during, and after Nucleus Basalis stimulation. Our overarching hypothesis is that Nucleus Basalis stimulation broadens the tuning of prefrontal cortical neurons, which results in better stability of working memory representations, at the expense of accuracy for some conditions. We hypothesize that this effect generalizes to the posterior parietal cortex, as well. We will also determine the effects of stimulation on other aspects of neuronal firing and whether alternate mechanisms can account for behavioral effects of stimulation. Both acute effects of stimulation, in daily sessions, and sustained effects over a period of months, will be assessed. Systemic administration of cholinergic agents will also be performed and its effects on neural activity will be compared with those of Nucleus Basalis stimulation. The experiments will allow us to understand the effects of cholinergic transmission associated with performance of visual cognitive tasks. They will also evaluate the relative effectiveness of drug administration compared to deep brain stimulation. Our research will also provide a primate model for the evaluation of an intervention that can potentially improve cognitive function across a range of mental illnesses and neurological conditions.

NIH Research Projects · FY 2026 · 2025-01

Project Summary The goal of this project is to study the cellular and circuit bases of motor control for active sensation. Accurate and context-specific movements of sensors is critical for acquiring sensory information during behavior. This requires coordination of ongoing sensory information and motor output, often across different levels of processing in the brain. However, these circuits can be complicated and difficult to access at the molecular and cellular level. Studying their function in either normal or disease states is thereby a major challenge. Fruit flies (Drosophila melanogaster) actively tune mechanosensory input using movements of their two antennae, and our recent work has expanded genetic access to the sensory and motor circuits in this small circuit model system. With a broad suite of genetic, physiological, and neural connectivity tools to study neural circuits in Drosophila, our project seeks to reveal mechanisms of motor control for sensation at the cellular and circuit levels. First, we will establish the role of a newly discovered set of antennal premotor neurons in controlling specific antennal movements during behavior. We will use a combination of optogenetics and in vivo electrophysiology in tethered, flying flies to determine how cellular activity in these neurons coordinates movement. Using supervised machine learning tools to analyze antennal video data recorded simultaneously with neural recordings, we will quantify the activity of individual genetically identified neurons in response to external deflections of the antennae and to self-generated motions during flight. Next, we will directly measure how actively controlled antennal movements alter sensitivity of an antennal mechanosensory neuron class, using a combination of in vivo electrophysiology and mechanical manipulations of active antennal movements. Finally, we will identify and characterize new descending neurons that project to antennal motor neurons in the central brain before synapsing onto motor output regions controlling wing and leg movements. We will use stochastic optogenetic activation with quantitative behavior analysis to map their role in producing distinct antennal motions, then evaluate the functional connectivity of these neurons with antennal motor neurons using optogenetic activation and intracellular recordings in intact, behaving animals. Together, this work will elucidate cellular strategies for coordinated tuning of sensation during behavior.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT This project takes a unique dynamic view of signaling by receptor tyrosine kinases (RTKs), testing the hypothesis that signaling specificity is kinetically defined, and that modulating dynamics might underlie a new therapeutic approach. Advancing with these questions will require new microscopy-based approaches in living cells – exploiting techniques that I have focused on throughout my career and taking advantage of the Lemmon lab’s biochemical expertise. Despite decades of study, and their importance as therapeutic targets, RTKs remain poorly understood mechanistically. Most RTKs dimerize upon ligand binding, and this is still believed to be the key step in their activation. The prevailing simple ‘on/off’ view is inconsistent, however, with the fact that RTKs can respond differentially to their multiple distinct activating ligands – displaying biased agonism or functional selectivity. Recent work in the Lemmon lab suggests that this selectivity is kinetically defined, with the life-time of the RTK’s activated state differing from ligand to ligand and defining the nature of the signaling outcome. Testing this new hypothesis requires single-molecule analysis of receptor activation kinetics in relevant cellular contexts. To date, kinetic arguments have only been inferred from structural and indirect signaling studies. My proposal focuses on directly observing the kinetics of RTK signaling in living cells. In particular, I will study the lifetime of different activated dimeric RTK states – and the resulting signaling kinetics – for the epidermal growth factor receptor (EGFR) when bound to its 7 different activating ligands. These studies will exploit advanced single-molecule fluorescence microscopy techniques in living cells that I have been developing, and will also correlate the results with structural and signaling work. My career goal is to obtain a research faculty position at a leading institute where I will continue to dissect the mechanisms of RTK dimerization and signaling. My successful transition to independence in this field would be significantly bolstered by augmenting my microscopy expertise with other biophysical and structural techniques in both in vitro and in vivo systems. It is with these acquired skills that I will be able to investigate how receptor dimerization dynamics define signaling specificity, and how they might be modulated pharmacologically. The success of this project will be greatly enhanced by the outstanding collaborators that I have assembled to advise me throughout my transition to independence. In addition, the exceptional research environment at the Cancer Biology Institute and the Yale Medical school area has all the necessary resources required for the proposed training and research studies. The K99/R00 would provide me with the protected time needed for this advanced training and allow me to continue to foster my growth under the mentorship of Dr. Mark Lemmon. I expect that the time provided by this award will allow me to elucidate the relationship between receptor dimerization dynamics and signal specificity, and will illuminate new avenues for pharmacological intervention.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT The proficiency of immune cells to react to environmental stimuli and mount specific responses are, in part, due to robust gene expression profiles that involve coordinated regulation. Monocytes are unique amongst immune cells in that they can also differentiate into osteoclasts (OCs) following exposure to the cytokine Receptor Activator of Nuclear factor KappaB-Ligand (RANKL). Once thought to be important only for the bone- resorbing function of OCs, RANKL is now known to regulate diverse facets of mammalian physiology outside of the skeleton, including processes such as secondary lymphoid organ development, intestinal homeostasis, and immune cell crosstalk, all of which are critical for host defenses against bacterial pathogens. Therefore, as monocyte lineage cells in many different tissues experience RANKL signaling and undergo profound transcriptional and epigenetic remodeling, RANKL has the potential to shape the outcome of infectious diseases. The broad goal of this proposal is to define how RANKL alters monocyte responses to bacterial pathogens. One model bacterial pathogen that replicates within monocytes during systemic dissemination is Salmonella enterica serovar Typhimurium (STm). In preliminary studies, we found that RANKL-treated monocytes harbor significantly higher numbers of intracellular STm. Moreover, these cells have decreased pro- inflammatory IL-1β production. Based on our preliminary findings and literature from the osteoimmunology field, the central hypothesis of this proposal is that RANKL signaling silences key monocyte effector genes to render cells more susceptible to intracellular infection. Therefore, we also predict that RANKL blockade will modify the outcome of infection in vivo. To test the hypothesis, Aim 1 will define how RANKL diminishes monocyte inflammatory responses to STm by elucidating the effects of RANKL signaling on monocyte IL-1β regulation and cell polarization. Aim 2 will explore how RANKL signaling increases STm replication in monocytes by examining STm virulence in the context of host intracellular cues including iron availability and phagolysosome formation. Aim 2 will also test how the RANKL signaling axis impacts STm disease in vivo using an FDA-approved RANKL- blocking antibody. Collectively, the Aims will define how RANKL-mediated cellular reprogramming alters the antibacterial and inflammatory properties of monocytes and modifies immune responses to STm. The proposed project will be completed in the Cassat laboratory at Vanderbilt University, a world-leading institution in biomedical research with a robust Medical Scientist Training Program (MSTP). The fellowship synergizes with the applicant’s goal to conduct independent research at the interface of innate immunity and cell biology. The training plan was designed to provide the applicant with foundational knowledge in host-pathogen interactions and immunology while integrating clinical programming throughout, equipping them with translatable expertise to conduct rigorous research focused on infection and immunity.

