Syracuse University

NIH Research Projects · FY 2026 · 2023-08

The rise in U.S. midlife mortality in recent decades has been substantial, ending the increase in life expectancy around 2010 and triggering its decline after 2014. The trend has been exacerbated since 2020. One of the most telling features of the rise is its geographic pattern. It has been pronounced in Midwestern and Southern states and in rural areas and small cities. Explaining these growing geographic disparities is a necessary step toward identifying the etiologies of rising midlife mortality overall. The overarching objective of this project is to assess how state policy contexts and county economic contexts collectively predict growing geographic disparities in 1) all-cause midlife mortality, 2) major trend-driving causes of death for midlife mortality: suicide, drug overdose, alcohol-induced causes, and cardiometabolic diseases, and 3) psychosocial and health behavior risk factors for those causes of death The project answers key unresolved questions about the growing geographic disparities in midlife mortality that have been major obstacles to understanding them. One question regards the collective influence of state and local contexts. Studies tend to focus on state or local contexts, providing an incomplete explanation. We advance this work by examining state and local contexts concomitantly, which is critical because they may affect mortality via independent and synergistic processes. A second question concerns the influence of states’ policy “contexts”. States have enacted highly correlated, or “bundled”, policies which necessitates new approaches for understanding their influence on mortality. We advance this work by using innovative methods to develop annual scores for interpretable policy bundles. A third question concerns the degree to which state and local contexts collectively predict individual-level psychosocial wellbeing and health behaviors—i.e., the proximate determinants of the four major causes of death behind rising midlife mortality. Deindustrialization, declines in good jobs, and concomitant disruptions to families and communities in some places may have harmed the psychosocial wellbeing of midlife adults, particularly those without a 4-year college degree, leading to consumption of drugs, alcohol, and unhealthy food. We advance this work by examining how state and local contexts collectively predict psychosocial and health behavior risk factors for the four major causes of death. The project will accomplish its objective through three Specific Aims. Aim 1 identifies how state policy and county economic contexts collectively predict county-level mortality (from all causes and the four specific causes) from 1990-2025 for all midlife adults and by age, sex, race-ethnicity, education, and metro status. Aim 2 identifies how state policy and county economic contexts collectively predict individual-level psychosocial and health behavior risk factors from 2021-2025, and examines hypothesized pathways, among all midlife adults and by age, sex, race/ethnicity, education, and metro status. Aim 3 merges the 100+ annual state and county measures into multiple geocoded surveys available via the UM’s Virtual Data Enclave. We will also disseminate the data, documentation, and code via ICPSR and offer workshops on these resources.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY/ABSTRACT Uncontrolled hemorrhage is the primary cause of trauma-related death, and approximately half of hemorrhage deaths occur before the patient reaches the hospital. Current techniques for hemorrhage control are insufficient for a large number of wounds and do not adequately address non-compressible hemorrhages. Thus, there is a critical need for improved hemostatic dressing materials that are inexpensive, easy to apply, effective, and safe to use over prolonged time frames. In the absence of such treatment options, tragic deaths from uncontrolled bleeding will continue. The long-term goal of the proposed work is to provide an accessible option for hemorrhage control that can be used with minimal training in remote situations. The overall objectives in this application are to characterize efficacy of a promising biomaterial platform, shape memory polymer (SMP) foams, in clinically-relevant hemorrhage models and to develop easy-to-use storage and delivery devices. In preliminary work in a porcine grade V liver injury, SMP foam treatment provided faster hemostasis, reduced total blood loss, and improved survival relative to treatment with clinical controls. The rationale for the proposed work is that future clinical translation efforts will be enabled by an improved understanding of how foam properties affect hemorrhage control and expanded pre-clinical characterization of this promising platform. To achieve these objectives, the following specific aims will be pursued: Specific Aim 1: Evaluate effects of SMP foam architectures on hemorrhage control in in vitro wound models, and design storage and delivery devices for non-compressible torso wounds and compressible extremity wounds. Specific Aim 2: Characterize SMP foam efficacy in vivo in a non-compressible grade V liver injury. Specific Aim 3: Characterize SMP foam application, efficacy, removal, and safety in vivo in a compressible femoral artery injury. At the completion of these studies, the expectation is to have clinically-relevant SMP foam- based hemostatic device designs for use in compressible and non-compressible traumatic wounds. The primary positive impact of these studies will be a hemostatic dressing that is easy- to-use and effective in a range of hemorrhagic wound types.

NIH Research Projects · FY 2026 · 2023-03

A strong scientific workforce is essential for fostering innovation, advancing research, and maintaining high-quality learning and work environments. Undergraduate research experiences, such as summer research programs, have been shown to enhance learning skills, career ambitions, STEM degree completion, and progression to graduate studies. The Summer Training in Alcohol and Health Research – Undergraduate (STAHR-U) program aims to: (1) recruit an annual cohort of five to seven undergraduate students nationwide who demonstrate academic potential and a strong interest in alcohol and health science research, as well as in pursuing graduate studies in related fields; (2) provide participants with a rigorous eight-week research internship and enrichment activities; (3) conduct ongoing evaluations during the summer program and follow-ups to assess recruitment, retention, and educational and career outcomes; and (4) disseminate program information and materials to students, academic institutions, and the wider scientific community. Ultimately, this program will contribute to the growth of the future health research workforce and strengthen alcohol, addiction, and related health sciences.

