Duke University

NSF Awards · FY 2025 · 2025-09

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors Michael Therien and David Beratan of Duke University and William DeGrado of University of California San Francisco are studying new approaches to design materials that direct, store, and release energy. Biology has developed numerous designs that carry out these functions; chemists, however, have yet to create energy harvesting, storage, and release systems from scratch that possess the sophistication of those seen in nature. Recent advances in protein design enable chemists to construct large molecules that capture and manage the flow of positive charges, negative charges, and energy. By designing protein-based materials that migrate and collect charges and energy, unique optical, electrical, and chemical functions will be realized. The experimental procedures used in this effort provide new tools to build proteins having innovative designed functions. This pursuit allow graduate students and postdoctoral fellows to acquire specialized training in synthetic chemistry, protein design, protein biochemistry, modern computational methods, and techniques to monitor fast processes that move charge and energy. The protein design methods developed are broadly applicable and enable construction of new biologically inspired materials that carry out novel functions not seen in nature. Outreach activities of this project introduce college and pre-college students to important new technologies and teach skills important for future careers in science and engineering. Biological energy transduction relies on protein-cofactor assemblies that possess physico-chemical functionality that far exceeds that realized to date through molecular and macromolecular design and synthesis. This effort designs redox proteins that transduce energy using bound cofactors, redox-active amino acids, titratable sidechains, and buried water molecules, to orchestrate the light-triggered flow of electrons, holes, and protons, elucidating rules and principles important for driving thermodynamically reversible reactions at low overpotential and engineering vectorial control over electron and proton currents. This project takes advantage of an integrated, multi-disciplinary approach that employs: (i) design and synthesis of light-harvesting and redox-active cofactors, (ii) de novo protein design using advanced computational methods to selectively bind cofactor units in precise, organized spatial arrangements, (iii) protein expression and characterization, (iv) state-of-the-art pump-probe transient optical methods and theoretical models that interrogate photo-induced electron and proton migration reactions, and (v) spectroscopic, potentiometric, and dynamical methods, high resolution protein structure, and predictions made by theory to provide insights into how atomic-level control of cofactor environments directs energy transducing function. Information from this study elucidate fundamental principles required to understand photosynthetic energy transduction and to design proteins that possess novel electro-optic function and can transduce energy via innovative pathways. 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 · 2025-09

An award is made to the Duke Lemur Center (DLC) to enable physical and database improvements to enhance, secure, and advance scientific access to the DLC BioBank. The DLC is the only place in the world where biological samples of strepsirrhines primates are available for researchers and educators along with living animals, associated life history and medical records, and fossil relatives of the living species. This project will produce educational materials including the creation of downloadable, 3D-print-ready media files (e.g., skeletal specimens) and an online Image Gallery exemplifying the scientific discoveries made from DLC BioBank specimens. The 3D-print-ready files will have supporting materials to facilitate use by educators, including a Media Guide and how-to video. The Image Gallery will include text descriptions that explain how biological science works and why the results are relevant to the general public. The continuity of knowledge generated by the multidisciplinary work carried out with DLC BioBank specimens contributes to an understanding of organismal and ecosystem biology and to conservation efforts in Madagascar. This project addresses an enduring requirement for biological research which is that properly stored and provenienced biosamples are necessary to address current and future questions at the molecular, cellular, and tissue levels. Existing infrastructure for storing and protecting specimens will be increased, existing cyberinfrastructure for cataloguing and tracking samples will be augmented, and an online inventory summary will be developed and made available for researchers to promote interest in and use of the collection. The outcomes will increase operability, access, and dissemination of BioBank resources to researchers, educators, and the general public. 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 · 2025-09

