Ohio State University

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY We propose a multi-center hybrid type I effectiveness-implementation trial to assess patient-facing evidence- based guidelines through a mHealth application plus (+) booklets in adults with sickle cell disease (SCD). Clinicians’ care of SCD is informed by evidence-based guidelines, which target the prevention of morbidity and mortality. The National Heart, Lung, and Blood Institute (NHLBI) and the American Society of Hematology (ASH) published guidelines for evidence-based management of SCD for healthcare providers. However, patient, provider, or system barriers prohibit adequate reach within and across all three domains, leading to poor guideline adherence. Our prior work demonstrates 1) the patient’s lack of knowledge of evidence-based guidelines, 2) the desire for guidelines to be patient-centered, accessible, and actionable in booklets and a mHealth app, 3) the development of patient-facing booklets with the guidelines, and 4) the successful pilot of an engaging mHealth app with the guidelines that adults with SCD will use. Promising preliminary data from our multi-center feasibility randomized controlled trial support using a mHealth app + booklets with patient-facing guidelines for reducing acute healthcare utilization in adults with SCD. In this feasibility trial, 91% (67 of 74) of screened participants were recruited and randomized into one of the two arms: (1) mHealth + booklet arm or (2) booklets alone arm. A total of 75% (50 of 67) of the participants agreed to be followed up for six months to assess healthcare utilization and answer surveys of knowledge and patient- reported outcomes. The mHealth + booklet arm had a 44% reduction in relative risk in acute healthcare utilization (a decrease of 1.5 emergency room visits or hospital admissions per year) compared to the booklet alone arm. Based on the preliminary results, we propose a three-center randomized controlled trial in adults with SCD (n=272) to test the following hypothesis: There will be a 44% relative risk reduction of acute healthcare utilization in adults with SCD, randomly allocated to mHealth app + booklets vs. standard care, defined as general guidance without patient-facing educational materials, for 12 months. The aims of this proposed study are Aim 1: evaluate the effectiveness of the patient-facing guidelines mHealth app + booklet intervention to decrease acute healthcare utilization (hospitalizations, emergency room visits, and day hospital visits) in adults with SCD over the standard care in a randomized controlled trial. Aim 2: evaluate the implementation outcomes of the mHealth app + booklet using the capability, opportunity, and motivation- behavior (COM-B) and reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) frameworks and Aim 3: evaluate the cost-effectiveness of patient-facing mHealth app + booklets vs. standard care in adults with SCD. This hybrid effectiveness-implementation trial design, according to the COM-B and RE-AIM frameworks with a mixed-methods approach, will give valuable insights into the effects, facilitators, and barriers to the implementation that will influence the effects of the patient-facing guidelines intervention.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Viral infections remain a challenging public health issue worldwide. The presence of many viruses, such as Influenza A and Hepatitis C, activate a latent Ribonuclease (RNase L) in human cells. Activated RNase L cleaves the single stranded regions of viral and host mRNAs. Cleavage of these RNAs leads to physiological changes in the cell, such as autophagy, senescence, decreased cell motility, interferon production and cell death. However, many aspects of RNase L activation in cells are not yet understood. Recent in vivo and in vitro kinetic studies suggested that RNA cleavage by RNase L is modulated in the cell by an unidentified factor. RNase L can directly interact with the ribosome and with several translation factors involved in different steps of protein synthesis. Due to these interactions it was proposed that RNase L’s cleavage activity is modulated by the translation of the host messenger RNAs (mRNA). Therefore, in specific aim 1, I will investigate this relationship between host mRNA cleavage by RNase L and translation at the global and individual gene level by combining two high-throughput sequencing methods, ribosome footprint profiling and RNA sequencing in RNase L activated human cells. In addition, ribosome-mediated RNase L cleavage activity will be also directly observed at the individual gene level by a novel technique, the real-time fluorescent single molecule detection of translating nascent peptides (SINAPS) in living cells. In aim 2, I will also explore the potential involvement of translation factors in translation-mediated RNA cleavage by RNase L by first mapping the details of interactions of RNase L and translation factors by mutagenesis studies and Cryo-Electron Microscopy. Then these interactions will be disrupted in living cells to probe their potential involvement in mediating RNA cleavage by RNase L. Furthermore, RNase L activation can lead to many physiological changes in the cell, such as autophagy and apoptosis. It is plausible that the level of active RNase L is the determinant of which physiological processes will occur. To investigate the correlation between active RNase L levels and RNase L mediated changes in the cell, I will develop a fluorescent RNase L activation indicator that will allow us to sort cells into homogenously activated populations in aim 3. Subsequently, in these sorted cells I will detect changes in the transcriptome and translatome and assess signatures of physiological changes of autophagy and apoptosis in the context of RNase L activation levels. In addition, I will also study how RNase L cleaved host RNA fragments contribute to activation of innate immune response pathways in cells by using Cross-linking Co-Immunoprecipitation and sequencing (CLIP-seq). In summary, the proposed project will investigate unexplored aspects and outcomes of RNase L activation. Uncovering new aspects of the defense against viral infections will enable further studies and potentially contribute to the development of new therapeutic strategies.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This exploratory study addresses the challenge of developing an effective HIV vaccine by focusing on natural killer (NK) cells and their ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Building on the RV144 vaccine regimen, which demonstrated some efficacy in preventing HIV infection, the study explores using a novel oral adjuvant to enhance NK cell cytotoxicity and ADCC activity in the nonhuman primate model. Preliminary studies in a murine model showed promising results with this adjuvant, leading to the expansion of KLRG1+ NK cells known for their ADCC capacity. The study aims to investigate phenotypic, functional, and molecular changes in NK cell subsets in various tissues following RV144-like vaccination with the novel adjuvant. Additionally, the research aims to assess the enhanced antiviral effects and increased ADCC capability of NK cells induced by the combined vaccine and novel adjuvant. This innovative approach seeks to discover a novel vaccine adjuvant that strengthens NK cell activity against SIV/HIV in different tissues, potentially advancing the development of preventive HIV vaccines and therapeutic interventions.