NIH Research Projects · FY 2026 · 2023-03

Project summary Protein detection and biomarker profiling have wide-ranging significance in many areas of disease prognostics, diagnostics, and therapeutics. For example, the progression and development of various cancers are accompanied by alterations in specific protein expressions. These variations in different biofluids are indicative of disease-like conditions. A long-standing difficulty of existing methods is the detection of multiple proteins in a complex biological sample with high sensitivity and a broad dynamic range. In addition, scalable protein identification and quantification techniques are usually created with sacrificed sensitivity, so their applicability in clinical settings remains limited. To overcome these fundamental and technical shortcomings, we will develop, optimize, and validate a next-generation class of sensing elements for targeted protein biomarker detection at single-recognition event precision. These proposed studies aim to engineer synthetic sensors made of a single-polypeptide chain protein nanostructure. This protein nanostructure encompasses a membrane protein pore and a programmable protein binder. The protein pore is a reporter that generates an output signature, which depends on the identity and quantity of the biomarker. A programmable binder is a small antibody- mimetic scaffold, such as a monobody or an affibody, sampling the targeted biomarker in solution. Hence, a generic binder can be modified for multiple protein analytes. This way, such a modular design significantly expands the utility of these sensing elements for numerous biomarkers while preserving their high sensitivity and specificity using the resistive-pulse technique. This critical benefit is facilitated by the genetically encoded nature of these sensors so that they can form combinatorial libraries of tethered binders. These manipulations of modular pore-based detectors equipped with antibody-mimetic binders have not been conducted previously. They are intended for use in challenging biofluids, where specific binder-biomarker interactions will be unambiguously distinguished from nonspecific interactions of the medium constituents. Further advantages of this real-time and label-free technology include maintaining an amplified signal-to-noise ratio in a wide dynamic range due to the superior bandwidth of time-resolved electrical recordings. The expected immediate outcomes of these proposed studies will be the following: (i) development, optimization, and validation of monobody- and affibody-based sensors for protein detection; (ii) protein biomarker detection in multiplexed and high- throughput formulations; (iii) protein biomarker detection in heterogeneous solutions. These results will represent a platform for fingerprinting panels of multiple protein targets in biofluids without impairing the sensitivity of these determinations. This proposed research will impact quantitative proteomics and biosensor technology by providing a fundamental basis and tools for ultrasensitive biomarker detection.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract Speech sound disorders impacting /ɹ, s, z/ may become chronic due to either ineffective or limited treat- ment. The long-term goal is to leverage theoretical and technological advancements to accelerate the develop- ment of accessible and effective treatments that mitigate reduced quality of life due to chronic residual speech sound disorders (RSSD). To this end, the validated motor-based RSSD treatment Speech Motor Chaining guides speech-language pathologists (SLPs) through high-fidelity, high-trial, rapidly adapting treatment by dosing and manipulating several principles of motor learning in real time. SLP-led Speech Motor Chaining has been effective for individuals whose errors persist after traditional treatment. However, at least two challenges remain: first, optimal treatment intensity is unknown. Second, SLPs need validated avenues for evidence-based practice when caseload size precludes optimal intensity. Therefore, the overall objective of this proposal is to optimize a suite of theoretically motivated, high-fidelity, motor-based treatments delivered at the appropriate intensity, despite practical barriers, for the sounds comprising 90% of RSSD: /ɹ, s, z/. The central working hypotheses, supported by our preliminary work, are that Speech Motor Chaining is (a) more efficacious when delivered intensively (i.e., closely spaced for a fixed number of sessions), and (b) also beneficial when practice is led by an artificial intelli- gence (AI) SLP. The theoretical rationale is that increasing intensity early in treatment will mitigate erred prac- tice between sessions, improving outcomes relative to more customary practice distributions, and that reliable AI-mediated practice is effective in the context of validated treatments. There are three aims: Aim 1: Deter- mine how intensive/distributed treatment affects speech sound learning in RSSD. A randomized controlled trial (n=84) will test the hypothesis that intensive SLP-led Speech Motor Chaining (i.e., bootcamp) leads to greater gains in speech sound accuracy compared to an equivalent number of customarily distributed sessions. Aim 2: Determine improvement in /ɹ/ production when Speech Motor Chaining practice trials are led by an Artificial Intelligence clinician. A multiple baseline single subject design will test the hypothesis that Chaining-AI, in which an AI SLP provides clinical feedback, facilitates clinically meaningful change in /ɹ/ production. Aim 3: Demonstrate breadth of clinical AI capability by optimizing mis- pronunciation classification algorithms for /s/ and /z/. Mispronunciation detection algorithms will be trained to recognize clinical speech errors affecting /s/ and /z/, replicating expert listener judgement with clini- cally-acceptable accuracy. This significant research addresses a critical need for theoretical/empirical guidance for treatment intensity, offering sorely needed recommendations in a system where ~6 million American adults have unresolved RSSD. This innovative research accelerates a paradigm shift in which combined SLP/AI service delivery could overcome barriers to effective, accessible, and sufficiently intensive treatment, for 90% of RSSD.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY One of the fundamental problems in evolutionary biology is to understand the molecular genetic basis of speciation. Recent advances in speciation research have improved our understanding of interspecific divergence, but we still lack a comprehensive understanding of the molecular processes that diverge among incipient species. In the handful of cases where the genetic mechanisms of reproductive isolation have been elucidated, these invariably tackle late-evolving and/or hybrid dysfunction. This means that we still lack a general understanding of the molecular processes that govern pre-zygotic reproductive barriers, even though these are often important early in the speciation process. My lab will tackle this problem by identifying the molecular genetic basis of pre-zygotic and post-zygotic re- productive isolation between members of the Drosophila virilis species sub-group. This species group provides an especially unique opportunity to dissect the genetic and molecular mechanisms of pre-zygotic barriers, as members of this group are prone to evolve these types of barriers quickly between species and even among populations of the same species. Our overall approach integrates several strategies to answer the following questions: What are the genetic mechanisms that cause reproductive isolation between species? Which molec- ular and cellular processes are affected by divergence of these genetic mechanisms? What are the evolutionary forces that drive divergence of the relevant genes between species? What is the landscape of natural genetic variation within and between species that facilitates evolutionary divergence of these genes? The first project within this proposal will focus on post-mating pre-zygotic barriers (i.e., gametic incompatibil- ities). I have previously shown that gametic incompatibilities are rampant in the D. virilis sub-group, and that the genetic basis is moderately complex but highly tractable using a combination of molecular genetics techniques coupled with transcriptomic and proteomic analyses of reproductive traits. The second project will tackle the mechanisms of hybrid male sterility that are caused by incompatibilities between the Y and X chromosomes. The Drosophila Y chromosome carries several male fertility factors, but it has seldom been directly implicated in interspecific hybrid sterility between closely related species. Our preliminary data show that the Y chromosome is necessary and sufficient to cause sterility in hybrids. The research in this proposal will be innovative because we will deploy cutting edge tools in creative ways that will allow us to dissect complex genetic mechanisms in a newly established model system.