PROJECT SUMMARY Lower urinary tract symptoms (LUTS) are common with high economic and social costs and significant effects on patients’ quality of life. Prevalence of LUTS increases with age, with estimates ranging from 45-70% of U.S. adults. It is clear from the range of conditions that produce LUTS, and the failure of current therapies to ameliorate symptoms in large segments of the population that have similar LUTS, that patients with LUTS are a heterogeneous population even when their symptoms are identical or overlap. Current LUTS treatment paradigms target narrow symptom groups, largely ignoring the heterogeneity in concomitant symptoms. Furthermore, clinicians have a limited understanding on how to integrate information from self-reported symptoms, clinical exam and laboratory results, and urodynamic testing into treatment decision-making. Improving treatment outcomes for patients with LUTS will require both (1) increased understanding of LUTS symptom clusters and underlying mechanisms behind the various subtypes and (2) comprehensive, validated, and responsive measurement tools for defining treatment efficacy. The Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) was assembled in 2012, the primary objective of which was to categorize patients with LUTS into distinct subgroups, a process known as ‘phenotyping’. The Network’s approach to defining patient subtypes was based on a probability-based consensus clustering approach using a myriad of patient data, resulting in the identification of novel LUTS-based clusters that are statistically and clinically distinct. Concurrently, the Network worked to improve the measurement of patient reports of LUTS through systematic development of a new, high-quality item bank based on qualitative input from patients, community participants, internists, urologists, urogynecologists, and clinical researchers. LURN II will build on the knowledge gained through multiple specific aims: to test and refine the original LURN clustering model in a new cohort including a wider range of symptom severity and a wider range of physical measures (n=1380 participants followed for 3 years); to identify a signature of proteins contained within plasma that can be used to identify specific subgroups of men and women with LUTS; to determine phenotypic characteristics of women with LUTS by measuring the functional components of the lower urinary tract; to validate a self-reported outcome tool for evaluating treatments, based on the comprehensive tool developed for phenotyping in LURN I; and to explore promising alternative analytic approaches to existing and future LURN data and characterize the broader experiences of patients with LUTS. This proposal brings together a multidisciplinary team of urologists, urogynecologists, bladder physiologists, data scientists, epidemiologists, and outcomes researchers. The proposed work has the potential to transform the diagnosis and treatment of LUTS.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY OF WORK: Correction of skeletal muscle remains a major challenge for the treatment of Pompe disease (PD, also known as glycogen storage disease type II), an inherited lysosomal storage disorder (LSD) caused by acid alpha- glucosidase (GAA) deficiency that leads to the buildup of lysosomal glycogen in skeletal muscle, heart, and the brain. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Alglucosidase alfa) is the current standard of care but has little effect on skeletal muscles. Insulin-like growth factor 2-tagged hGAA (IGF2- hGAA, reveglucosidase alfa) greatly improved the efficiency of enzyme uptake in skeletal muscles via IGF2 receptor mediated endocytosis, however, hypoglycemia caused by the off-target binding of the IGF2 moiety to the insulin and IGF1 receptors were frequently observed in patients. AAV gene therapy has shown promise for PD with successful translation to early phase clinical trials. Direct muscle gene therapy requires administration of very high doses of AAV vectors that can cause significant hepatotoxicity and genotoxicity; liver-depot gene therapy relying on secretion of hGAA from liver-specific transgene expression requires lower vector doses but has limited effect on skeletal muscles (similar to ERT). Hence, there is a critical unmet need for an improved therapy for PD that can correct the genetic defects in skeletal muscles. In absence of an effective therapy, patients with PD will continue to experience progressive neuromuscular dysfunctions accompanied by increased morbidity and mortality. In this application, we aim to develop an improved AAV gene therapy over current approaches for PD with enhanced efficacy in skeletal muscle and the brain using a mouse model of PD. We hypothesize that site-specific mutagenesis of IGF2-hGAA to prevent its off-target binding will reduce the adverse effects, and thereby increase its safety and clinical translatability for the treatment of PD. We will first identify a lead clinical candidate AAV-hGAA vector with a modified IGF2-hGAA transgene that can be used for liver-depot gene therapy in adult patients (Aim 1). We will next identify a lead clinical candidate AAV-hGAA vector using a combination of a high potency ubiquitous immunotolerizing promoter and a high potency MyoAAV capsid that can be used for muscle gene therapy in both infant and adult patients (Aim 2). Data generated from the proposed studies will lay the foundation for translating these innovative gene therapy approaches to patients with PD. Modification of IGF2-hGAA will reduce the adverse effects and increase the safety, efficacy, and clinical translatability. This approach can be broadly applied to other lysosomal storage diseases in the context of AAV gene therapy and/or ERT. The development of muscle gene therapy for PD will increase the efficacy in correcting skeletal muscles and lower the risk of high-dose vector induced toxicities, and this treatment approach can be adapted for gene therapy in other inherited metabolic disorders that affect skeletal muscles.