NSF Awards · FY 2025 · 2025-01

This Major Research Instrumentation award supports the Vanderbilt Institute of Nanoscale Science and Engineering (VINSE) with the acquisition of a state of the art 50-kV Elionix ELS-BODEN electron beam lithography (EBL) tool that will be housed within the cleanroom, a shared-use facility. This facility also serves universities such as Fisk University (HBCU), Tennessee State University (HBCU), Belmont University, Middle Tennessee State University, University of Tennessee Space Institute, and Austin Peay State University, Auburn University, and University of Alabama – Huntsville, along with industrial partners, making this a regional resource for the southeast United States. The instrumentation will enable high-speed, ultra-high-precision nanoscale lithography over large areas enabling extended structures of critical interest within a tool that is highly automated for both alignment and preparation, ideal for the broad VINSE userbase and for streamlined training, and easy integration into course work and outreach efforts. The usage by students, postdocs, and faculty at other local universities, especially the HBCUs coupled with the on-going Bridge program, where master’s students from Fisk University may transition into graduate programs at Vanderbilt directly, has significant broader impacts upon the inclusion of underrepresented minority groups within STEM fields. In addition, this EBL tool will become a centerpiece of the robust education and outreach activities within VINSE, while also serving to attract diverse faculty, postdocs, and students, aided by the Chancellor’s Destination Vanderbilt Initiative. The tool will also offer undergraduate and graduate students hands-on experience in nanofabrication, providing the necessary training for the future semiconductor, integrated photonics, nanophotonics, and quantum science workforce. The acquisition of a state of the art 50-kV Elionix ELS-BODEN electron beam lithography (EBL) instrument will enable a broad variety of research that is not currently possible at Vanderbilt, such as the realization of large-area meta-optics for low-power image processing at the speed of light, optical nanotweezers capable of single exosome trapping and analysis for early cancer detection and for energy applications, fabrication of silicon photonic waveguides and on-chip photonic devices, as well as fundamental studies into the dissipation of heat using light. The intellectual merit is therefore found in the knowledge gained from these improved research outcomes and the new collaborations that are to be developed between nanoscience researchers at Vanderbilt, local HBCUs and in the region. 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 2026 · 2025-01

PROJECT SUMMARY The 2nd meal phenomenon describes the substantial improvement in glucose tolerance that occurs during a subsequent identical meal (e.g. improved glycemic response at lunch vs. breakfast). We have shown that 1) hyperinsulinemia is the essential factor during the 1st meal, and 2) the enhanced glycemic response during the 2nd meal is due to increased hepatic glucose uptake and glycogen storage. This proposal seeks to elucidate the mechanisms by which morning (AM) hyperinsulinemia enhances the liver’s subsequent response. These studies will be executed using complex metabolic clamping experiments performed in the multi-catheterized conscious dog model. Aim 1 will determine the impact of the AM insulin route of delivery (i.e. we will compare the effect of portal vein insulin infusion, as occurs with endogenous insulin secretion, vs. peripheral insulin delivery, as typically occurs with therapeutic treatment for individuals with insulin-dependent diabetes). Secretion of insulin into the portal vein results in exposure of the liver to 3-times more insulin than the rest of the body. Intravenous (peripheral) insulin infusion eliminates that gradient, exposing the liver to relative insulin deficiency. We hypothesize that AM hyperinsulinemia generated by peripheral (vs portal vein) insulin delivery will severely impair the liver’s amplified afternoon (PM) meal response. This is highly relevant to the treatment of patients with insulin- dependent diabetes since most of the currently available insulin therapies involve delivery by the peripheral route (e.g. subcutaneous insulin injection). Previous work has shown that 3 factors are primarily responsible for regulating hepatic glucose uptake: 1) insulin action, 2) the effect of glucose itself (glucose effectiveness), and 3) the portal glucose signal of neural origin, generated when glucose concentrations are greater in the portal vein compared to the hepatic artery, such as occurs when glucose is absorbed from the gut during a meal. Aim 2 will investigate which of these factors are contributing to the enhancement of hepatic glucose metabolism during the 2nd meal phenomenon. We hypothesize that AM hyperinsulinemia primes the liver for greater PM glucose uptake and storage via an enhancement of insulin action in the afternoon. The proposed studies are significant because they will provide a more thorough understanding of the impact of AM feeding on hepatic glucose metabolism during the remainder of the day, leading to new ways to improve glycemic management in individuals with impaired glucose tolerance and diabetes. The training plan will be carried out with the support of the excellent resources that the Cherrington lab and Vanderbilt University have to offer. The Cherrington lab has over 50 years of experience with the techniques outlined in this proposal. Paired with the career development opportunities that The Biomedical Research Education and Training office provides for biomedical research graduate students and the longstanding history of excellent physiology and diabetes research conducted in the Department of Molecular Physiology and Biophysics, Ms. Waterman is placed in the ideal environment to successfully obtain the necessary expert training and skill acquisition to shape her into an independent researcher.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Neurodevelopmental events occurring after axons innervate their targets can be categorized as either progressive (e.g., cell survival, axon stabilization, promotion of synapse formation) or regressive (e.g., cell death, axon degeneration, synapse restriction). While the molecular and cellular basis of long-distance progressive signaling is relatively well-characterized, the understanding of long-distance regressive signaling remains limited. Many target-derived regressive cues, such as trophic factor deprivation (TFD), repulsive axon guidance cues, neurotrophin and pro-neurotrophin binding, converge on the p75 neurotrophin receptor (p75NTR). Studying this single receptor offers an opportunity to explore the molecular basis of various long-distance regressive signaling events. This research holds significance for understanding neurodevelopmental disorders such as autism and schizophrenia, as well as a wide range of neurodegenerative conditions, including ALS, Huntington's, Parkinson's, and Alzheimer's disease. The mechanism regulating the transmission of target-derived regressive cues back to the cell body is an emerging area of study. Currently, there is a significant gap in our knowledge regarding how p75NTR transitions from the plasma membrane to endosomal signaling and from the axon to the cell soma. The general concept motivating this application is that p75NTR must be internalized, cleaved, and palmitoylated to traffic and convey long-distance degenerative signals. However, it is unclear whether all regressive ligands and trophic factor deprivation relying on p75NTR require each of these events or how progressive signals interfere with these processes. The rationale for this proposal is based on our preliminary findings that: 1) p75NTR is cleaved and becomes endosomally associated after distal axon treatment with a regressive cue, and 2) palmitoylation of p75NTR is required for endosomal localization and retrograde death signaling. The exact regulatory mechanism behind this remains an open question. In Aim 1, we will characterize the features of p75NTR long-distance regressive signaling during apoptosis, axon degeneration and synapse restriction, as well as investigate how crosstalk from NGF-TrkA progressive signaling influences these processes. In Aim 2, we will examine the role of p75NTR palmitoylation in regressive signaling and assess the physiological effects of palmitoylation on regressive developmental events in vivo. Our overarching goal is to unravel the role of long-distance regressive signaling in nervous system development and its regulation.