NIH Research Projects · FY 2025 · 2022-09

Abstract Posttraumatic stress disorder (PTSD) co-occurs frequently with hazardous alcohol outcomes, presenting considerable public health burdens and challenging traditional treatment approaches. Although accessible interventions able to adapt to individuals’ fluctuating internal risks within their natural environments are emerging, these just-in-time adaptive interventions have largely not yet considered the role of trauma sequalae in alcohol use. To do so, research needs to identify the acute risks for drinking operating in-the-moment as individuals experience PTSD symptoms in their daily lives. There is a critical need to define and operationalize acute cognitive processes underlying PTSD-related drinking (Aim 1), examine variability in such cognitions amid PTSD symptoms in real-world settings (Aim 2), and establish which of these acute cognitions are linked to actual drinking events and mediate PTSD-related drinking (Aim 3). During the K99 phase, Aim 1 comprises a fine-grained qualitative examination into acute risk cognitions among frequent drinkers with PTSD, utilizing focus groups to identify key acute cognitions and cognitive interviewing approaches to operationalize measures of such cognitions. Aim 2 field-tests these cognitive assessments by examining whether they vary across drinkers’ daily lives and are active amid PTSD symptoms within a 14-day ecological momentary assessment (EMA) study. During the R00 phase, Aim 3 considerably extends such work to test whether these acute cognitions are linked to actual drinking events as well as whether they are mechanisms of PTSD-related drinking across another 14-day EMA. Collectively, this mixed methods investigation will identify proximal cognitive mechanisms of PTSD-related drinking that can be targeted in future just-in-time interventions. As a K99/R00 NIH Pathway to Independence Award, these research efforts would support the emergence of a dedicated early career researcher (Dr. Zaso) with unique expertise in acute cognitive trauma-related drinking processes. This K99/R00 also would afford Dr. Zaso instrumental development in acute PTSD-related drinking processes, momentary assessment of affective alcohol cognitions, and the methodological/statistical techniques necessary to characterize momentary, real-world drinking processes. The mentorship team offers expertise in the intersection of trauma and alcohol use (Dr. Jennifer Read), with collaboration support on daily processes in PTSD-related drinking (Dr. Tracy Simpson), acute activation of alcohol cognitions (Dr. Robert Dvorak), optimization of mobile alcohol assessment and intervention (Dr. Tammy Chung), and statistical modeling of multilevel alcohol etiologies (Dr. Craig Colder). Dr. Zaso’s career development will occur within the Department of Psychology and Clinical and Research Institute on Addictions at the University at Buffalo, which comprise a rich intellectual environment with a network of productive addictions researchers. Overall, this K99/R00 will propel Dr. Zaso’s emergence as an independent trauma-related alcohol researcher with the skills necessary to maintain a clinically impactful research program aimed at curtailing alcohol harms.