NIH Research Projects · FY 2025 · 2025-09

Project summary Enterovirus D70 (EVD70) is an understudied human enterovirus that causes acute hemorrhagic conjunctivitis, a highly contagious and painful ocular disease and that can, in rare instances, progress to polio-like paralysis. The molecular mechanisms underlying EVD70 infection, including 1) the host factors required for the viral life cycle and the 2) cellular tropism within the eye, remain poorly understood, due in part to a lack of eye-specific models. EVD70 attaches to ocular cells, at least in 2D cell culture, via sialic acids. There is, however, limited evidence suggesting the existence of an as-yet-unidentified proteinaceous receptor for EVD70 that triggers entry and uncoating in ocular cells. Through a genome-wide genetic knockout screen, I have identified host factors necessary for EVD70 infection in vitro, including the orphan receptor Jumping translocation breakpoint (JTB), which has limited demonstrated cellular functions. Notably, genetic knockout of JTB confers resistance to EVD70. I hypothesize that JTB serves as a receptor critical for EVD70 entry and uncoating in ocular cells and that JTB expression contributes to cellular tropism for corneal and conjunctival epithelial cells in the eye. The objectives of this proposal are to 1) determine the mechanism by which JTB is required for EVD70 infection and 2) define the cell-specific tropism and host immune responses to EVD70 in corneal organoids, which recapitulate the cellular diversity and organization of the ocular surface. Aim 1 will systematically evaluate if JTB is an entry and uncoating receptor for EVD70. Aim 2 will define the tropism of EVD70 and investigate host responses, such as interferon signaling, in corneal organoids using unbiased single cell RNA- sequencing and multiplexed cytokine analysis. Together, these aims will provide critical new insights into EVD70 biology and its interaction with ocular cells. Completing the proposed aims will advance our understanding of EVD70 molecular biology and pathogenesis and provide training to better equip me to progress towards independence as a scientist.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This application brings together a highly collaborative and experienced team of ophthalmic surgeons, engineers, and an industry partner to develop a next-generation ophthalmic microscope to maximize visualization in the dynamic ophthalmic surgical environment. We seek to overcome limitations inherent to the decades-old ophthalmic surgery stereomicroscope which limits the true integration of modern visualization technologies like optical coherence tomography (OCT). Over the past decade, members of our team developed the leading intraoperative OCT program in ophthalmic surgery in the US. Under initial R21 support, our first-generation microscope-integrated OCT (MIOCT) design enabled live cross-sectional imaging during surgery and has been the approach adopted by multiple vendors in current commercial offerings. Our subsequent Bioengineering Research Partnership (BRP) funded work introduced the first live “4D” (volumetric imaging through time) MIOCT technology which images microsurgery with micrometer-scale resolution at several rendered volumes per second, interactively viewable by the surgeon from an arbitrary perspective through a novel stereoscopic heads-up display. We have demonstrated and documented the performance of these systems in hundreds of live human eye surgeries at the Duke Eye Center, with innovations and results documented in over 100 peer-reviewed publications and hundreds of presentations by the Multiple Principal Investigators and other team members. Our prior foundational work in intrasurgical OCT has resulted in a state-of-the art capability; however, the technology still requires considerable effort on the part of both the surgeon and a dedicated engineering operator. Unlike the outpatient clinic with stabilized patients, the dynamic surgical environment currently requires a dedicated engineering operator to assist the surgeon with image tracking and optimization to keep OCT at the surgical point of interest. Current stereomicroscopy is also insufficient to provide the depth resolution needed to keep the OCT depth window in frame for tracking solutions. The overall goals of this proposed project, then, are to develop a compact multi-camera array microscope capable of supporting and tracking the surgical scene at high spatial resolution and pair it with an active robot-based scan head to maintain the surgical point of interest in a dynamic scene. Together, these will allow true integration with OCT, dynamically placing the OCT view where the surgeon needs it – such as for monitoring a microneedle as it advances in depth through the retina and into the subretinal space. Each of these developments are motivated by specific current needs in ophthalmic surgery visualization based on our ophthalmic surgical and industry partners and will be developed through our well-established multidisciplinary translational methodology of incorporating constant feedback between multidisciplinary team members. We believe these developments will improve ophthalmic surgical visualization and also potentiate novel ophthalmic and other microsurgeries not currently possible due to limitations in surgical visualization.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT. Meniscus tears are common sports-related injuries and are associated with injuries to the anterior cruciate ligament (ACL) in up to 70% of cases. Acute hemarthrosis (bleeding into the joint) occurs with ACL tears, peripheral meniscus tears, and intra-articular fractures. Traumatic injuries to the meniscus cause acute pain and joint immobility, and frequently lead to post-traumatic osteoarthritis (PTOA). However, the exact mechanism(s) by which PTOA develops following these traumatic injuries is unknown. Recently, bleeding from femoral drill holes in a rabbit model showed increased inflammatory and catabolic gene expression in the meniscus tissue. Furthermore, a variety of blood-derived orthobiologics, including platelet rich plasma (PRP), are utilized as potential therapeutic tools to enhance meniscus repair, despite the lack of a thorough understanding of the effects of these products on meniscus tissue. Therefore, it is critical to perform well-controlled studies that evaluate the factors that impact meniscus repair in the injured joint microenvironment. Currently, there is a gap in knowledge regarding the direct effects of blood and blood-derived components on meniscus tissue, and there is controversy related to the effectiveness of certain blood-derived orthobiologics as therapy for meniscal injuries. Consequently, our overall goal is to elucidate the effects of blood and blood-derived components on meniscus tissue homeostasis, repair, and PTOA development. In this proposal, we will elucidate the biological drivers of blood-mediated meniscus tissue catabolism and determine the effects of acute hemarthrosis and blood-derived orthobiologics on meniscus repair and PTOA development. We hypothesize that blood-derived immune cells mediate catabolism of meniscus tissue, prevent meniscus repair, and exacerbate PTOA development, and also reduce the effectiveness of orthobiologics for meniscus repair. In Aim 1, we will determine the effects of blood components on meniscus tissue homeostasis and the biological drivers of blood-mediated meniscus tissue degeneration. In Aim 2, we will elucidate the consequences of hemarthrosis on meniscus tissue repair and PTOA development. In Aim 3, we will determine the effects of PRP on meniscus homeostasis, repair, and PTOA development. There is a critical clinical need to understand the effects of blood-derived factors on meniscus healing and PTOA development. The results of this work will likely improve both surgical and non-surgical outcomes, and lead to the development of new orthobiologics.