NIH Research Projects · FY 2024 · 2025-01

Our group seeks to identify new molecular structures formed by unusual enzymatic transformations. We focus on the ribosomally synthesized and post-translationally modified peptides (RiPPs), of which nearly 50 distinct structural classes exist. Decades of research show that while RiPPs harbor diverse structures and functions, the biosynthetic routes share a blueprint. Typical RiPP precursor peptides contain fewer than 60 amino acids. The modification enzymes engage the N-terminal portion, while the C-terminal region receives all post-trans- lational modifications (PTMs). Genome mining for RiPP biosynthetic gene clusters (BGCs) had been ex- tremely time-consuming and often unsuccessful owing to the difficulty of locating the requisite substrate pep- tide(s). The short length and hypervariability of RiPP precursor peptides frequently preclude their detection by automated gene finders. RODEO, an AI-based genome mining tool, has largely solved this problem for a subset of RiPP classes. The current proposal unites RODEO-enabled genomics analysis, enzyme chemistry, structural biology, and microbial physiology to characterize several “RiPP-like” BGCs that do not conform to the current definition of a RiPP natural product. With the breadth and depth of RiPP genomics coming into sharper focus, it has become increasingly clear that many “RiPP-like” BGCs lack a canonical precursor peptide. Rare PTMs such as backbone thioamidation and thioether crosslinks between cysteine and the side chains of other amino acids are known on larger protein substrates, such as methyl-coenzyme M reductase, ribosomal protein uL16, and quinohemoprotein amine dehydrogenase. These examples establish limited but critical precedent, and we herein predict that many more “RiPP-like PTMs” occur on protein substrates. Comparative analysis in prokaryotes supports this prediction, as a substantial level of sequence and genome neighborhood similarity exists between pathways encoding a canonical precursor peptide versus a larger protein substrate. This renewal project tackles several questions of outstanding interest regarding the interplay and utility of RiPP-like PTMs on non-canonical substrates. The specific aims are independently achievable and robustly combine in silico, in vitro, and in vivo methods. In one aspect, we will elucidate the biochemical function of ribosome thioamidation and the extent to which this PTM is propagated among other prokaryotes. Additional thioamidated proteins and their physiological roles will be discovered during this project. Further, we will pur- sue biosynthetic pathways predicted to produce poly-thioether-stabilized protein nanotubes and poly-isopep- tide-containing branched copolymers. The enzymes performing this usual PTM chemistry will be thoroughly evaluated, and the biological roles of the protein ultrastructures will be determined. Our preliminary data, rich environment, and strong investigative team place us in an ideal position to address these aims that will sig- nificantly advance the study of RiPP protein chemistry and microbiology.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Medicinal chemists have consistently sought inspiration from natural products and their synthetic derivatives when exploring potential therapeutic lead compounds. These compounds frequently exhibit polycyclic architectures with numerous Csp3 stereocenters, contributing to heightened molecular rigidity. Additionally, clinical candidates which contain many stereocenters, topologically rich molecules, have been shown to exhibit less off-target effects. However, many synthetic methods solely modify the periphery of a molecule, which results in negligible three- dimensional change to the core scaffold. This proposal aims to develop protocols to alter the molecular topology of biologically active molecules; therefore, providing access to untapped chemical space and novel approaches to potentially improve a clinical candidate’s biological properties (Project 1). This project centers around developing several photochemical deconstructive epimerization protocols, involving an initial C–C bond cleavage, formation of a radical intermediate, and C–C bond reformation with the altered stereochemistry. This new mode of precision molecular editing may enable the opportunity to rapidly modify existing natural product and therapeutic libraries as well as the ability to synthesize compounds that would previously be challenging to access without lengthy de novo syntheses. Nevertheless, certain secondary metabolites are isolated from natural sources in minute quantities, which may limit the potential for direct modifications to a core scaffold. To overcome this hurdle, we also seek to develop new convergent retrosynthetic strategies that allow for the rapid and scalable total syntheses of natural products (Project 2). Our second proposal aims to utilize common, stable, and widely available precursors, such as alcohols and amines, for the direct execution of convergent fragment coupling reactions. By in situ cleavage of these inert C–C and C–heteroatom bonds, a radical intermediate is formed which we harness in various coupling reactions. We will further employ these protocols in the synthesis of several biologically active terpenoids.