NIH Research Projects · FY 2025 · 2022-09

When faced with health and economic challenges, Americans often rely on family members, including those who are not coresident, to provide time help, financial assistance, and shared housing. Yet, for many disadvantaged Americans, the increased need for help from family often comes at a time when the ability of family to provide help is diminished. Public transfers designed to alleviate economic hardships may interact with family transfers, but the combined effects are unknown. Despite the interdependence of health and economic challenges across generations and the effect of family support on health outcomes in the face of challenges, most research on the effects of health and economic challenges focuses on individuals and households. This project fills this gap in the research creating a multidimensional contextual database linked to the Health and Retirement Study (HRS) and the Panel Study of Income Dynamics (PSID) to examine the effects of health and economic challenges across generations of American families. The HRS and PSID have collected data on the health and well-being of individuals and their family members for decades, include supplements on health and economic challenges and on public and private transfers to combat these challenges, and will continue indefinitely to support an understanding of the health impacts in the future. This project enhances these data by building a contextual database linkable to the generations of families in the HRS and PSID across dimensions of exposure to risk; state, local, and school policies; local economic conditions; health care availability; preexisting health factors; and economic differences. The proposed project addresses four Aims: (1) build and maintain a multidimensional contextual database linked to generations of HRS and PSID families; (2) describe how health and economic challenges differed across groups and were shared within families; (3) assess how care, financial support, and coresidence from family members responded to health and economic challenges and how each interacted with public transfer programs; and (4) study the physical and mental health effects of these challenges and whether family support and public transfers mitigated negative health effects. Differences across race-ethnicity, socioeconomic status, sex, age and retirement status, and family structure are assessed in each aim. Causal effects of the impact of health and economic challenges will be estimated using a combination of subjective assessments elicited from respondents and analytic strategies. The results provide a comprehensive understanding of the health and economic challenges faced by American families and how they impact their physical and mental health. Consortium collaborations will facilitate harmonization of contextual factors and health outcomes and support dissemination of the contextual data resource to the broader research community.

NIH Research Projects · FY 2025 · 2022-07

Adults with intellectual disability (ID) experience significant negative health outcomes and may benefit from advances in precision medicine research (PMR) but are often excluded from research. Key reasons for this outcome are common presumptions about incompetency to consent and questions about the appropriateness of proxy consent. In the Parent R01, Project ENGAGE, we address these challenges by creating The ENGAGE Toolkit, an empirically-based, ID-tailored, PMR study-adaptable consent toolkit comprised of legal, educational, and practical tools to support the inclusion of adults with ID in PMR. Yet, we identified through this work an additional key barrier: how to practically, fairly, and accurately screen for consent capacity among adults with ID. Despite evidence that most adults with ID have consent capacity and NIH’s guidance that those with questionable capacity should be individually assessed, adults with ID are often presumed to lack consent capacity for research decisions. Additionally, existing consent capacity tools are not appropriate for adults with ID—a resource gap that may also partially explain why standardized consent capacity evaluations are rare. Evidence shows that tools may not transfer across populations and that tools without tailoring to the study population are likely to result in inaccurate evaluations. Adults with ID are thus at risk that they will be determined to lack capacity, regardless of ability, or to have capacity when they do not. Both options undermine autonomy, consent and protection of research participants—contrary to foundational principles in bioethics and research, including PMR. Tailored consent capacity tools that are practical and cognitively accessible for adults with ID can enhance the culture of responsible inclusion in PMR and remove a barrier to research that might offer direct benefit to adults with ID. They can minimize inaccurate conclusions, preserve first person consent, reduce unneeded proxy consent, and in the long run, enhance representativeness in cohorts, increase generalizability of PMR findings, and promote more applicability of emerging knowledge from PMR to adults with ID. Yet, no validated ID-tailored consent capacity screening tool currently exists. The proposed bioethics research study leverages our academic-community partnership to close this gap by: (1) Adapting an ID-tailored cognitively accessible brief and easy-to-administer consent capacity screening tool for adults with ID; and 2) Validating the ID-tailored tool by establishing its a) content validity via cognitive interviews with adults with ID and subject matter expert review, and b) psychometric properties via its administration with 100 adults with ID and studying its reliability and validity. The ID-tailored consent capacity screening tool will be added to the web-based Parent R01’s ENGAGE Toolkit for PMR, and available for use in an array of clinical studies. We will disseminate findings through workshops, webinars, peer-reviewed publications, and professional presentations. This work will, over time, generate real-world knowledge for biomedical research while promoting health.