NSF Awards · FY 2025 · 2025-09

The Center for Innovation in Risk, Catastrophes, and Decisions (CIRCAD) is an Industry–University Collaborative Research Center (IUCRC) that addresses the financial and societal impacts of natural hazards, extreme events, and systemic disruptions. Insurers are confronting challenges in maintaining coverage availability and affordability, leaving households, communities, and markets exposed. CIRCAD responds by producing data-driven tools, decision frameworks, and risk transfer strategies that strengthen industry’s ability to evaluate and manage emerging risks. By linking fundamental academic research and state-of-the-art methods with industry priorities, CIRCAD supports the development of next-generation insurance solutions, enhances investment planning, and informs decision-making. These efforts can help safeguard economic stability, support effective risk mitigation, and reduce the burden on public resources. The Center also serves as a hub for professional training and workforce development, engaging students and practitioners to build the technical and analytical capacity required for risk-management focused sectors. In doing so, CIRCAD positions these sectors as critical partners in confronting the nation’s most pressing hazard and infrastructure challenges. CIRCAD’s research portfolio addresses key challenges at the intersection of hazard science, insurance analytics, and financial decision-making. Its projects focus on developing and evaluating innovative insurance mechanisms, improving the transparency and applicability of risk models, advancing the use and accessibility of hazard and exposure data, and analyzing the broader consequences of risk management decisions across systems and sectors. CIRCAD also investigates the role of infrastructure and land use investments in reducing losses and informing insurance and investment strategies. The Center’s methods span simulation modeling, geospatial analysis, data integration, behavioral research, and stakeholder collaboration. By combining academic rigor with industry relevance, CIRCAD ensures that its research products are directly applicable to the evolving needs of insurers, regulators, and public agencies navigating the complexities of catastrophe risk. 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 · 2025-09

ABSTRACT Overdose continues to be a leading cause of death in the US with certain social and structural vulnerabilities increasing risk. People who are exposed to or impacted by the criminal legal system (CLS) disproportionately report using substances and experience high rates of overdose. In recent years, deep investment in assuaging the impact of the CLS on overdose risk has been made. However, less work has been done to uncover how best to deploy and optimize community interventions at earlier points of the sequential intercept model (e.g., preventing arrest and incarceration) to prevent adverse substance use and CLS outcomes for those at greatest risk. Community paramedic (CP) programs have launched nationally in response to the overdose epidemic in large part due to the acknowledgement that non-punitive interventions are effective. While different models exist, a main component of CP programs is the deployment of non-armed first responders via 911 after an overdose call, a de-facto alternative to police. CPs provide life-saving intervention (e.g., naloxone), MOUD, linkage to community-based health and social services, and follow-up after the initial interaction. Early results of these programs show promise as a non-carceral oriented substance use intervention that also reduces further CLS penetration. CPs outreach is not limited to one-time encounters, and the longevity of contact with people who overdose is important to establish trust, “meet people where they’re at” and provides consistent post-overdose follow-up after the initial interaction. However, CP programs intervene primarily on the individual level and, increasingly, research indicates that, for optimal impact, structural-level factors must be considered. Particularly relevant to CLS populations is the need to address health harming legal needs (HHLN) including lack of access to public benefits, housing issues, and other unmet legal needs. Medical Legal Partnerships (MLP) are a collaboration between legal and healthcare professionals that attempt to bridge structural, social, and individual needs, and in this context, specifically those that increase the likelihood of further adverse substance use harms. To our knowledge, few CP programs incorporate services traditionally offered via MLPs. Therefore, we propose the Community Paramedic Response and Overdose Outreach with Supportive Medical-Legal Services (CROSSROADS) Study. CROSSROADS will take place in Durham, NC; Pittsburgh, PA; Miami, FL; and Portland, ME. Our aims are to: 1) Determine the core components of the proposed CROSSROADS intervention (CP program + MLP); 2) Compare the CROSSROADS intervention versus standard of care (SOC) CP programs across the four locations on 1) frequency opioid and/or stimulant use, and 2) CLS (police, incarceration, and probation/parole involvement); and 3) Identify the acceptability, appropriateness, penetration, and sustainability of the CROSSROADS intervention and multilevel factors that affect overdose and future interactions with the CLS.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Infectious diseases (ID) continue to threaten individual human health and shape human populations. There is a strong and persistent need for a multidisciplinary workforce in ID research however this demand is not matched by a sufficient supply. Many critical roles for ID specialist researchers remain effectively hidden from early trainees including medical students. In this project, we will establish TRIDENT: Trans-disciplinary Research in Infectious Diseases to Engage Third-year medical students. TRIDENT capitalizes on the unique curriculum of the MD program of Duke, which reserves the 3rd year of training for rigorous, mentored quantitative research. TRIDENT will leverage this unique opportunity, a productive trans-disciplinary investigator pool, and Duke’s strong record in microbiology and physician-scientist training to engender early trainee interest in ID research. Our Aims are to (1) Recruit and match MD students with trans-disciplinary investigators for directly-mentored research projects in Infectious Disease. Trainees will choose from among validated mentors in the following thematic areas: Infection Control/Hospital Epidemiology, Bacteriology & Antimicrobial Resistance, HIV Prevention, Care, and Management, Global Health, Infections in Immunocompromised Hosts, Microbial Pathogenesis, and Immunology & Vaccinology, (2) Provide interdisciplinary, tiered faculty- and peer-mentorship in ID research, and (3) Implement skills- and career-development curricula tailored to trainee needs. As with all research programs, ID research is best conducted by teams with cross-disciplinary content expertise, technical skills, and professional perspectives, and we are committed to building the future of ID research by recruiting individuals who can bridge these disciplines and ultimately lead complex teams. This application builds on current educational programs within Duke’s MD curriculum, research assets across Duke’s clinical, global health, microbiology, and vaccinology enterprises, and established and complementary training infrastructure for physician-scientists. The impact of the program will be measured by tangible scholar products of the TRIDENT scholars, comparative surveys of TRIDENT scholars, and tracking career trajectory.