NIH Research Projects · FY 2024 · 2025-01

Our group is broadly interested in the chemical biology of natural products (NPs). We seek to identify new mo- lecular structures that are formed by unusual enzymatic transformations. One successful approach was the de- velopment of an innovative discovery workflow that embraces big data genomics. With the sequencing revolution picking up pace, we are leveraging this vast resource to bioinformatically identify, classify, and experimentally characterize carefully selected novel NPs. For this project, we focus on bacterial NPs for several reasons: (i) Bacteria are the most historically significant source of molecular probes and drug leads. Such compounds re- vealed fundamentally new biology and also transformed the treatment of many human diseases. (ii) Bacteria dominate all other forms of life in terms of genetic/taxonomic breadth, chemical/metabolic capabilities, and geo- graphic/environmental diversity. (iii) Bacteria tend to organize the genes involved in NP biosynthesis into neatly organized clusters, which facilitates their bioinformatic identification and subsequent experimental characteriza- tion. This proposal unites big data genomics, synthetic biology, and modern chemical biology to structurally and functionally characterize novel NPs. Herein we target pathways predicted to showcase the molecular results of new enzymatic transformations with a strong focus on metagenome-derived pathways, especially from bacteria that associate with invertebrate animals. Several readily cultivated bacterial genera have been extensively studied, which established certain taxa as prolific sources of NPs (e.g. soil-dwelling Streptomyces). However, knowledge is sparse on less cultivable bac- teria, which represent the overwhelming majority of microbial diversity. Only relatively recently have the requisite technologies emerged to sequence and assemble metagenomic data into reads of useful length. As part of this project, we have repurposed RODEO, our open access, user-friendly genome-mining tool to analyze data deriv- ing from metagenome/microbiome sequencing projects. “MetaRODEO” will be validated through isolation and characterization of several distinct NP classes. We center our efforts on NPs from symbiotic bacteria of inverte- brates, given that numerous species have longstanding and intimate partnerships with their lower animal hosts. Evolutionary forces have undoubtedly shaped the bioactivity, improved the pharmacokinetics, and reduced the animal toxicity of NPs from bacterial symbionts compared to soil-dwelling counterparts. This project involves three interconnected but independently achievable specific aims. Aim I focuses on genomic sequencing, bioinformatics analysis, and isolation/characterization of first-in-class RiPPs from the invertebrate microbiome. Aim II centers on new RiPPs and other NPs derived from microbiome-derived biosynthetic path- ways that employ radical SAM enzymes. Aim III expands the environmental origin and chemistry of NPs identi- fied by our algorithm by targeting polyene macrolides. Each aim will elucidate new NP structures and evaluate biological activity using a rigorous, multi-tiered strategy.