NIH Research Projects · FY 2026 · 2022-01

Project Summary/Abstract Faithfully segregating chromosomes during mitosis relies on a properly assembled spindle apparatus with centrosomes anchoring mitotic microtubules on both sides of it. The centrosome is a major microtubule- organizing center (MTOC) in animal cells. It consists of a pair of centrioles surrounded by the pericentriolar material (PCM). The PCM nucleates and anchors microtubules and thus dictates the MTOC activity of the centrosome. Centrosomes rapidly expand their PCM at the onset of mitosis. This process, termed centrosome maturation, is critical for spindle organization and chromosome segregation. However, there is a fundamental gap in understanding how the PCM is assembled and regulated at the onset of mitosis. In addition, while the framework of centrosome maturation has been elucidated at the molecular level, the fundamental principle of PCM assembly remains elusive at the organellar level—without an enclosing membrane, what keeps the crowded PCM proteins from dispersing? What glue holds this membraneless ensemble together as a micron- sized centrosome during mitosis? In vertebrates, centrosome maturation is driven in part by pericentrin (PCNT), a large PCM protein linked to human developmental disorders, including primordial dwarfism, microcephaly, and Down syndrome. PCNT acts as a scaffold in the recruitment of other PCM proteins during centrosome maturation. Our recent work reveals that PCNT is delivered co-translationally to mitotic centrosomes and this co-translational targeting of PCNT facilitates centrosome maturation. Our long-term goal is to understand how the centrosome is assembled and functions. The overall objective is to elucidate the role of PCNT in regulating centrosome maturation and PCM assembly. Based on our recent work and preliminary studies, we hypothesize that co-translational protein targeting promotes PCNT phase separation via proximity- driven condensation, a process that facilitates proper PCM assembly, and that PLK1 regulates the co- translational targeting process in addition to its role at the mitotic centrosome. We will test our hypothesis in three specific aims: (1) determine the contribution of PCNT condensation in centrosome maturation, (2) determine the relationship between co-translational targeting and phase separation of PCNT, and (3) determine the molecular mechanisms through which dynein and PLK1 regulate co-translational targeting of PCNT. The molecular mechanisms underlying centrosome assembly in vertebrate cells remain to be elucidated. Understanding these processes is the key to fully understanding how centrosome function is normally regulated and disrupted in human disease.

NIH Research Projects · FY 2025 · 2021-09

The COVID-19 pandemic and the mitigation policies it prompted may have had profound consequences for the psychological health of U.S. adults, including their risk of dying from drug overdose and suicide. To mitigate the spread of COVID-19, some U.S. states enacted policies like stay-at-home orders and business closures. To mitigate adverse economic and health effects, some states enacted policies like eviction moratoria and extended unemployment benefits. These policies may have affected adults’ psychological health and related mortality through social isolation, work-family conflict, interpersonal strain, economic wellbeing, employment disruptions, and more. The overarching objective of this proposal is to rigorously assess how state-level COVID-19 mitigation policies have affected psychological health and related mortality from drug overdose and suicide among working age and older adults. The project is significant and will have a sustained impact because it: 1) identifies how states’ mitigation policies affect psychological health and mortality in both the short and longer- terms, 2) leverages adults’ self-reports of how COVID-19 and mitigation policies affected their lives and psychological health with county-level administrative data on drug overdose and suicide mortality, and 3) empirically develops meaningful composite measures of state mitigation policies to assess their impact on psychological health and mortality. The project is innovative in that it: 1) uses and extends novel survey data from working-age adults on how the pandemic and its mitigation policies affected their lives, 2) uses recently- developed methods for analyzing large contextual datasets containing high-dimensional and correlated data and 3) focuses on the impacts of policies on psychological health and related causes of death, specifically drug- overdoses and suicides, in the short and longer terms. The project will accomplish its objective through three Specific Aims. Aim 1 identifies how U.S. states’ COVID-19 policies are associated with adult psychological health. It uses a new, national survey of U.S. adults aged 18-64 (National Wellbeing Survey) conducted in Feb/Mar 2021 by PI Monnat. Using its self-reported data on how COVID-19 has affected people’s lives, we will assess: a) how states’ COVID-19 policies predict individuals’ psychological health approximately one year after COVID-19 began in the U.S., b) how economic, social, and health care conditions help explain the associations; and c) how the associations vary by age, sex, race/ethnicity, and education. Aim 2 identifies how U.S. states’ COVID-19 policies affected fatal drug overdose and suicide rates at the county level. Using mortality data from the National Vital Statistics System, we will assess: a) the immediate and lagged effects of states’ COVID-19 policies on county-level fatal drug overdose and suicide rates among adults aged 18 and older, b) how economic, social, and health care conditions explain these effects, and c) variation by age, sex, and race/ethnicity. Aim 3 collects four new annual waves of the NWS, in close collaboration with the Consortium, to identify longer-term consequences of states’ COVID-19 policies and individuals’ adaptations on adult psychological health.