NIH Research Projects · FY 2025 · 2025-09

Gene therapy targeting CFH and lipoprotein dynamics in AMD ABSTRACT Age-related macular degeneration (AMD) is the most common cause of irreversible blindness among the elderly in industrialized countries, and there are no treatments for the majority of patients. Early hallmarks of AMD are the formation of lipid- and protein-rich, extracellular sub-retinal pigmented epithelium (RPE) drusen and basal laminar deposits that contain many constituents that are attributable to the activation of the complement cascade and lipid metabolism. Complement and lipoprotein pathway genes have also been independently associated with AMD through genetic risk association and epidemiological studies. Efforts to understand contributions of lipid metabolism/trafficking and complement dysregulation to AMD pathogenesis have been limited by the lack of age-dependent in vivo models that recapitulate these features of the disease. The aim of the proposed studies is to leverage data derived from novel animal models of AMD that we have developed. These models integrate advanced age, complement dysregulation and lipid/cholesterol perturbation, all known contributors to human AMD risk. Specifically, we generated mouse models based on the most replicated genetic risk variant associated with AMD risk, the tyrosine (Y) to histidine (H) substitution at amino acid position 402 (Y402H) of human complement factor H (CFH), the soluble regulator of the alternative complement pathway. Only mice expressing the human H402 AMD risk variant (CFH-H/H) develop an AMD phenotype compared to mice expressing the normal human Y402 CFH variant. Significantly, the AMD phenotype correlates with lipoprotein level changes in blood and in the RPE/Bruch’s membrane (BrM)/choroid complex. Thus, we are the first to observe a functional consequence of the Y402H polymorphism in vivo, which promotes an AMD-like pathology and affects lipoprotein levels in aged mice. Our analysis of ApoA-I containing lipoproteins isolated from BrM and plasma of elderly human donors found that these tissues have very different protein compositions. The most striking difference is the significantly higher concentration of ApoB and ApoE in BrM, which are known to bind to glycosaminoglycans (GAGs) and could promote lipoprotein deposition onto BrM GAGs; likely initiating downstream effects that contribute to RPE dysfunction/death. Based on these observations and other studies we hypothesize that aberrant RPE-derived high-density lipoprotein (HDL)-like secretion contributes to AMD development and is modulated by CFH. The goals of the proposed studies are to use our novel animal models of AMD and human RPE to test the extent to which AAV-gene therapies augmenting normal CFH and/or enhancing local HDL clearance are viable strategies for treating AMD. Outcomes from these studies will mechanistically determine the interaction of two risk factors, CFH and lipoproteins in AMD and provide preclinical evidence for these factors as therapeutic targets for AMD.

NIH Research Projects · FY 2025 · 2025-09

Intracranial aneurysm (IA) is a prevalent disease affecting ~2–5% of the population. Aneurysm rupture leads to aneurysmal subarachnoid hemorrhage (aSAH), which accounts for 2–5% of all new strokes and affects 21,000 to 33,000 patients each year in the United States (US). It poses an extremely high rate of mortality (~60%) and morbidity, with a large proportion (30–40%) of survivors rendered functionally dependent. Tragically, compared with others forms of stroke, aSAH disproportionately affects people of color, women, and young people. Delayed cerebral ischemia (DCI) is a prevalent and serious complication of aSAH, occurring in 30–40% of cases. It is the most consistent treatable predictor of morbidity, and plays an essential role in the persistent cognitive, social, emotional, and functional morbidity of survivors. Despite the complex pathophysiology of DCI, prior investigation has been almost exclusively focused on a narrow conception of DCI arising from narrowing of the arteries within the brain (arterial vasospasm). Our group has focused on arterial microthrombosis as a potential substrate for DCI after aSAH and has generated robust pre-clinical data supporting a role for anti-platelet therapy in ameliorating the devastating consequences of DCI. We completed an FDA-IND approved, single-center, double-blinded, randomized, clinical trial which aimed to determine the feasibility of delivering a continuous intravenous (IV) infusion of tirofiban or matched saline placebo to patients with aSAH. Thirty subjects with aSAH who were treated by external ventricular drain (EVD) then endovascular coiling were enrolled and treated with continuous IV tirofiban or placebo for 7 days post- treatment. There was no significant difference in hemorrhage associated with EVD and adverse events between groups. However, tirofiban-treated patients had a lower incidence of DCI compared with placebo- treated patients. Tirofiban also reduced the incidence of clinical vasospasm. The study was limited by its single center design and the fact that the EVD was placed in the operative room (OR) rather than bedside. A logical next step is to deploy IV tirofiban in a pragmatic, multi-center setting and to determine the maximum tolerated treatment dosage in advance of a fully-powered efficacy trial. Our primary objective is to determine the maximum tolerated treatment dosage for IV infusion of tirofiban in patients with aSAH who status post successful endovascular coiling are. Secondarily, we will examine the pharmacology of tirofiban in the setting of aSAH to better inform dosage schedules in a future clinical trial. To accomplish these objectives, we propose a pragmatic, randomized (2:1), double- blinded, placebo-controlled, multi-center clinical trial. Participants with aSAH (with and without EVD placement) will be randomized to IV tirofiban (at an infusion duration of 1, 3, 5, or 7 days) or saline placebo. Two large-volume endovascular centers (Duke University and University of Texas-Houston) will recruit and enroll subjects. The primary end point is dosage-limiting toxicity (any intracranial hemorrhage, major bleeding, thrombocytopenia, or serious adverse event due to tirofiban). Exploratory end points will include DCI, clinical vasospasm, and functional outcome as measured by the modified Rankin Scale (mRS) score at 90 days. Rigorously-ascertained data from this study will be used to select the appropriate dosage of IV tirofiban in this context. These data will be tested against explicitly-defined “Go-No Go” criteria to determine whether progression to the next phase is warranted.