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Acute Myeloid Leukemia (AML), driven by rapid myeloid cell proliferation, presents a significant challenge due to its high mortality and limited treatment options. Despite advances in AML biology, chemotherapy remains the primary treatment, often failing to prevent relapse. Immune checkpoint blockade (ICB) therapies, effective in solid tumors, show limited efficacy in AML, likely due to distinct immune pathways in its tumor microenvironment (TME). This underscores the need for therapies targeting AML’s unique immunosuppressive environment. PD- 1H (Programmed Death-1 Homolog, also known as VISTA) has emerged as a promising immunotherapeutic target. Our recent studies reveal that PD-1H is highly expressed in the AML microenvironment, and mouse models show that PD-1H promotes immune suppression and accelerates AML progression, underscoring its therapeutic potential. These findings set the stage for determining the mechanisms by which PD-1H regulates immune suppression in AML and its potential as a therapeutic target. Aim 1 seeks to elucidate the cellular and molecular mechanisms by which PD-1H mediates immune suppression in AML. We hypothesize that (1) PD-1H shifts myeloid cell populations from pro-inflammatory to anti-inflammatory states, and (2) uses its unique structural domains to interact with LRIG1 on T cells, leading to direct T cell suppression. To test this, we will use myeloid lineage-specific PD-1H knockout mice, combined with single-cell profiling and functional assays, to analyze how PD-1H regulates different myeloid lineages within the AML microenvironment. We will then use PD-1H structural mutants to identify critical functional domains underlying immune suppression. To examine LRIG1’s role as a receptor, we will employ LRIG1 knockout T cells and T cell-specific LRIG1 knockout mice to determine its role in T cell inhibition and AML progression. Aim 2 focuses on developing novel immunotherapeutic strategies by targeting the PD-1H pathway in AML. We hypothesize that PD-1H inhibition will enhance anti-AML immunity. To thoroughly assess the role of PD-1H in human AML, we will analyze longitudinal bone marrow samples from AML patients at various stages to track the expression dynamics of PD-1H and other immune checkpoint markers. We will test new monoclonal antibodies that fully block PD-1H/LRIG1 interaction, evaluating their efficacy in primary mouse AML models and humanized AML models with patient-derived xenografts. We will also test a novel combination of anti-PD-1H with anti-TIM3 in AML. This approach integrates patient-derived data with in vivo efficacy testing to support the translational potential of PD-1H-targeted therapies, laying the groundwork for clinical applications. This project combines mechanistic studies with innovative therapeutic approaches, aiming to establish PD- 1H as a central target in AML. By addressing AML's immune-suppressive TME through PD-1H, we hope to advance immunotherapeutic strategies that could significantly improve patient outcomes.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Cardiac muscle contraction fundamentally relies on the activity of myosin to generate force. For a basic understanding of cardiac muscle contraction and to address the unmet needs in treating heart diseases, it is essential to elucidate the molecular mechanisms by which cardiac myosin and its regulatory partner, cardiac myosin-binding protein-C (cMyBP-C) modulate force generation. A disruption in the equilibrium between the structural states of cardiac myosin is known to cause altered energy consumption and impaired muscle contraction. Thus, manipulation of myosin structural states is a promising approach to treat cardiomyopathies. However, our understanding of the basic mechanisms underlying the regulation of myosin structural states is poor. In particular, the lack of detailed structural information on myosin and cMyBP-C interactions presents a significant barrier to developing more effective approaches to manipulate myosin structural states to benefit patients. Therefore, the central goal of this proposal is to fill this knowledge gap by establishing previously unrecognized structural and functional mechanisms in basic thick filament function. To achieve this goal, we have devised a unique experimental plan and a multidisciplinary team to systematically address thick filament function from the atom to whole organ levels. In Aim 1, we will determine the structures of distinct myosin states in a double-headed configuration. In Aim 2, we will determine how myosin conformations govern cMyBP-C binding and regulate cardiac thick filament. In Aim 3, we will determine the in vivo functional consequences of manipulation of thick filament structure using cMyBP-C phosphorylation and myosin binding small molecules. Collectively, these studies will enhance our understanding of basic biological processes mediated by myosin and cMyBP-C in the heart and have the potential to advance the development of more precise cardiac thick filament targeted treatments.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Research shows that nearly half of suicide decedents visit a health care provider in the weeks prior to their death. Yet, existing suicide screening approaches in healthcare settings fail to identify most patients who go on to engage in suicidal behavior (SB) or die by suicide. We propose a large-scale study to develop clinically actionable strategies to identify which individuals will experience clinically meaningful increases in suicide risk, what tools or behavioral markers are most sensitive to detecting transitions between suicide risk states, and when these shifts are likely to occur to inform clinical care. The proposed study builds on our team’s extensive expertise in large-scale recruitment, intensive longitudinal assessment, behavioral phenotyping, clinical signatures of suicide risk, and dynamic and computationally intensive modeling approaches to risk prediction. Approximately 13,500 participants between the ages of 18 and 55 will be recruited, representing varying levels of risk for suicide. Most participants will be recruited nationally with postcard mailings to targeted zip-code representative areas (n=8- 10,000), and include those with a primary health care visit in the past 3 months (lowest risk category). Additional, higher-risk participants (n=4200) will be recruited based upon recent health care visits, including individuals from depression clinics, PTSD programs, psychosis and risk for psychosis clinics, sleep clinics, pain clinics, and clinics for underinsured people, to include a range of moderate and high risk groups for suicide risk. We will collect six total weeks of self-report assessments, with ecological momentary assessment, cognitive and affective behavioral tasks, and passive sensing data to develop a richly phenotyped sample for modeling variable trajectories of suicide risk over time (Aim 1). We will leverage this data to predict temporal patterns that signal transitions from low to high-risk states, and vice versa, using innovative and computationally intensive dynamical systems analyses (Aim 2). We will identify individual characteristics that modulate these transitions and identify the minimum data required for robust model estimates (Aim 3). With the completion of this project, a novel computational approach to signaling an individual patient’s current probability for transitioning to a higher or lower suicide risk state within clinically relevant timeframes (days to weeks) will be available, along with a rich cross-diagnostic dataset of cognitive, affective, and behavioral data from a nationwide sample.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY All life forms must maintain a homeostatic gene expression program, which is achieved at many different steps in gene expression, including by the degradation of specific mRNAs and non-coding RNAs. Many evolutionarily conserved RNA processing enzymes mediate these key post-transcriptional events, with important roles for endo and exoribonucleases. A number of inherited diseases are caused by mutations in endo- or exoribonuclease genes, further underscoring their importance for human health. Eukaryotes use exonucleases for the degradation of most cellular mRNAs and for the 5' and 3' end processing of many different ncRNAs. In addition, endonucleases target specific mRNAs as an initiating step in mRNA degradation and other endonucleases process ncRNAs. This proposal will focus on the functional characterization of ribonucleases, especially functions in cytoplasmic mRNA degradation.