NIH Research Projects · FY 2025 · 2021-09

Nearly one in five human proteins are post-translationally lipidated, and while the critical role of post- translational modification in regulating different facets of cell biology (e.g., signaling, membrane localization, etc.) has been well established, many mechanistic questions remain unanswered. These include the effects of lipidation on the energetics, conformations, and function of lipidated proteins (LP) — and on human diseases. Advancing our understanding of protein lipidation at the biophysical level and elucidating the sequence– structure–function rules in various biological milieus, require study of the changes in protein structure and conformation as the physicochemistry of lipid, lipidation site, and proteins are systematically modified. However, such efforts have been stymied by the challenging and laborious methods to synthesize lipid- modified proteins. To advance understanding of protein lipidation, my program will genetically engineer prokaryotes to incorporate a diverse set of lipids into proteins, enabling the rapid generation of comprehensive libraries of model LPs with broad physicochemical diversity. The overarching hypothesis of this program is that the biophysical consequences of protein lipidation is governed by a “molecular syntax”, which is based on the interplay between the physicochemistry of the lipid, protein, and the lipidation site that (de)stabilizes folding or assembly of intermediates via (non)native interactions between lipid, protein sidechains, and the aqueous milieu. To test this hypothesis, diverse and complementary biophysical and soft-matter characterization techniques will be used to (1) study the tertiary structure and quaternary organization of model globular and disordered LPs across three distinct structural hierarchies—single protein chains, lipid-driven supramolecular assemblies, and liquid-liquid phase separation-driven higher-order assemblies (condensates); and (2) quantify the contribution of these structures and the LP’s physicochemistry to encoded functional/material properties such as biomolecular switching, viscoelasticity, and contact mechanics. By establishing platforms to engineer sequence-defined LPs and revealing a rigorous, biophysically rooted molecular syntax underlying their structure and energetics, this research program will substantially broaden the design space and functional landscape of biomolecules beyond protein’s amino acid-based motifs. Ultimately, this program will enable a better understanding of the role of LPs in diverse biological mechanisms in health and disease, and the development of materials and therapeutics with complex structural and functional properties whose capabilities rival natural biosystems for wide applications in nanomedicine and biotechnology.

NIH Research Projects · FY 2025 · 2021-08

ABSTRACT Cell migration is essential to many fundamental processes, including embryonic development, wound repair, and cancer metastasis. Central to this process is the cellular cytoskeleton comprised of three polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that is essential to the mechanical resilience of cells and regulates cross-talk amongst the cytoskeleton, but its role in how cells squeeze through small pores in tissues is poorly understood. We have shown that loss of vimentin enhances cell motility through three-dimensional 3D micro-fluidic channels and protects the nucleus from damage during migration. Vimentin is thought to play a distinct role in the transfer of forces from cell surface matrix adhesions to the nuclear surface, but new evidence suggests that vimentin may also play a more active role in persistent cell motility via its interactions with actin stress fiber formation and microtubule positioning. Still, the specific mechanisms by which vimentin enables 3D migration through dense tissue remains unclear. This project addresses the overarching question: how does vimentin influence cytoskeletal functions, adhesions with the extracellular matrix, and cell-cell interactions to coordinate 3D cell migration? To address this question, we will pursue three sub-projects. First, we will determine the effects of vimentin in cytoskeletal- mediated 3D cell motility. Second, we will identify vimentin’s role in integrin expression and focal adhesion activation, and third, we will identify the mechanisms by which vimentin mediates collective cell migration through extracellular matrix networks. These studies will be conducted in both 2D and 3D settings to define how changes in the cellular environment impact the critical determinants of cytoskeletal polymers in cell motility. We expected that these projects will determine new functional roles of vimentin in cell migration, which has important implications for understanding healthy tissue maintenance and diseases that progress by the migration of cells through tissues.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT Defects in programmed cell shape changes during embryonic development can disrupt organ morphogenesis and cause structural birth defects. There are fundamental gaps in our understanding of how cells change their shape during organ formation. While the biochemical signals and morphogen gradients that help govern organogenesis are well-studied, evidence is growing that robust control of organ form and function often also depends on multiple mechanical mechanisms that remain poorly understood. Thus, there is a critical need to tease apart how multiple mechanisms – including tissue-scale dynamic forces and cell-autonomous contractile forces – work together to generate “mechanical gradients” that program cell and organ shape during organ formation. A challenge is that mechanical perturbations that affect the entire embryo often result in the same global phenotype, making it difficult to pinpoint the role of each mechanism. Our long- term goal is to develop a combined cell biology and modeling toolkit that allows us to predict cell-scale phenotypes and appropriate perturbations that can be used to distinguish between multiple mechanical mechanisms. This project uses Kupffer’s vesicle (KV), a transient epithelial organ that establishes left-right asymmetry in the zebrafish embryo, as a model system. No upstream biochemical signaling gradients have been identified that regulate KV cell shapes as required for left-right patterning, but multiple mechanical mechanisms have been implicated. Preliminary results – from (4D = 3D + time) experimental perturbations and measurements of single KV cell shapes, and novel mathematical models that simulate interacting 3D tissue structures while retaining cell-scale resolution – lead us to formulate our central hypothesis that cell shape changes critical for KV organogenesis result from mechanical gradients generated by interactions between the KV and surrounding tissue structures as well as cell-autonomous contractile forces from inside KV. The goal of Aim 1 is to determine how interactions between KV and notochord impact cell shape changes. 4D modeling predictions for cell shapes and cell movement combined with live in vivo imaging and localized laser ablations will determine how asymmetric forces generated by the rod-like notochord impact KV cell shape changes during organogenesis. The goal of Aim 2 is to understand mechanisms by which actomyosin contractility in surrounding tailbud cells and inside KV generate KV cell shape changes. Novel mathematical models will predict how localized optical perturbations to tailbud mechanics, as well as perturbations to volume and cell- autonomous contractility in cells inside the KV, affect KV organ shape. Key outputs include a modeling toolkit for high-throughput simulations of dynamic interactions between complex 3D tissue structures complemented by a cell biology toolkit that tests model predictions with spatially and temporally modulated activation of biomechanical and biochemical signaling molecules. These results will pinpoint mechanical mechanisms that regulate organogenesis, and may ultimately aid in the prediction or prevention of birth defects.