NIH Research Projects · FY 2025 · 2025-09

Summary of Work Glucagon is canonically viewed as an essential counterregulatory hormone that prevents hypoglycemia by driving endogenous glucose production (EGP) in the liver. We and others have revealed additional roles for glucagon that emphasize a much more complex control of metabolism beyond hypoglycemia. For instance, glucagon is a potent insulinotropic peptide in β-cells, which we have shown to be essential for postprandial glucose control. Furthermore, hepatic glucagon receptor signaling drives an increase in insulin sensitivity, which is a paradoxical action for a counterregulatory hormone posited to limit insulin-induced hypoglycemia. However, insulin- induced hypoglycemia is only a century old phenomenon that is unlikely to have had significant evolutionary pressure. Collectively, it seems reasonable that the current dogma describing the metabolic actions of glucagon exclusively in the hypoglycemic state is limited and incomplete. To this end, we have found that enhancing endogenous glucagon secretion or providing exogenous glucagon to mice has limited efficacy at correcting insulin-induced hypoglycemia. We have also found that glucagon receptor signaling in hepatocytes can engage multiple signaling nodes. Based on these ideas, the primary hypothesis driving this work is that hepatic glucagon receptors engage div ergent signaling pathway s that differentially regulate glucose metabolism. In addition to the canonical pathways that increase EGP through G-protein signaling, glucagon can also utilize β-arrestin signaling nodes to driv e insulin sensitiv ity. We propose to test our hy pothesis by carrying out complementary physiological and pharmacological approaches in novel mouse models to resolve the role of hepatic glucagon signaling. Importantly, we also propose to perform parallel experiments in human subjects to validate the translational potential of this work. Unravelling this biology has significant implications on current and futureglucagon-based therapies for both type 1 and type 2 diabetes, obesity, and liver disease.

NSF Awards · FY 2025 · 2025-09

Non-technical Abstract: Quantum information science and engineering (QISE) is an expanding multidisciplinary field that draws on expertise from chemistry, physics, computer science, mathematics, and engineering. It promises applications in computing, sensing, and networking. Just as the computing sector did not stop research and development with the first integrated circuit, QISE will continue to evolve beyond small-scale devices, and is expected to prompt new discoveries and innovation across all of science and engineering. Employers in this domain have indicated a persistent need for a quantum-ready workforce with varying levels of proficiency in concepts, hardware, theory, experiment, and more. Aligned with this, quantum education has expanded over the last five years, but the future of implementation remains uncertain and unstable compared to education in other critical technologies like artificial intelligence. This project curates, develops, and disseminates ready-to-go quantum learning materials, and supports cohorts of educators in every state to develop QISE knowledge. This project also provides crucial information on viable methods for adapting quantum education to different localities. The project leverages members of the National Q-12 Education Partnership and explores a model for multi-sector collaboration on developing the domestic quantum-ready workforce. Technical Abstract: This project utilizes a robust network of professionals to introduce tens of thousands of pre-college students to quantum information science and engineering topics, future applications, and career information. The central feature of the project is ‘quantum-in-a-box,’ inspired by both private and public sector science and engineering programs connecting students with activities. Specifically, the project builds upon QuanTime, a project that encourages educators to dedicate one class period to quantum science. This was initially piloted as a quick-turnaround response to community input and currently disseminates one-off quantum activities to educators. The project aims to reach at least 500 teachers across the United States. Typically, each teacher instructs 100-150 students per year, demonstrating a powerful multiplier. The project explores the feasibility of scaling quantum education through local implementation, and contributes knowledge to the discipline by (1) Designing and distributing quantum materials with input from National Q-12 Education Partnership and wider educator community, (2) Expanding the distribution network for QuanTime, leveraging employers, (3) Supporting implementation with educator office hours, and (4) Collecting and analyzing data on implementing quantum education. 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 · 2025-09