NIH Research Projects · FY 2024 · 2025-08

Project Summary Up to 70% of manual wheelchair users experience shoulder pain, and as many as 90% develop pathologies like rotator cuff tendinopathies and glenohumeral instability. This can have profound negative effects on quality of life through reduced participation in everyday activities and can increase the lifetime risk of secondary medical conditions like cardiovascular disease through reductions in physical activity. Yet, clinical guidelines for the preservation of upper limb function in manual wheelchair users are only applicable to users with adult-onset disabilities, and do not account for sex. As a result of this gap in knowledge, pain begins in adolescence and increases significantly during the transition to adulthood in users with pediatric-onset disabilities. In addition, the increase in pain during this period is far greater for females than males, even when accounting for years of wheelchair use. Our central hypothesis is that this sex-related divergence in pain is precipitated by sex-specific musculoskeletal adaptions to wheelchair use in childhood and adolescence. During this period of life, females experience far lower upper extremity muscle and bone growth velocities and a shorter window in which to adapt to wheelchair use. Moreover, musculoskeletal adaptations are driven by the mechanical demands one experiences. We have evidence that wheelchair use is far more demanding of upper extremity musculature for females than males, even when accounting for individual size. We will test our central hypothesis by establishing the relationships between sex-specific adaptations to (Aim 1) glenohumeral muscle morphology, (Aim 2) scapula shape, and (Aim 3) scapular kinematics and pain, while accounting for years of wheelchair use and arm dominance. Our approach will leverage bilateral magnetic resonance imaging to determine the influence of sex and wheelchair use in childhood and adolescence on the balance of glenohumeral musculature and the shape of the glenoid and acromion, advanced biomechanical modeling to determine adaptations to scapular kinematics at rest and during humerothoracic elevation and wheelchair propulsion, and patient-reported outcomes to quantify shoulder pain and pain interference. We expect to reveal sex-specific musculoskeletal adaptations to wheelchair use in childhood and adolescence associated with pain that can be immediately addressed with established rehabilitation paradigms including strengthening exercise and motor training. Moreover, the results of the proposed research will provide foundational knowledge for the development of sex-specific wheelchair use guidelines for pain prevention. Finally, we expect to uncover potential mechanisms underlying the development of glenohumeral instability and rotator cuff pathologies. By determining the etiology of shoulder pain with consideration for sex, we hope to increase equity in the prevention and rehabilitation of secondary musculoskeletal conditions associated with manual wheelchair use.

NIH Research Projects · FY 2025 · 2025-08

Raman Spectroscopy for Rapid Non-invasive Radiation Exposure Triage A radiological (Rad) incident from a nuclear (Nuc) reactor accident or a terrorist attack using an improvised nuclear device (IND) can generate mass casualties from exposure to substantial doses of ionizing radiation. Effective treatment requires triage methods that can rapidly assess exposure greater than 2 Gy and then higher doses, where medical outcomes are known to change significantly. Depending on the absorbed dose, the onset and intensity of Acute Radiation Syndromes (ARS) and Delayed Effects of Acute Radiation Exposure (DEARE) will vary. Early detection of the extent of radiation injury and rapid triage are critical for timely administration of medical countermeasures. There is no current method available for rapid triage based on biochemical evidence of exposure. In this project, we propose to combine Raman spectroscopy and artificial intelligence to generate and assay for exposure to ionizing radiation greater than 2 Gy and then to assess whether larger doses (>5 Gy), where outcomes are less favorable, can be further distinguished. To develop our model, we will use hair plucked from mice exposed to controlled doses of radiation. We will assess the extensibility of these models by testing against samples obtained from other mouse strains, nonhuman primates, and human patients undergoing radiation therapy. We hypothesize: 1) The changes in pigment can be observed and used for triage applications where exposure is > 2 Gy; 2) Biochemical changes in the hair root can be correlated to exposure independent of pigmentation in the hair. We will further evaluate confounding factors, such as the type of radiation exposure (e.g. – gamma rays, x-rays, or neutrons), sex, and strain; to further assess the applicability of the changes observed in mice to other animal models to facilitate translation to humans. To accomplish these goals, we will pursue the following specific aims: 1. Determine and assess the extensibility of Raman spectroscopy on melanin in the hair shaft for triage decisions. 2. Determine and assess the extensibility of hair root Raman signals from triage decisions. These data will improve dosimetry models and facilitate improved triage decisions in the event of a mass nuclear tragedy or other radiation exposure events.

NSF Awards · FY 2025 · 2025-08

This collaborative research project investigates the factors that impact variability in STEM training programs across the nation. The investigators specifically measure the institutional factors that contribute to development of career-ready science curricula and how successful best practices can be leveraged for translational impact on workforce development for industry. The investigators also identify strategies for addressing curricular challenges with a goal of strengthening the STEM workforce. The broader impacts identify strategies for curricular and institutional change in STEM training programs that would support the workforce and career development of students and translate to leveraging partnerships between higher education and industry. The project has a significant training component in research methods and best practices in STEM translational research for students at the PI and Co-PI institutions. The study sample represent a range of educational institutions across the nation. Interview, focus group, and behavioral data will be collected with stakeholders in STEM training and education, and with undergraduate and graduate students and alumni at each institution to understand the factors that impact the development of a career-ready STEM curriculum. The research is focused on measuring institutional change in STEM training and education, and the training and reskilling/upskilling of the STEM workforce for education and industry. Broader impacts leverage partnerships with various sectors to enable the translation of STEM education to other sectors of priority in the economy. 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 2025 · 2025-08