NIH Research Projects · FY 2026 · 2020-08

PROJECT SUMMARY Intrinsically disordered protein regions (IDRs) exist in over 70% of the proteins in the human proteome. Despite this abundance, the mechanistic underpinnings of IDR function remain largely unknown. An emerging consensus is that the structural preferences of IDR ensembles - the collection of interconvertible structures in which they exist - can determine their function. In the past five years, my lab has developed new computational and experimental tools to study these ensembles in live cells. Our research showed that structural preferences of IDR ensembles persist inside the cell, but at the same time can be sensitive to changes in sequence or in cellular composition. The functional implications of this sensitivity, however, remain unresolved. My goal for the next five years is to understand how structural preferences in IDR ensembles, and changes to these preferences, affect IDR function. I target three knowledge gaps: 1) When do ensemble structural preferences affect IDR function? 2) Can disease-linked, single-point missense mutations alter ensemble structure and function? 3) Can changes to ensemble structural preferences, caused by a stressed cellular environment, alter IDR function? To bridge these knowledge gaps I will focus on IDRs in transcription factors (tfIDRs). Transcription factors are DNA-binding proteins that initiate gene transcription. Remarkably, the sequence of most of the ~1,500 transcription factors in the human proteome is largely disordered. It is widely accepted that tfIDRs play key roles in recruiting transcriptional machinery, but the mechanism by which they do this, how they may perform other functions, or how functions are modified by changes in their ensemble, remains unknown. Studying the ensemble-function relationships using tfIDRs is ideal because of their clear downstream product - mRNA or gene expression - which provides a quantitative handle on their activity. Experiments targeting these knowledge gaps will focus on using methods previously developed and validated in our lab to correlate tfIDR structural ensemble with transcriptional activity in live cells. Successful completion of these experiments will uncover the impact of mutations and environmental changes on tfIDR function, and reveal fundamental mechanisms in transcription factor function, regulation, and dysfunction. More broadly, our experiments will provide a clear demonstration that the context-dependent structures of IDR ensembles can change their function, turning them into sensors and actuators of the cellular environment.

NIH Research Projects · FY 2024 · 2020-07

Project Summary/Abstract for the Center for Aging and Policy Studies (CAPS) The overarching goal of the Center for Aging and Policy Studies (CAPS) is to improve the health, well-being, and independence of older adults by directly addressing some of today’s most pressing issues facing middle- age and older adults and the families that care for them. Scientific research at CAPS focuses on two signature themes of health and well-being and family and intergenerational supports and three cross-cutting themes of policy, place, and specific populations. These signature themes are long-standing and essential areas of study, while the cross-cutting themes have emerged as critical determinants of older adult health, well-being, and independence. Significantly, by emphasizing policy and place as cross-cutting themes, CAPS brings a distinctive and vital dimension to the NIA Centers on the Demography and Economics of Aging program. The innovative organizational approach of CAPS provides a firm foundation for achieving its overarching goal. First, CAPS will use a hub-and-spoke operational model encompassing three R1 institutions in Upstate New York with a long history of collaboration on the demography and economics of aging. Syracuse University will serve as the hub, with nearby Cornell University and the University at Albany–State University of New York as the spokes. Guided by state-of-the-art principles of collaborative management, this model combines the benefits of both a brick-and-mortar Center and a virtual network that is nimble, cost-effective, and wide-reaching. Second, CAPS will have a strong, multi-disciplinary, five-person leadership team comprised of scientific leaders experienced in directing NIH-funded Centers and cross-site programs. Third, CAPS will offer a strategically selected and tightly coordinated set of activities across its Administrative Core, Pilot Core, and Dissemination Core. CAPS will achieve its goal through three overall specific aims. Aim 1 is to foster innovative and interdisciplinary research on CAPS signature and cross-cutting themes. CAPS will achieve this aim through multiple dynamic activities, including its integrated pilot project program; teaming program featuring a research incubator; and visiting scholars program. Aim 2 is to enhance human capital in population-based aging research among emerging, underrepresented, and established scholars. CAPS will provide numerous opportunities for scientific development among CAPS affiliates and non-affiliates, including an onsite-online colloquium series, grant writing workshops, and workshops on new methods related to CAPS thematic areas. Aim 3 is to advance understanding of the latest population-based aging research by disseminating findings and data resources to scientists, practitioners, decision makers, and the public. CAPS will draw on the communications expertise at its three sites, and their extensive social media reach, to disseminate information that is timely and broadly accessible. Contributing to the greater scientific enterprise, CAPS will promote the use of its primary data collection through data user sessions at national conferences and by coordinating with other NIA-funded Centers to link CAPS place-based data to existing survey data on older adults.