PROJECT SUMMARY (ABSTRACT) Thyroid cancer is common, but up to 77% of thyroid cancers have been attributed to overdiagnosis. The problem of overdiagnosis is rooted in current management strategies for thyroid nodules that do not appropriately account for the fact that most thyroid cancers are indolent and do not impact morbidity or mortality. As a result, patients are exposed to unnecessary diagnostic workup and treatment, resulting excessive costs to both patients and healthcare systems. The workup for thyroid nodules begins with ultrasound (US), during which US images are analyzed to decide if a nodule looks suspicious and requires biopsy to assess for possible cancer. While several standardized criteria exist to guide this analysis and decision-making, they suffer from multiple problems including (1) low specificity, leading to a large number of benign biopsies, (2) high inter- reader variability, causing heterogeneity in decision-making, and (3) an emphasis on a binary malignancy diagnosis rather than an assessment of nodule risk in terms of morbidity or mortality. With these factors in mind, our goal is to foundationally change how nodules are analyzed on US and to revise current systems that contribute to overdiagnosis. To accomplish this, our research will proceed with three specific aims. First, we will establish a definition of high- and low-risk nodules that focuses on mortality rather than cancer status. Many types of thyroid cancer can be watched rather than removed, and these cancers will be considered low-risk. Using these innovative definitions, we will establish a comprehensive multi-institutional repository of thyroid nodules that will allow us to better understand the previously unknown incidence of high-risk nodules and rates of unnecessary biopsies. In the second aim, we will develop a novel multi-task deep learning model for predicting high- vs low-risk thyroid nodules on US. An accurate model that can consistently diagnose low-risk nodules will reduce unnecessary biopsies and result in downstream cost savings. In the final aim, we will create a feature-based risk stratification system (RSS), which will also differentiate high- from low- risk nodules. This system will mimic feature-based RSSs already used worldwide (but which focus on the less relevant question of benign vs malignant). We will compare the performance of our two systems (deep learning and feature-based) and demonstrate the potential for biopsy reduction. Ultimately, our goal is to accurately characterize low-risk nodules and demonstrate how focusing on risk rather than malignancy status could reduce unnecessary biopsies and surgeries. This project will be conducted by an interdisciplinary team including several members who have served in international leadership roles to help set standards for thyroid nodule management.

NSF Awards · FY 2025 · 2025-09

Many headwater streams have mosses present, yet these plants are rarely included in current conceptual models of stream ecology. Bryophytes, including mosses, liverworts, and hornworts, are common in small streams where they can provide critical habitat for other aquatic organisms, and store large quantities of carbon, nitrogen, and phosphorus. This project will study the role of stream bryophytes as hotspots of freshwater biodiversity and nutrient cycling, with a particular focus on how bryophyte presence in small streams may have large impacts on water quality downstream. The project supports fifteen or more early career researchers across all career stages and multiple institutions. The research team will disseminate findings to broader audiences at conferences, local homeowners’ meetings, and field trips, and is partnering with the Hubbard Brook Research Foundation and a local school to develop environmental science curricula (5th-12th grades) that enable young students to examine and study mosses in nature. The research uses three complementary approaches to evaluate how and where aquatic bryophytes contribute to the structure and function of headwater stream ecosystems. First, researchers will experimentally remove bryophytes from two stream segments within the Hubbard Brook Experimental Forest (New Hampshire) to directly measure the impact of bryophytes on nutrient uptake, organic matter storage, and in-stream biodiversity. Second, the research team will conduct a regional survey of moss abundance and freshwater biodiversity across 50 headwater streams across the White Mountains National Forest that vary widely in stream pH. Results from both experimental and survey efforts will be used to parameterize a stream network model to estimate the effects of bryophytes on nutrient dynamics at river network scales and to predict the impact of bryophyte loss on river nutrient cycling. The project will inform our understanding of how bryophytes support freshwater biodiversity by providing flow and drought refugia and enhance stream nutrient cycling through their high surface area and capacity to trap and sequester materials. By initiating new, long-term records of moss cover at Hubbard Brook, this effort will inform our understanding of how droughts, extreme floods, and river ice affect moss cover over time. In addition to training of postdoctoral researchers and undergraduate students, and outreach to grade school students, this project will enhance understanding of processes that maintain clean freshwater streams, an essential and limited resource for U.S. citizens. 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 · 2025-09