The field of dynamics studies how processes evolve over time, such as the motion of planets, population growth, or the behavior of digital networks. The mathematical theory of dynamical systems offers a powerful language to describe these changes, uncover patterns, predict future behavior, and identify when systems may become chaotic. One-dimensional holomorphic dynamics is a mature field of mathematics, rooted in the famous work of Fatou and Julia on fractal sets. In contrast, higher-dimensional holomorphic dynamics is a newer but rapidly developing area, marked by fundamentally different behavior and rich phenomena absent in the one-dimensional setting. The PIs will advance understanding of dynamical systems in several complex variables by bridging this gap between dimension one and higher dimensions. The project will also provide training opportunities for graduate students and postdoctoral researchers. This is a project funded jointly by the National Science Foundation's Division of Mathematical Sciences, in the Directorate for Mathematical and Physical Sciences, and the Romanian Executive Agency for Higher Education, Research, Development and Innovation Funding (UEFISCDI), in accordance with the Memorandum of Understanding between the NSF and UEFISCDI. The PIs will investigate the dynamics of higher-dimensional germs of holomorphic diffeomorphisms, particularly those with neutral fixed points, which pose unique challenges. A key goal is to characterize the structure of the dynamical system near the fixed points and to extend concepts like hedgehogs—intricate invariant sets from one-dimensional dynamics—to higher dimensions, especially in the setting of conservative holomorphic germs. The PIs will also analyze the dynamics and bifurcations of polynomial automorphisms of two-dimensional complex space, with particular attention to the relationship between Julia sets and critical loci—sets of tangencies between dynamically defined foliations. The research activity conducted under this award will generate pioneering techniques in higher-dimensional dynamics, with impact in other areas of mathematics such as topology and geometry. 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 2025 · 2025-08

Neural stem cells are cells that divide to create new neurons and other supporting cells in the nervous system. In adult mammalian brains, neural stem cells are rare, existing in only a few, distinct subregions. One of these subregions, the hippocampus, relies on new neurons generated by neural stem cells to support memory processes. Within the hippocampus, there are many signals that can regulate whether neural stem cells survive and continue to make new neurons throughout life. One of those signals is the abundant neurotransmitter glutamate. Glutamate stimulates neural stem cell division and new neuron production, but it is unclear how. The investigators’ data point to a surprising role of a glutamate transporter as a way that glutamate is brought into neural stem cells and then used to fuel metabolism and promote neural stem cell division. This project uses mouse models to investigate the mechanism by which glutamate promotes healthy self-renewing neural stem cell division and new neuron generation. The research portion of this project will inform the public-health-relevant field of neural stem cell transplants for brain disease/injury. The project’s research activities are coupled with several outreach activities. For instance, a new, freely available textbook for Behavioral Neuroscience launched by the lead investigator is developed further to include art and videos produced by and explaining relevant research carried out by students. By being free, the textbook reduces financial barriers to neuroscience education throughout the U.S. In addition, the project includes summer research opportunities for undergraduate students and summer lab tutorials for local high school students. Neural stem cell (NSC) interactions with their niche are critical to supporting hippocampal function in adult mammals. The adult dentate gyrus, the hippocampal subregion where NSCs reside, is characterized by abundant glutamatergic signaling from resident neuronal populations. NSCs proliferate robustly in response to glutamatergic activity, providing a parsimonious mechanism whereby neurogenesis can be linked to activity demands of local circuits. Yet, attempts to define the molecular mediator of glutamate influence on NSCs have produced perplexing findings. Though glutamate receptor activation would be the canonical mechanism, manipulating these receptors directly has produced conflicting findings. The investigators’ preliminary data suggest that NSCs interact with glutamate directly via abundantly-expressed excitatory amino acid transporters (EAATs), particularly EAAT1. The project’s objective is to investigate the role of EAAT1-mediated glutamate transport in NSC self-renewal. The central hypothesis that EAAT1 cell-autonomously supports NSC self-renewing proliferation is tested by providing metabolic stimulation in adult mice. The proposed studies will establish NSC-expressed EAAT1 as a unique mechanism by which adult NSCs can respond to niche signals. As such, the project advances foundational understanding of NSC functional capabilities. Broader Impacts are achieved through the applicability of these findings to the development of stem cell-based therapies, as well as outreach activities focused on expanding an openly accessible undergraduate textbook, incorporating undergraduates in summer research, and holding lab practicals for summer high school students. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-08

The objective of this EArly-concept Grant for Exploratory Research (EAGER) project is to support research on developing new economic theory and estimation models for studying dynamic economic resilience—how these firms can bounce back rapidly and cost-effectively. The research intends to facilitate optimal investment decision-making for businesses, government, insurance companies, and other key decision makers in the aftermath of disasters. Small and mid-sized enterprises (SMEs) are the lifeblood of our economy. Unfortunately, many SMEs hit by catastrophic disasters go out of business or face a long and costly recovery. In many regions of our country, these SMEs are also hit more than once, and some are still recovering from a prior disaster. This research aims to support the cost-effective decisions regarding the timing and level of investment in repair and reconstruction activities, ensuring that businesses and insurance companies do not spend unnecessarily. When hit by a disaster, businesses scramble to repair damaged facilities, work around disrupted utility services, manage a disrupted workforce, or respond to other key disruptions in their operations. Knowing which investments in repair and reconstruction are going to be most effective and cost-effective, and knowing when to invest, are critical to achieving successful recovery. This project seeks to develop microeconomic production theory and resilience metrics to improve our collective understanding of how decision makers can improve these important decisions. The research then looks to map the theory and metrics to a data collection effort, using advanced survey techniques to collect economic and recovery data from firms hit by recent disasters. The work then seeks to develop statistical approaches for evaluating those data to identify optimal investment in dynamic economic resilience. These activities could help identify best practices and obstacles that limit efficient recovery. They can also potentially inform federal, state and local agencies of more targeted policies. Ultimately, efficient recovery reduces the need for public-sector assistance, reduce insurance liabilities, and improves economic development. 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 2025 · 2025-08