NIH Research Projects · FY 2025 · 2020-04

Project Summary Currently, drug embryotoxicity risk for safe pregnancy is not well established, thus many pregnant women are exposed to the drugs with unknown effects on fetus development. Many drugs are still neither well understood regarding their effects on human organogenesis, nor is there a well-established human embryotoxicity drug screening platform available. Currently, human induced pluripotent stem cells (hiPSCs) have been proposed for human-relevant drug toxicity screening. However, the use of hiPSC maintenance and differentiation on 2D culture is not an ideal embryotoxicity assay due to their inability to predict the drug toxicity on 3D tissue morphogenesis, which potentially leads to the structural malformations manifested in late prenatal fetus development. With the emergent concept of stem cell organoids, these 3D cultures of developing tissues imply the similarity to the manner in which different organs establish their characteristic organization during development. Therefore, the overall goal of this proposal is to establish an in vitro hiPSC-based cardiac organoid model for embryotoxicity testing based on the drug effects on hiPSC growth, cardiac differentiation, and early heart formation, so we can establish a risk classification system for more precise assessment of human-specific drug effects on early embryonic development. To achieve this goal, we will pursue three specific aims. In Aim 1, we will optimize the cardiac organoid model by investigating the effects of biophysical confinement on the formation and function of cardiac organoids. In Aim 2, we will validate the cardiac organoid-based embryotoxicity assay by comparing to well-established standard zebrafish whole embryo culture assay. By testing a “training set” of chemicals with known embryotoxicity level, we will better calibrate the drug response from human cardiac organoids based on a variety of endpoint evaluation parameters. In Aim 3, we will establish a new biostatistical predictive model based on linear discriminant analysis for embryotoxicity risk classification. We envisage that this in vitro cardiac organoid model can improve traditional pharmaceutical screening for the drugs that will be administered during pregnancy.

NIH Research Projects · FY 2025 · 2016-08

This conference grant proposal seeks support for the Annual Scientific and Technology Meeting of the American Auditory Society, which is unique in the field of hearing and balance because of the focus on clinical/translational research. Support is requested to provide 1) Translational Research Lectures, 2) an Interdisciplinary Session addressing a new or controversial topic, 3) a lecture by a New Investigator 4) 20 competitively awarded Mentored Student Travel Awards for Student and Resident Posters, and 5) Career Development experts to lead workshop-type sessions. The Translational Research Lectures provide support to invite prominent scientists from related fields to present their research and interact with attendees. These lectures, often from basic scientists, have been stimulating and exciting and receive high ratings from the AAS participants. The Interdisciplinary Session provides a forum for discussion of a controversial topic in the field that is presented from different scientific viewpoints. The topics for all lectures chosen are based on member suggestions, so they are timely and of interest to the membership. Support for the New Investigator Lecture is requested to provide an inspirational talk aimed specifically towards graduate students, post-doctoral fellows, and residents. This award acknowledges early excellence in the individual scientist and also serves to motivate aspiring scientists and clinicians. To foster scientific development among students and residents and invest in the future, we propose to support twenty (20) graduate students or otolaryngology residents with Mentored Student Travel Awards to present their research in the form of posters. This mechanism is designed to encourage promising students/residents to attend the meeting, become integrated with other clinical scientists, benefit from the stimulating lectures, and form collaborations. An innovative component of the meeting that is new with this submission is the plan for a series of two Career Development workshop sessions and activities. One session will focus on career development topics relevant to students and new researchers and the second will provide support for topics germane to established researchers. Topics will be chosen based on data from attendees at previous meetings. Abstracts and summaries of the information from the meetings will be distributed at the meeting and posted on the website. The outcome of the annual meeting will be judged by the participants through surveys and questionnaires, with special questionnaires for students and new scientists on how the society can support them. The information will be reviewed annually by the Executive Board, as well as the Program and Student and Mentoring Committees. Suggestions will drive content that will be incorporated into future meetings.