NIH Research Projects · FY 2024 · 2024-12

Project Summary Alzheimer’s disease (AD) is a progressive disorder that is currently the leading cause of dementia worldwide. AD pathology is marked by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain, leading to neuronal dysfunction and cell death. The recently characterized glymphatic system, thought to be important for the clearance of β-amyloid, has increasing relevance in the context of AD pathogenesis. Furthermore, the astrocytic water channel aquaporin-4 (AQP4) serves a critical role in the glymphatic system by facilitating the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). Rodent models and post-mortem histological analysis of human brains point to upregulation and mislocalization of the AQP4 channel in AD. This mislocalization is theorized to hinder the convective flow of fluid through the interstitium and exacerbate amyloid accumulation. Importantly, the dystrophin-associated complex (DAC) serves as the primary molecular regulator of AQP4 localization, and genetic deletion of specific DAC components leads to mislocalization of the AQP4 channel. Despite this evidence, changes in AQP4 and DAC gene expression and its influence on AD pathology have yet to be explored in large-scale human studies. To further investigate how changes in AQP4 and DAC genotype and expression affect AD-relevant outcomes, our group intends to leverage computational approaches in large and well-characterized studies of aging and AD. Using bulk RNA sequence data from the Religious Orders Study (ROS) and Memory and Aging Project (MAP), we will be able to identify associations of AQP4 and DAC gene expression with amyloid and tau burden measured at autopsy. Further, we will pair our transcriptomic data with harmonized metrics of cognition, thus allowing for the examination of downstream consequences of AD pathology. Finally, we will incorporate an innovative approach using PrediXcan to separate causation from correlation by leveraging advanced models that determine levels of genetically-regulated gene expression. A benefit of this approach is the ability to greatly expand statistical power by incorporating additional cohort studies of aging and determine the effect of AQP4 and DAC genetic regulation on neuropathology and cognition. To fulfill the research aims of this F31 application, we will leverage exceptional resources at Vanderbilt University and the Vanderbilt Memory & Alzheimer’s Center. The candidate, Jared Phillips, will conduct the proposed research with the support of an interdisciplinary mentorship team, including experts in the neurobiology and genetics of AD, geriatric neuropsychology, neuroscience, and glymphatics. The parallel training plan will provide Jared Phillips with the necessary knowledge and skillset to complete the proposed research aims and develop into a successful independent scientist working to improve the field’s understanding of glymphatic contributions to AD. Results from this research will offer crucial information about the initiation and progression of AD pathology due to changes in glymphatic gene expression which will inform future prevention and therapeutic efforts.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT Aortic stenosis is one of the most common and serious heart valve disease problems, in which the aortic valve opening is narrowed and the left ventricle is under greater load to pump sufficient blood to the body. Transcatheter aortic valve replacement (TAVR) is a minimally invasive and now common approach for treating this disease. However, the long-term durability of transcatheter bioprosthetic valves has become a major concern due to bioprosthetic structural valve degeneration (SVD), a well-known complication post-TVAR and the main cause of impaired valve durability. SVD is a multifactorial process presented as leaflet calcification of the prosthetic valve, leading to valve dysfunction (stenosis and/or wear and tear). To address the SVD and early valve failure, we have identified a new tissue material based on the pulmonary visceral pleura (PVP) that promises to be a superior candidate for the bioprosthetic valve. The bioprosthetic valves for the current TAVR are typically made of bovine or porcine pericardial tissue, which has a collagen-based extracellular matrix (ECM) containing little elastin. In comparison, the PVP contains abundant elastin (ratio of elastin to collagen is ~1:1 in the ECM) and is therefore more resilient, which may lead to less mechanical stresses and improved calcification resistance while providing great hemodynamic performance of the valve. Furthermore, the swine and bovine PVP has a smaller thickness than the pericardium and could thus occupy less volume in the delivery catheter. In our preliminary study, we have demonstrated the xenogeneic PVP’s properties in minimal cytotoxicity, biocompatibility, non-thrombogenicity, mechanical durability, and resistance to calcification through in vivo animal studies. Furthermore, we successfully performed TAVR of the PVP bioprosthetic aortic valve in sheep that showed promising outcomes. In the current proposal, we have assembled a multidisciplinary group of engineers, scientists, and clinicians to launch an integrated study of the PVP aortic valve that includes in vitro experiments, computational modeling, and in vivo animal investigations. The research approach includes accelerated wear tests to study fatigue life and progressive calcification, laser techniques to measure the hemodynamics, high-speed cameras to track leaflet motion, computational modeling of fluid-structure interaction to study hemodynamics, stress distribution, and turbulence characteristics, and in vivo animal study to confirm the performance of the PVP bioprosthetic aortic valve. Our overarching hypothesis is that, due to its high elastin composition, durability, and greater calcification resistance, the PVP valve will outperform the existing bioprosthetic valves in the long term and thus will have a longer lifespan. The success of this proposal would deliver significant benefits to TAVR in managing severe heart valve diseases.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Metabotropic glutamate receptors are G Protein-Coupled Receptors (GPCRs) that serve as critical regulators of neurotransmitter release. Within the mGlu family, the three widely expressed members of the group III mGlu receptor subfamily (mGlu4, 7 and 8) modulate glutamate and GABA release from presynaptic terminals throughout the brain. Recently, it has been shown that the group III mGlu receptors are “anchored” at specific presynaptic locations by the postsynaptic expression of laminin proteins termed Extracellular Leucine Rich Repeat and Fibronectin Type III Domain Containing 1 and 2 (Elfn1 and Elfn2). Of the group III receptors, mGlu7 and Elfn1 have been reported to form a critical pairing, as mutations in each protein in humans are correlated with ADHD and seizures. Additionally, both Elfn1 and Grm7 knockout mice exhibit cognitive and motor impairments, blunted responses to amphetamine, and seizures that develop with a similar developmental time course. mGlu7/Elfn1 interactions localize the receptor to the active zones of glutamatergic pyramidal cell synapses onto somatostatin-containing GABAergic interneurons (SST-INs) in the hippocampus and prefrontal cortex (PFC). Dysfunction of SST-INs interneurons has now been described in numerous diseases such as schizophrenia, autism and epilepsy; therefore, the mGlu7/Elfn1 interaction in SST-INs is in a position to fine tune inhibitory synaptic responses onto pyramidal cells to provide distinct circuit-level control of hippocampal and cortical networks. In vitro, Elfn1 allosterically inhibits agonist-mediated activation of the group III mGlu receptors. Using a system in which we have co-cultured cells expressing mGlu7 with cells expressing Elfn1, we have now identified a positive allosteric modulator (PAM) and a negative allosteric modulator (NAM) of mGlu7 that are no longer active when Elfn1 is present; in contrast, other PAMs and NAMs exhibit activity at mGlu7 regardless of the presence of Elfn1. In the current application, we will test a suite of control agonists, PAMs, and NAMs for activity at mGlu7 with and without Elfn1 and perform analogous studies with mGlu4/Elfn1, mGlu8/Elfn1 and mGlu7/Elfn2 to understand compound specificity. We will then prepare the mGlu7/Elfn1 assay for HTS and conduct a pilot screen of an existing 1,000 compound collection of mGlu7 receptor modulators to identify new activators and antagonists to probe this interaction. Finally, we will test the hypothesis that the pharmacological profiles we observe in vitro in the presence and absence of Elfn1 will also be seen in a native tissue preparation at SST-INs. It is anticipated that these small molecules will assist in understanding the basic biology of mGlu7/Elfn1, create novel assays to assess GPCR signal bias, generate highly selective tools to specifically modulate SST-INs versus other types of interneurons, and could eventually represent a highly selective way to modulate mGlu7 activity only at specific synaptic locations.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Hypertension (HTN) is the leading risk factor for morbidity and mortality worldwide, accounting for nearly half of all heart disease and stroke-related deaths. Emerging evidence implicates immune cells as key mediators of HTN and its associated end-organ damage. Recently, our lab used mass cytometry to deeply phenotype the circulating immune cells of hypertensive and healthy control individuals. Notably, a key difference identified in the circulation of hypertensive patients was a selective decrease in a subset of regulatory T cells (Tregs) expressing the skin-homing receptor CCR10. Tregs are immune cells that primarily limit inflammation and are thought to be protective in HTN. Yet, Treg manipulation in rodent models has yielded inconsistent effects on blood pressure (BP), suggesting Treg subset- and/or context-specific functions in hypertension. In addition, the role of CCR10 and CCR10+ Tregs in hypertension is unknown. My preliminary studies demonstrate that in murine models of Angiotensin II (Ang II)-induced HTN, CCR10+ Tregs are decreased in the blood and selectively infiltrate the skin. In addition, CCR10-deficient (CCR10-/-) mice displayed blunted elevations in BP in response to Ang II. It is unclear how a receptor involved in immune cell recruitment to the skin elevates BP. In murine asthma and heart failure models, Tregs have been reported to promote loss of microvessels (microvascular rarefaction) through endothelial cell (EC) apoptosis. In hypertension, microvascular rarefaction occurs in the skin and contributes to BP elevations through increased vascular resistance. As a result, we hypothesize that CCR10 promotes hypertension and associated end-organ damage via cutaneous Treg recruitment leading to skin microvascular rarefaction. The goal of this proposal is to evaluate the role of CCR10 and CCR10+ Tregs in HTN using two complimentary approaches. First, I will use CCR10-/- mice and adoptive transfer studies to evaluate the role of CCR10 and CCR10+ Tregs specifically in altering skin microvessel density and hypertension development. Second, using EC tube formation co-culture assays, I will determine the impact of CCR10+ Tregs on EC apoptosis and microvessel loss in vitro. I will also test DLL4 signaling as a putative mechanism for this process. Proposed studies will provide key insight into the pathogenesis of hypertension and have significant therapeutic implications. Notably, studies will test the novel hypothesis that certain Treg subsets can play pathogenic roles in HTN, challenging the paradigm that all Tregs are beneficial. In addition, studies will test a novel role for the skin in HTN and offer the potential for future therapies targeting cutaneous immune cells. Proposed studies will also provide a foundation for development of potential new HTN therapies that will help patients live longer, healthier lives.