This project develops a statistical framework for understanding Digital Twins, a next-generation technology that integrates modeling, data collection, prediction, and decision-making in a two-way, real-time cycle for a physical, biological, or engineering system. This project explores a Digital Twin for a robotic surgical plate bending system that is integrated into a virtual surgical planning process to assist surgeons in planning and executing cranio-facial reconstructive surgery. This Digital Twin could maintain synchronized models of a human mandible after traumatic injury and a surgical fixation plate designed to stabilize it. A robotic plate bender - part of the system’s physical asset - would iteratively bend the plate, monitor changes in its shape, update the corresponding digital model, and plan the next bending operation, all in real time. This model is then coupled with the patient’s jaw geometry to ensure that the applied forces will not induce long-term weakening or failure. Each step of this complex process involves uncertainty, including errors in the plate or mandible models, noisy observations, and unmodeled variation in the robot’s performance. These uncertainties propagate throughout the Digital Twin system in nonlinear, interacting ways, posing potential risks to patient outcomes. Current Digital Twin frameworks often ignore or oversimplify these sources of uncertainty. This project addresses the critical need for robust, real-time methods to quantify, propagate, and manage uncertainty in Digital Twin systems, thereby promoting safer and more reliable medical interventions and supporting NSF’s mission to improve health and advance technological innovation. The investigators will develop a Bayesian data assimilation framework for Digital Twins, enabling structured uncertainty quantification (UQ), verification, and validation across modular components and real-time physical interactions. This project addresses key Digital Twin UQ challenges by: (1) designing modular representations of uncertainty across system components; (2) developing a Bayesian approach to dynamically update Digital Twin models with real-time sensor data; and (3) formalizing two-way digital–physical interactions to support predictive decision-making. The framework will be demonstrated using a Virtual Surgical Planning system that includes robotic plate bending for autonomous point-of-care manufacturing of patient-specific implants. This testbed provides a rigorous platform for evaluating how Bayesian UQ methodologies improve real-time adaptation, predictive reliability, and decision support in safety-critical applications. The developed methods will also be portable to Digital Twin applications in autonomous manufacturing, such as those pursued in the NSF HAMMER-ERC Engineering Research Center (Hybrid Autonomous Manufacturing Moving from Evolution to Revolution). 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 2025 · 2025-08

Project Abstract Aging is associated with an increased incidence of fracture, subsequent increased morbidity and mortality, increased rates of nonunion and delayed bone healing. Aging is thought to result in an increased baseline inflammatory state, known as “inflamm-aging”. Strategies to improve fracture healing in these patients must start with a clear understanding of why fracture repair is inhibited with age so targeted interventions can be developed. Fracture triggers a robust inflammatory response to initiate healing. Following this initial inflammatory phase, an anti-inflammatory response is initiated that drives tissue regeneration. Disruption of this transition may result in decreased fracture healing. Macrophages are thought to play a vital role in this process, with classically activated (M1) macrophages driving early inflammation, followed by a transition to an anti-inflammatory alternatively activated (M2) macrophage response. Aging is associated with an increased baseline inflammatory state, known as “inflamm-aging”. This imbalance may drive the delayed healing observed in geriatric fracture patients. However, work in human subject has been minimal, and the role of aging in fracture healing remains a poorly understood area of study. We hypothesize that this imbalance drives the impaired geriatric fracture healing response and expect that elderly patients have an increased initial inflammatory response at the time of fracture with a decreased ability to mount the subsequent anti-inflammatory response required for initiation of the regenerative phase of fracture healing and derangements in macrophage polarization. Two primary aims well assist in quantifying the differences in the fracture microenvironments between young and elderly patients. AIM1: To determine if geriatric fracture patients have altered macrophage polarization and an increased inflammatory response at the site of acute fracture compared to younger individuals. AIM2: to determine if geriatric fracture patients have an altered transition to M2 polarization and a delay in the production of anti-inflammatory cytokines at the fracture site during fracture healing compared to younger individuals. This innovative study would be the first to critically examine the role of macrophage polarization in human subjects, bridging the gap between animal and human models and identifying potential therapeutic targets for further study.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Bacteriophages (phages), or viruses that infect bacteria, are key drivers of ecological fluctuations within microbial communities and can have broad impacts on bacterial abundances and behaviors. With recent advances in ecogenomics from metagenomic/metatranscriptomic sequencing as well as computational approaches, an eco-systems biology approach has been developed to interrogate the role of phages in different environments: from the oceans and soils to human-related microbiomes such as the gut. Over the last decade, a handful of studies have explored phage in the human oral microbiome in the context of health and periodontal disease. However, there has been no robust study of phage (their abundance, characteristics or their gene products) during the dysbiotic microbial events that lead up to the formation of dental caries. This Katz R01 proposal from a multi-PI team featuring a clinical pediatric dentist and basic science microbiologist aims to leverage a phage-specific computational platform built up from studying the impact of viruses in our earth’s oceans into defining the role of phage in dental caries and the broader oral microbiome. Within Aim 1, the composition, abundance and role of the oral phageome in early childhood caries (ECC) will be explored through the collection of caries-free and caries-active plaque samples, DNA/RNA sequencing of total and/or virulent phage populations, and utilization of the iVirus 2.0 toolkit for sequencing analysis. Results from this aim will describe key phage taxa and accessory genes that are contributors to previously described shifts in bacterial population structures during the transition from health to disease. In addition, there has been renewed interest in phage for use as a therapeutic approach (i.e., phage therapy) to kill select bacterial pathogens. Since 2020, 50 different clinical trials have been initiated, either observational or interventional, involving phages. None of these involved the oral cavity. We propose within Aim 2 to isolate and characterize phages against a panel of cariogenic organisms including Streptococcus mutans to develop phages cocktails and combination therapies for in vitro testing. This includes establishment of the first U.S.-based oral phage bank, testing of specific phage cocktails on multi-species biofilms, and beginning to define how oral bacteria respond to phage infection (both target and non-target species). In all, the summation of this project begins to shed light on the role of phage and their potential as an intervention strategy in dental caries and represents a change in research direction for both principal investigators. Advances here will integrate phage into our broader understanding of the oral microbial ecosystem, providing a sustainable research direction for two early career investigators in oral microbiology.