NIH Research Projects · FY 2026 · 2024-12

Summary Brain myeloid cells, including microglia and macrophages, selectively express several genes that confer risk for late-onset Alzheimer’s disease (AD)—for example CD33, which regulates amyloid beta clearance. As such, there is substantial interest in using oligonucleotide drugs—including siRNA—to knock down genes such as CD33 in brain myeloid cells as a therapeutic intervention. However, it remains challenging to deliver siRNA to these key cells in the brain. Oligonucleotide drugs are typically administered directly into cerebrospinal fluid (CSF), but free siRNA is cleared rapidly and exhibits poor cellular uptake. To combat this issue, conjugation to lipophilic moieties like cholesterol has been explored as a strategy to improve siRNA tissue retention and knockdown activity. Unfortunately, current lipid modifications can impart dose-limiting toxicity and generate steep concentration gradients around the injection site that cannot necessarily reach distal brain structures by diffusive transport. In prior work, we have developed a novel diacyl fatty acid carrier for siRNA (“siRNA-EG18”) that binds albumin with high affinity to extend circulation half-life of the conjugated siRNA. In the brain, albumin is transported effectively along perivascular spaces that reach deep brain structures, leading us to hypothesize that siRNA-EG18 could leverage convective perivascular transport to improve targeting of myeloid cells throughout the entire brain after delivery into CSF. Our extensive preliminary and supporting data support this premise, where we have demonstrated the ability of siRNA-EG18 to distribute through perivascular spaces and silence genes in brain myeloid cells using both bulk and single-cell assays. Moving forward, Aim 1 will comprehensively analyze siRNA- EG18-mediated bulk gene and protein silencing activity in brain myeloid cells as a function of injected dose. Aim 2 will extend these analyses into contexts of aging and amyloidosis and incorporate single-cell sequencing to understand siRNA-EG18’s ability to target myeloid cell subtypes under disease-related conditions. Aim 3 will focus on translation by benchmarking the efficacy of siRNA-EG18 against a lipid-siRNA conjugate that has entered phase 1 clinical trials for early-onset AD. All aims will target Cd33 for its connection to myeloid cells and late-onset AD. Successful completion of this work will establish siRNA-EG18 as a promising technology for AD treatment through myeloid cell gene targeting.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Eliminating health disparities for vulnerable populations is an important goal. Legal recognition of who is eligible for marriage has expanded throughout the world and may contribute to mental health. We will provide new evidence on the effects of legal access to marriage on the mental health of vulnerable populations using comprehensive, high-quality linked administrative data for individuals in New Zealand – which expanded marriage access in 2013 – and rigorous difference-in-differences and event study methods. New Zealand (NZ) offers an unparalleled opportunity for understanding the effects of legal marriage availability on the mental health of vulnerable people due to its availability of multiple linked administrative datasets. Publicly funded healthcare provides information on all healthcare utilization for everyone in NZ, including prescription medications, mental health referrals and treatment, and hospitalizations. We will use administrative data from New Zealand on the universe of marriages to examine the effects on outcomes, including marriage, anxiety, depression, self-harm, substance abuse, and drug overdose, using difference-in-differences and event-study models. These analyses will rely on rich administrative data on pharmaceutical prescriptions, mental health and substance use treatment referrals, and hospital discharge data. We will also examine whether these effects are heterogeneous across groups.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Facial expression is a complex sensorimotor behavior involving precise contraction of the facial muscles guided by dynamic sensory and proprioceptive feedback. Atypical facial expressivity is a common characteristic of autism that impairs interpersonal communication and hinders the recognition of discomfort and pain, leading to the inadequate address of social and homeostatic needs for autistic individuals. Although these effects are strongly tied to negative mental health outcomes in autism, including high comorbidity with anxiety and mood disorders, the etiology of and appropriate treatment for atypical facial expression remain unknown. While atypical facial expressivity in autism has long been assumed to reflect reduced social motivation or differences in the experience of emotion, interventions focused on the development of social and emotional skills are largely ineffective for improving atypical facial expressivity. Considering that i) facial expressions are a sensorimotor behavior, ii) sensorimotor deficits are a core characteristic of autism, and iii) other facial sensorimotor functions such as feeding and speech are disrupted in autism, it is likely that sensorimotor differences contribute to atypical facial expression behavior and represent a potential therapeutic target. However, to date there is very little published work investigating the sensorimotor basis of atypical facial expression in autism, a gap which prevents the development of evidence-based interventions for this critical communication barrier. I propose to address this gap by using neuroimaging, clinical, and behavioral data to test the hypothesis that atypical facial expression in autism is associated with differences in functional connectivity within the facial sensorimotor brain network. This work will illuminate the sensorimotor basis of atypical facial expression in autism to inform the necessary development of targeted therapeutic approaches. A major barrier to the study of facial sensorimotor network differences in autism is the lack of prerequisite work characterizing the topology of this network in neurotypical individuals. Using extant functional magnetic resonance imaging (fMRI) data collected by my laboratory, I will address this gap by applying a graph theoretical approach to characterize connectivity between facial sensory and motor brain regions in a neurotypical sample (Aim 1a). Then, I will utilize fMRI, clinical assessment data, and behavioral measures of facial expressivity collected from a sample of autistic adults to test the hypothesis that functional connectivity in the facial sensorimotor network is reduced in autistic individuals with atypical facial expressivity compared to neurotypical controls (Aim 1b). Finally, I will replicate these analyses using an open-source dataset - the Autism Brain Imaging Data Exchange - to assess if group differences in facial sensorimotor network connectivity are independently observed across larger samples of autistic and neurotypical adults (Aim 2). This work will interrogate the brain basis of a critical nonverbal communication barrier in autism to inform the necessary development of evidence-based interventions and prevent social and psychiatric sequelae.

NSF Awards · FY 2024 · 2024-10

Gun violence and the reckless use of firearms have been a pervasive problem in the United States, especially in low-income communities. This problem has only become exacerbated by increasingly lax gun control laws, easy access to firearms, and growing mistrust of law enforcement that often inhibits reporting by the public. Gun-related crimes cost millions of dollars in medical expenses, law enforcement, and lost wages, not to mention the trauma and shattered lives they leave behind. Many gunshots go unreported or are difficult to identify and localize. Current commercial solutions to gunshot localization are expensive and out of the control of the local communities in which they are used. Motivated by real-world events in an economically disadvantaged community in Austin, Texas, this project seeks to build a community-based system for detecting, localizing, and classifying gunshots using a distributed network of inexpensive acoustic sensors connected via residents’ wireless internet services. The team will engage directly with the neighborhood community, law enforcement, and local government to provide a technological system and practical implementation that provides a scalable, sustainable, effective, and community-controlled solution to address the widespread prevalence of unsanctioned gunfire. Building off pioneering work by Vanderbilt University in the area of wireless sensor network-based gunshot localization, the team will work with law enforcement and members of the community to determine both the community’s and the police department’s needs and concerns related to gun violence and to determine a path forward for creation of a system that adequately addresses both. To that end, the team will conduct surveys and organize a workshop with members of the community and law enforcement to develop system specifications in Phase 1. In Phase 2, a live pilot will further refine these specifications and lead to rapid system implementation based on an existing codebase and large library of urban gunshot recordings. This pilot system will be deployed in an Austin neighborhood, allowing the team to measure its technical efficacy and assess its impact on public safety and community attitudes. It will also provide a model for similar communities to adopt and adapt to their unique needs and circumstances. The research conducted under this project will advance the state of knowledge in low-cost gunshot localization technology and provide a valuable assessment of the impact and cost effectiveness of such systems when combined with a broad program of community engagement and education. This project is in response to the Civic Innovation Challenge program’s Track B. Bridging the gap between essential resources and services & community needs and is a collaboration between NSF, the Department of Homeland Security, and the Department of Energy. 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 · 2024-10

One of the best ways to help students learn is to have them experience realistic simulations of the situations they will confront in practice. Simulation learning is particularly important in medical settings where students can practice skills without risking patient safety. However, one of the consistent challenges in simulation learning is to ensure that students can effectively review and learn from experiences that may be overwhelming in the moment. In this project, a multidisciplinary research team will implement technologies that record rich, detailed information about the events that occur during nursing simulations. This information will be used to support reflection-based learning by allowing students and instructors to review and elaborate upon key events during simulations. Developing artificial intelligence (AI)-assisted reflection tools will also make strides toward increasing the availability and reach of complex simulation training. In this project, the research team will develop procedures and technologies that support simulation training in the domain of nursing. The approach combines recent visual cognition research on event understanding (e.g., integrating action identification and goal recognition with basic attentional and memory processes), learning sciences research on self-regulation, and technical developments in the processing of multi-modal learning data. The team will use a multimodal data analysis pipeline to collect and integrate learning analytics (including eye gaze, video, movement data, and computer action logs) to develop AI-based learning supports that can help assess the quality of learning actions and reflections and guide students to effective reflection. These goals will be embodied in a novel system for reflection on mixed-reality simulation learning. The initial version of the system will use a multimodal data pipeline and an AI engine to support two learning modules. The Debrief module will help students and instructors mark key events and focus on discussing them in a debriefing session immediately after they have participated in a learning activity. The Reflect module will engage students to comprehensively review simulations some days after they occur by segmenting their experience into discrete events and identifying the specific actions and goals associated with the events. These segmentations will be based on video and gaze replays that will allow students to observe what they attended to during their simulations. Each module will use a data dashboard to foster student and instructor reflection in support of self-regulation. The team will develop and conduct initial effectiveness studies of the system in in supporting conceptual understanding, metacognitive judgement accuracy, and subsequent simulation performance. This project is funded by the Research on Innovative Technologies for Enhanced Learning (RITEL) program that supports early-stage exploratory research in emerging technologies for teaching and learning. 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 · 2024-10

Right-of-way closures, i.e., the closing of streets, bike lanes, sidewalks, and roads, frequently occur in urban areas due to construction projects, cargo delivery, and special events. Dynamic construction schedules, lack of compliance, and potentially outdated technological systems hinder the ability of city transportation authorities to effectively issue, monitor, and inspect permits, leading to compliance violations and traffic disruptions. The rate of permit violations is exceptionally high in urban areas, and the cost of these violations and the resulting inspections is staggering: Nashville Department of Transportation (NDOT) currently loses an estimated $2 million from the unpaid permit fees alone and pays external contractors an estimated $5 million annually for inspection. Most importantly, road closures (particularly illegal closures and violations) harm traffic, commuter safety, and local businesses. This problem is not restricted to Nashville alone; urban areas across the USA face challenges with enforcing and monitoring right-of-way closures. This project is a collaboration between Vanderbilt University, NDOT, the Metropolitan Government of Nashville, and Nashville Metropolitan Information Technology Services (ITS) to tackle these challenges through fundamental and civic-engaged research. Specifically, this project will design and develop data-driven artificial intelligence models that will 1) automate the detection of permit violations and 2) estimate the effects of right-of-way closures to optimize future permit issuance. Our goal of automating the detection of right-of-way closures and estimating the impact of future closures requires fundamental advances in data science, machine learning, and software engineering. Specifically, the intellectual merit of our project lies in 1) the design and implementation of novel neural network architectures to automatically detect road closures; 2) the design and implementation of a data-driven approach to infer locations of road closures from heterogeneous and noisy crowdsourced data; 3) the development of an urban digital twin to estimate the effect of road closures in Nashville; 4) the development of an optimization engine for the issuance of right-of-way permits; and 5) system and data integration to deploy the proposed technology in Nashville. The resulting technical framework will be available for other urban areas, and it will apply to problems beyond right-of-way monitoring, e.g., emergency response and traffic management, and generally to the broader problem of monitoring societal-scale cyber-physical systems. This project is in response to the Civic Innovation Challenge program’s Track B. Bridging the gap between essential resources and services & community needs and is a collaboration between NSF, the Department of Homeland Security, and the Department of Energy. 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 · 2024-10