NIH Research Projects · FY 2026 · 2025-08

Modified Project Summary/Abstract Section Dental caries continues its decades-long reign as the most chronic condition of childhood—nearly 40% of kindergarteners and 60% of adolescents have the disease. Both the overall disease prevalence and rates of untreated disease are greatest among low-income families, children living in rural areas, and those with Medicaid insurance. Medicaid-enrolled children experience greater burden of disease and have a more difficult time accessing care. Silver diamine fluoride (SDF) is an effective treatment for dental caries, and it can be especially useful in limited resource settings or in clinics with limited capacity to treat Medicaid enrollees. Clinical guidelines suggest SDF can be used to defer or avoid future dental treatment. Originally cleared for use in the United States in 2014, the American Dental Association developed a procedure code for SDF use and reimbursement in 2015. In 2017, 13 state Medicaid programs reimbursed SDF, increasing to 43 in 2023. Despite these clinical guidelines and Medicaid policies, it remains unknown if variation in Medicaid reimbursement policies across states impacts dentist use and patient outcomes following SDF treatment. Prior studies have focused primarily on the clinical effectiveness of SDF treatment in arresting disease on the tooth-level rather than population oral health outcomes. The proposed multistage mixed methods study will determine the role of Medicaid policies in supporting the use of SDF to reduce downstream caries-related treatments. Using national Medicaid data and qualitative interviews with dentists with the highest and lowest use of SDF, we will 1) determine the impact of Medicaid SDF reimbursement policies on A) downstream state-level oral health outcomes, and B) provider adoption of SDF treatment using a staggered adoption difference-in-difference approach, 2) identify specific combinations of clinical, provider, and community factors associated with increased or attenuated SDF efficacy using an ensemble classifier machine learning technique, and 3) identify clinical, personal, and policy drivers influencing the clinical decision to use SDF for Medicaid-participating dentist using qualitative interviews. Our proposed study will identify how reimbursement policies contribute to improving caries treatment and reducing more expensive treatments that have suboptimal outcomes among Medicaid-enrolled children, which aligns with NIDCR Strategic Priority to accelerate the translation of new discoveries into practices that improve oral health outcomes for all individuals and communities.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Sudden unexpected death in epilepsy (SUDEP) is the primary cause of death in individuals with epilepsy, representing a significant public health concern. Unfortunately, there are currently no methods to predict or prevent SUDEP. In recent work, we demonstrated that ictal (i.e., during a seizure) local field potential (LFP) suppression in the dorsal raphe nucleus (DRN) precedes seizure-induced sudden death in a mouse model of SUDEP. In unpublished data, we can significantly reduce the SUDEP rate using closed-loop electrical DRN stimulation upon detecting ictal DRN LFP suppression. Our preliminary data also point to reduced ictal serotonergic (5-HT) neuronal activity and increased extracellular GABA levels in the DRN of SUDEP model mice. Building on our compelling preliminary results, we propose to test whether closed- loop stimulation of ictal DRN function can prevent SUDEP in two mouse models (Aim 1) and further refine this therapeutic approach by elucidating the cellular (Aim 2) and synaptic (Aim 3) mechanisms of ictal DRN function in regulating SUDEP. This proposal will test our data-driven central hypothesis that closed-loop restoration of DRN neuronal activities prevents SUDEP by modulating 5-HT and GABAergic systems. This hypothesis will be tested via the following specific aims in two SUDEP mouse models. In Aim 1, we will leverage logistic regression and two newly developed machine-learning techniques to identify ictal events that can predict the lethality of seizures. We will then test whether closed-loop ictal DRN electrical stimulation can prevent SUDEP. In Aim 2, we will determine the dynamics of DRN5-HT and DRNGABA neuronal activities (calcium imaging) during fatal seizures using simultaneous LFP-fiber photometry recordings. We will subsequently assess their contribution to SUDEP by utilizing the closed-loop optogenetic approach to selectively manipulate DRN5-HT and DRNGABA neuronal activity when fatal seizures are detected. In Aim 3, we will delineate the specific contributions of GABAergic synaptic inputs to DRN by inhibiting GABA release at DRN presynaptic terminals. Using parapinopsin (PPO) for presynaptic optogenetic inhibition, we will target GABAergic inputs from each of the DRNGABA, the bed nucleus of the stria terminalis (BNSTGABA), and central amygdala (CeAGABA), and subsequently assess their efficacy in rescuing SUDEP. We have developed and validated the necessary tools for accomplishing these cohesive aims to expand our knowledge of SUDEP and develop effective SUDEP prevention strategies toward clinical translation.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT Menthol enhances the appeal of cigarettes and promotes nicotine dependence, leading the US FDA to propose a rule prohibiting menthol as a characterizing flavor in cigarettes. However, following restrictions on the sale of menthol cigarettes in California and Massachusetts, synthetic coolants have been added to cigarettes, potentially nullifying the public health benefit of the menthol restriction. This novel study aims to provide critical knowledge to understand the abuse liability and substitutability of synthetic coolants for menthol in cigarettes, employing both laboratory and naturalistic experiments. A total of 40 adults who smoke menthol cigarettes will complete a 3-phase, 3-week study. In phase 1, participants will smoke their usual brand menthol cigarette (UBMC) during a lab session and report daily usage for a week. Phase 2 will use a double-blinded, randomized crossover design, where each participant will complete three intensive lab sessions to smoke three, lab-prepared study products varying only in the absence or presence of menthol and synthetic coolants: menthol cigarette (MC), non-menthol cigarette with synthetic coolants (NMC+SC), and non-menthol cigarette control (NMC). Data on participants’ puffing behavior and the subjective effects of the products will be collected for each session. In Phase 3, participants will be instructed to replace their UBMC with their preferred study product from Phase 2 and report daily usage and perceptions for a week to assess substitution and perceived subjective effects. This Tobacco Regulatory K01 project will yield much-needed evidence on the abuse liability and substitutability of synthetic coolants for menthol in cigarettes, while providing valuable training to a promising new investigator with guidance from leading experts in the field of tobacco regulatory science.