Elementary school-aged children use and have interest in technologies with integrated AI applications, yet they rarely critically investigate the sociopolitical contexts in which people consume and produce AI technology. Without engaging in this form of critical computing, elementary school students will not be prepared to participate ethically in a digitally reliant society and tackle the increasingly discriminatory affects of algorithmic decision-making as they continue their schooling and careers. Moreover, there is still a limited understanding on how elementary students apply critical lenses to computing and few computing education programs are available that focus on sociocultural issues. This CAREER project proposal will address these research gaps by co-designing, implementing, and analyzing an innovative critical computing education curriculum, referred to as CritComp Pop-Ups. The research goals will be to (1) characterize co-design processes that involve teachers, researchers, and students; (2) measure elementary school students’ critical computing knowledge and practices using quantitative ethnography; and (3) evaluate the effectiveness of an AI critical computing curriculum on students’ interest and confidence in computer science. The education goals will be to 1) broaden participation in computing by engaging underserved students in rural areas; (2) foster children’s interest in computer science through culturally relevant instructional methods focused on AI; (3) provide elementary school teachers with strategies for integrating critical computing; (4) host critical computing community events; and (5) train undergraduate/graduate students in research competencies and critical computing. The potential contributions will be to (1) extend understanding of how elementary students construct knowledge through a critical sociopolitical lens; (2) provide researchers a framing for studies on critical computing education; and (3) inform the development of critical computer science educational standards and curriculum. This CAREER project is funded through the Racial Equity in STEM Education program (EDU Racial Equity). The program supports research and practice projects that investigate how considerations of racial equity factor into the improvement of science, technology, engineering, and mathematics (STEM) education and workforce. Awarded projects seek to center the voices, knowledge, and experiences of the individuals, communities, and institutions most impacted by systemic inequities within the STEM enterprise. This program aligns with NSF’s core value of supporting outstanding researchers and innovative thinkers from across the Nation's diversity of demographic groups, regions, and types of organizations. Programs across EDU contribute funds to the Racial Equity program in recognition of the alignment of its projects with the collective research and development thrusts of the four divisions of the directorate. 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 · 2024-10

An exit ticket is a recommended and widely used way to end a lesson. A typical exit ticket format in mathematics lessons is for students to solve a few problems related to the day's lesson and turn it in when they exit the classroom. The most common purpose of exit tickets is to provide formative feedback to teachers about whether students have met the objectives of a given lesson. However, the psychology of learning literature suggests that there is an untapped potential for exit tickets to also benefit student's learning directly. This project explores two potential enhancements to exit tickets, with the goal of improving high-school student's mathematics knowledge and ability to regulate their own learning processes. These enhancements can be implemented easily by teachers in the context of exit tickets to support students self-reflection. This project will explore the impact of enhancements for supporting students in (1) determining how well they know material and (2) evaluating their strategy use and answers. These enhancements could benefit student's mathematics performance on content tests and improve the quality of high-school mathematics instruction. The findings could generalize to a wide range of grades and domains and to other formative assessment types. Dissemination efforts will include sharing the results with practitioners, district administrators, and digital learning creators to increase the use of enhanced exit tickets if they are successful. The project team will work with Integrated Mathematics I teachers to add enhancements to exit tickets for one curriculum unit and investigate whether and how the enhancements improve student outcomes. At least 680 students in a metropolitan school district that serves racially and economically diverse students will participate. The project uses a pretest-intervention-posttest design, with students randomly assigned to one of two conditions within their classroom: 1) enhanced exit tickets or 2) typical exit tickets. At pretest and posttest, students will complete measures of targeted self-regulated learning components (confidence calibration, metacognitive evaluation, mathematics self-efficacy, and mastery-approach goal orientation) as well as an assessment of mathematics performance. Using hierarchical linear models, analyses will investigate whether the enhanced exit tickets show more positive effects on student outcomes than typical exit tickets. Teacher interviews will explore whether the exit tickets were feasible for teachers to regularly implement and informed their instructional practices. Student interviews will explore student's perceptions of the exit ticket enhancements. The research will expand existing theories of self-regulated learning by evaluating whether specific supports for self-reflection can each benefit multiple self-regulated learning outcomes as well as mathematics performance. The proposed studies will also reveal ways that this formative assessment device can be adapted to enhance student's self-regulated learning and content knowledge. These enhancements could lead to exit tickets serving as a formative assessment of student's self-regulated learning practices. This project is funded by the Discovery Research preK-12 program (DRK-12) that seeks to significantly enhance the learning and teaching of science, technology, engineering, and mathematics (STEM) by preK-12 students and teachers, through research and development of innovative resources, models, and tools. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for proposed projects. 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 · 2024-10

The purpose of this project is to plan, organize, and execute the 20252 National Science Foundation (NSF) Cyber-Physical Systems (CPS) Principal Investigator (PI) Meeting. This meeting convenes all PIs of the NSF CPS Program for the 14th time since the program began. The PI Meeting is to take place during the spring of 2025 in Nashville, TN. The PI meeting is an annual opportunity for NSF-sponsored CPS researchers, industry representatives, and Federal agency representatives to gather and review new CPS developments, identify new and emerging applications, and to discuss technology gaps and barriers. The program agenda is community-driven and includes presentations (oral and poster) from PIs, reports of past year program activities, and showcase/pitch new CPS innovations and results. The meetingt will be largely in-person with streaming of plenary sessions available. The virtual component of the PI meeting will also enable a larger community of researchers spanning academia, industry, and Government to also participate. The annual PI Meeting serves as the only opportunity where the NSF-funded CPS Principal Investigators meet to share their research, discuss new research opportunities and challenges, and explore new ideas and partnerships for future work. Furthermore, the PI meeting is also an opportunity for the academic research community to interact with industry entities and government agencies with vested interest in CPS research and development. Special effort will be made to encourage additional Government and Industry participation. The PI Meeting is a forum for sharing ideas across the CPS community. It has played a major role in growing the community across a broad range of sectors and technologies, and performing outreach to others who have interest in learning about the program and participating as future proposers, transition partners, or sponsors. The 2025 PI meeting will feature lightning talks from researchers, poster sessions, special topic workshops, demonstrations and keynotes from leaders in the research community. 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.