NSF Awards · FY 2025 · 2025-08

The 2025 MVAPICH User Group (MUG) Conference is scheduled to take place in Columbus, OH, from August 18-20, 2025, gathering experts, including users, system administrators, researchers, engineers, and students, to focus on sharing knowledge about the MVAPICH libraries. To support student participation, this project will provide funding to enable students to engage with the MVAPICH research and user community. The conference organizers aim to recruit students from all backgrounds. Attending the conference offers students benefits such as 1) exposure to cutting-edge high-performance computing (HPC) technologies, 2) in-depth understanding of designing open-source software environments for HPC systems, 3) training on optimization techniques, and 4) opportunities for interaction with industry professionals and national laboratory experts. This participation significantly impacts the future careers of researchers in HPC, Artificial Intelligence (AI), networking, and message passing technologies. MVAPICH is an open-source Message Passing Interface (MPI) library; MVAPICH and its derivatives have played a significant role in exploiting the potential of Remote Direct Memory Access (RDMA)-capable networks, resulting in the rapid growth and adoption of InfiniBand in the High Performance Computing (HPC) community. The MVAPICH library is used by many applications and is installed in HPC Systems worldwide including in the HPC systems at supercomputing centers funded by NSF. The annual MVAPICH User Group conference (MUG) provides a collaborative platform for users, researchers, administrators, and students to exchange knowledge, share experiences, and discuss optimization strategies, troubleshooting guidelines, and other relevant topics. The MVAPICH project and MUG conference help advance the fields of HPC and Artificial Intelligence (AI), and support education and benefits to society at large. 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 2025 · 2025-08

The Psychiatry, Psychology, and Public Health Collaborative Learning Disabilities (LD) Innovation Hub brings together experts from distinct fields–-LD and neuropsychology, child psychiatry, cognitive neuroscience, public health and environmental science–-to improve our etiologic understanding of learning difficulties (LDiff), defined both dimensionally and categorically by performance in the lowest quartile on standardized measures of reading and math. Our study includes children from economically disadvantaged families—populations at high risk for prenatal exposure to neurotoxic chemicals and learning problems. The Hub will establish infrastructure to (a) foster innovative research into the complex etiology and neural underpinnings of LDiff in the context of economic disadvantage, and (b) train future interdisciplinary LD scholars and leaders in cutting-edge neuroscience and to engage with the wider child educational system. The Hub will document how prenatal chemical exposures contribute to the achievement gap in the United States. Long term, the Hub will help close the achievement gap by identifying behavioral and neural pathways from prenatal exposures to LDiff—pathways that may be amenable to change. The Embedded Research Project will identify neural and cognitive pathways through which prenatal exposure to air pollution and early life stress (ELS) lead to LDiff in children and adolescents. We will use novel magnetic resonance imaging (MRI) of neuromelanin, a by-product of midbrain dopamine, and model-based functional MRI to probe dopaminergic circuits and related inhibitory control (IC) and reinforcement learning (RL) in relation to prenatal exposure. We hypothesize that midbrain dopamine serves as a critical mechanism mediating air pollution and ELS effects on domain-general cognitive factors (IC and RL) and LDiff. The Leadership Core will establish the Hub's administrative and training infrastructure and foster the next generation of interdisciplinary LD researchers, trained in public health and LDiff through an innovative program including neuroscience research experience, methodological and translational coursework, mentoring and interdisciplinary practicum training in the educational setting. We continue our commitment to the recruitment of early career scientists preparing them for research and leadership positions in LD. IMPACT: Through our innovative, high-risk project and integrated training/mentorship opportunities we will identify novel circuits and potentially modifiable risk factors implicated in LDiff in children from economically disadvantaged families. We will develop an intellectual and administrative infrastructure to serve as a foundation for future research, capable of translating our research findings into actionable prevention and intervention programs.

NSF Awards · FY 2025 · 2025-08

Controlling how tiny particles come together is essential for creating new materials used in various technologies such as medical imaging and flexible electronics. However, controlling particles that are nanometers in size is still very challenging using available techniques. This project will develop new methods to guide these particles into organized structures by using an alloy mixture of five or more metals. By using their natural magnetism, this project aims to make the particles line up into chains, loops, and eventually larger networks. This award will push the boundaries of materials science and engineering and will support future innovations in areas like high-density data storage, soft robotics, and environmental monitoring. It will also provide training for students at multiple levels as well as outreach to K–12 students through hands-on workshops and science education modules. This project will use the magnetic self-assembly of high-entropy alloy (HEA) nanoparticles as a platform for directing the formation of hierarchical nanostructures. Traditional strategies for nanoparticle assembly are ineffective in the nanometer regime due to weak depletion forces and insufficient directional interactions. This project will use multicomponent HEA nanoparticles that can retain stable dipolar magnetic domains at these scales, overcoming the superparamagnetic limit common in conventional nanomagnets. The project is structured around three integrated thrusts: (1) synthesis of HEA nanoparticles with intrinsic magnetic properties; (2) directed assembly of these nanoparticles into chains and loops through intrinsic magnetic interactions; and (3) alignment of these structures into higher-order architectures using external fields. Experimental techniques such as electron holography, electron microscopy, and magnetic force mapping will be combined with theoretical modeling of interparticle interactions to understand and control the assembly mechanisms. Outcomes are expected to help in developing scalable routes to synthesize nanoparticles with customized properties and advance knowledge in nanomagnetism and colloidal self-assembly. 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 2025 · 2025-08

PROJECT SUMMARY Approximately 60% of clients who enter substance use disorder (SUD) treatment have had at least one lifetime exposure to traumatic brain injury (TBI). TBI of any severity can result in chronic cognitive and behavioral impairments that, if unaddressed, can undermine the effectiveness of SUD treatment and lead to early treatment termination. The Ohio State University TBI Identification Method is a well-established, validated method for identifying clients with TBI, and neurocognitive accommodations can be used to overcome impairments and optimize client treatment success. However, our preliminary research demonstrates that neither TBI screening nor neurocognitive accommodations have been adopted in outpatient SUD treatment settings due to inadequate provider knowledge and skills to implement these interventions, as well as poor implementation readiness and support. External facilitation is an implementation strategy that can address these barriers to increase the adoption, reach, implementation, and sustainment of these interventions, but few studies have evaluated facilitation on intervention uptake in outpatient SUD treatment. Guided by Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) and Exploration, Preparation, Implementation, and Sustainment (EPIS) frameworks, I will conduct an embedded mixed methods hybrid type 2 effectiveness-implementation feasibility trial to: [Aim 1] Evaluate facilitation as a strategy for increasing the adoption, reach, implementation, and maintenance of the TBI-RECOVER intervention model (i.e., OSU TBI-ID, symptom screen, and neurocognitive accommodation) in outpatient SUD treatment; [Aim 2] Examine the feasibility and preliminary effectiveness of the TBI-RECOVER intervention model compared to treatment as usual on clients’ treatment self-efficacy, substance use severity, and treatment retention; and [Aim 3] Assess client satisfaction and provider acceptability of TBI-RECOVER, and utility of the facilitation strategy for implementation of TBI-RECOVER. The following training objectives will support these research aims and my career goals: (1) Gain advanced training in dissemination and implementation science, specifically in hybrid effectiveness-implementation trials, and implementation strategy development and evaluation; (2) Acquire training in substance use treatment research for adults with comorbid SUDs and TBI; and (3) Advance my career independence through conceptualizing and leading implementation trial research, R01 grant writing, and leading research teams. This proposal is directly aligned with NIDA’s 2022 – 2026 strategic plan to investigate novel treatment interventions and enhance optimal implementation outcomes in real-world treatment contexts. This NIDA K01 will provide me with the necessary resources to advance and maximize my skills to launch an independent, NIH-funded career and situate me as a leader in implementation science, TBI, and substance use treatment research. The results and training gained through this K01 will inform a fully powered hybrid effectiveness-implementation trial to scale-out TBI-RECOVER using facilitation.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY There has been a dire need for developing a rapid biodosimetry tool for triaging victims in the aftermath of any radiological/nuclear mass casualty incident(s). Rapid triage is critical for timely administration of medical countermeasures and proper allocation of resources, thus saving lives. Currently, there are no US Food and Drug Administration (FDA) approved tests or assays that allow early exposure categorization of victims for effective medical countermeasures. The current gold standard for radiation biodosimetry is the dicentric chromosome assay (DCA) but its application to mass casualty incidents is severely restricted as it requires 48- 72 hours for dose estimation. To provide a rapid absorbed dose estimation within a few hours, we have developed a highly sensitive test tracking two-microRNAs found in blood samples collected by a simple finger prick. The miRAD assay enables accurate does estimation in less than four hours, covering dose ranges and time points critical for medical intervention in victims. In the miRAD assay, radiation dose dependent changes in evolutionarily and functionally conserved miR150-5p in the blood is internally calibrated with miR23a-3p which is non-responsive to radiation as it is not expressed at a significant level in blood cells, yet abundant in blood and passively released into circulation from non-blood cells. Our assay, tested so far in blood samples from irradiated mice, non-human primates and human radiotherapy patients and has shown a great potential for development as an effective triage tool. Robustness of the baseline expression of both the responder and normalizer using blood samples collected by a finger prick has been validated in volunteers, including individuals afflicted with common chronic medical conditions. The kinetic response of the miRAD assay will favorably allow integration with other clinical signs (clinical symptoms, time of emesis) and help prioritize treatment in the “life savable” group. As further development and refinement of the assay for triage applications is needed, the current proposal is designed to test the accuracy of dose prediction by miRAD with the gold standard DCA by using an in vivo total body irradiated mouse model system. Since alteration in miR150-5p in blood after radiation exposure appears to be an intrinsic in vivo phenomenon, we will systematically compare the miRAD assay with DCA for absorbed dose validation in pediatric and geriatric population mimicking a heterogeneous human population. The assay has potential utility at different stages in radiological/nuclear disaster management, including early triage, precision dosimetry, follow-up and evaluation of countermeasures. Beyond its utility in radiation disaster preparedness and management, the assay will have utility in evaluation of bone marrow ablation and reconstitution kinetics in radiotherapy patients.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Nerve injuries are highly prevalent worldwide and are associated with sensory and motor impairment, neuropathic pain, and permanent disability, resulting in significant health burden and costs for the healthcare system. While axons in the peripheral nerves can regenerate following an injury, their growth rate is too slow for successful functional recovery. The study of the molecular mechanisms regulating the regenerative capacity of the peripheral axons is paramount to provide insights for strategies aimed at boosting their regenerative potential. One key factor for long-distance regeneration of peripheral axons is the transcriptional reprogramming of neurons into a growing state, involving activation of regenerative gene networks. For this reason, epigenetic mechanisms that broadly open the chromatin, affecting the expression of multiple genes, are preferred therapeutical targets to enhance nerve regeneration. The folding of the genome into three-dimensional topologically associating domains (TADs) allows coordinated changes in gene expression in response to specific inputs, by facilitating the interaction between gene promoters and regulatory enhancers. Our unpublished data in mouse dorsal root ganglia sensory neurons show that the full activation of regenerative genes after nerve injury depends on regulated chromatin interactions within TADs. Thus, we hypothesize that TADs and the enhancer–promoter interactions formed in response to nerve injury regulate the regenerative program. Furthermore, we hypothesize that modulating TADs and enhancer–promoter interactions can represent a novel therapeutical approach to enhance nerve regeneration. In Aim 1, we will use high-throughput transcriptomics and genome-wide mapping methodologies in isolated mouse dorsal root ganglia neurons following sciatic nerve crush injury or sham control to investigate the molecular mechanisms by which enhancer–promoter interactions generated in response to injury can promote regenerative gene transcription. We will identify novel molecular modulators of these genomic interactions, and we will perform functional studies to investigate their role in axon regeneration. In Aim 2, we will use super-resolution imaging, biochemical, and genome-wide mapping approaches to identify regulators of the transcription machinery at these chromatin contacts. We will perform functional studies to investigate their role in axon growth. In Aim 3, we will characterize known regulators of TADs and address the extent to which these regulators can be manipulated to enhance nerve regeneration. Findings from this project will add critical knowledge about how regenerative gene expression is regulated by genome conformation, providing key insights into how to activate the regenerative program in a specific and sustained way to promote axonal regeneration and relieve the burden of nerve injury.