Modified Project Summary/Abstract Section Psoriasis (Ps) is an autoimmune-mediated systemic inflammatory skin disease. Approximately one-third of Ps patients eventually develop psoriatic arthritis (PsA). PsA is one of the most common forms of arthritis, impacting around 1 million individuals in the US. Mechanical pain associated with PsA in joints and skin, triggered by joint loading, movement, and skin touch, is a leading cause of hospitalization for patients and represents a serious unmet medical need. Current PsA therapeutics, including recently developed interleukin 17 (IL17), interleukin 23 (IL23), and Janus kinase (JAK) inhibitors, only offer partial relief from pain. Furthermore, these treatments prove ineffective for some individuals and have side effects. Therefore, there exists a pressing need to identify new targets for PsA pain. Animal pain models can facilitate the rational discovery of novel analgesics. Although current animal models of PsA have advanced our understanding of PsA pathogenesis, it is unknown if they can be used for studying PsA pain because pain has not been characterized in any of these models. Importantly, most of them have limitations that hinder their use for studying chronic PsA pain. We propose to improve, characterize, and validate a mouse model for PsA pain-induced by mannan (Aim. 1). Due to the lack of animal models, we know little about the mechanisms underlying PsA pain. Emerging evidence demonstrated that the systemic and local tissue levels of lysophosphatidylcholine (LPC), a proinflammatory mediator and the most abundant systemic phospholipid in humans, are elevated in psoriatic patients, suggesting its potential involvement in the pathogenesis of PsA pain. Using our improved and validated mouse model in Aim 1, we will examine whether elevated LPC contributes to PsA pain (Aim 2). Success completion of this project will lead to the development of the first animal model of PsA pain that can be used to substantively advance our understanding of PsA pain mechanisms. In addition, this project will pave the way to identify LPC as a mechanistic therapeutic target with exciting potential to mitigate PsA pain.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Embryogenesis is an energetically demanding process in which a single cell initiates divisions, giving rise to progeny that undergo diverse cell fate decisions and complex morphogenetic behaviors to form a multicellular organism with distinct tissues. Mitochondrial oxidative phosphorylation (OXPHOS) and subsequent ATP production play a central role in meeting the dynamic energetic and ROS-mediated signaling demands of embryogenesis. OXPHOS consists of four ETC complexes that each contain multiple protein subunits (~100 total). Importantly, when the function of ETC proteins is impaired, variable developmental defects occur, suggesting that development is dependent on specific ETC proteins. However, how the mitochondrial ETC is regulated to meet the varying energetic and signaling demands of development remains unclear because of the vast complexity of the ETC and difficulty of studying the ETC in development. The Sherwood lab has recently created the first in vivo mitochondrial ETC toolkit in C. elegans, through endogenous fluorophore tagging of ~20 nuclear encoded ETC components from the four ETC complexes. Through whole embryo analysis of fluorescence levels, I have found that ETC complex expression increases ~1.5-3 fold per mitochondria from the two-cell to the two-fold stage when major tissues have formed. ETC protein levels differ between the developing primordial tissues, with striking divergence in the increased levels of ETC proteins per mitochondria in the epidermis compared to the intestine. Overall, this proposal will test the hypotheses that unique mitochondrial ETC levels develop after tissue specification to meet the distinct energetic and possibly signaling demands of the tissue and that these unique mitochondria are essential to tissue differentiation. Completion of the proposed aims will develop C. elegans as a new model to understand mitochondrial ETC regulation and specialization in development, which has important implications to our understanding of development, mitochondrial biology, and metabolic disorders.

NIH Research Projects · FY 2025 · 2025-08

Abstract Recombinant AAV vectors have emerged as promising gene delivery vehicles in the treatment of monogenic disorders. With 6 different FDA approved AAV-based therapies, many additional disease targets requiring systemic dosing continue advancing towards the clinic. However, immune responses arising from prior natural AAV exposure or nascent exposure to recombinant AAV vectors dosed in human subjects poses a major challenge. Evidence from multiple gene therapy clinical trials confirms that high vector doses can trigger cytokine release leading to nausea, fever, and vomiting, and manifest in liver toxicity (elevated enzymes). In some patients, complement activation following systemic AAV dosing has been shown to result in thrombotic microangiopathy (TMA) and acute kidney injury (atypical hemolytic uremic syndrome-like), thrombocytopenia, myocardial injury, and even death. Many of these adverse reactions can be attributed to AAV capsid-antibody interactions highlighting a major (if not predominant) role for humoral immunity. Prophylactic measures or symptom management have generally included plasmapheresis, administration of tapering, high doses of glucocorticosteroids, hemodialysis, platelet transfusion, different drugs or monoclonal antibodies to block complement/B cell activation or induce B cell depletion amongst others. More recently, preclinical testing of agents such as Imlifidase or Vyvgart for promoting IgG clearance has been initiated. However, these current management or mitigation strategies for these clinical sequalae are applied on a case-by-case basis with no specific consensus immunomodulatory regimens (IMRs) in place. Thus, there is a clear and urgent need to better understand, preclinically model and manage these complex sequalae (focus of the current proposal). To this end, our lab recently engineered a novel immunomodulatory agent, IceMG – a recombinant, dual activity protease that can selectively and efficiently cleave human and monkey IgG/IgM. Here, we propose to build on our exciting findings and validate that IceMG is a potent blocker of complement activation as well as modulator of B cell signaling pathways in human models in vitro and humanized mice as well as non-human primates in vivo, thereby charting a path for first-in-human Phase I trials utilizing this IMR. Further, we will engineer and characterize next generation immunomodulators (IceRx) for clinical translation. If successful, the current proposal will enable development of new and improved IMR, essential for the success of AAV gene transfer vectors in the clinic. The proposed strategies may also pave the path for clinical applications in autoimmune disease and organ transplantation.

NIH Research Projects · FY 2025 · 2025-08

Abstract At the end of 2021, an estimated 1.7 million children were living with HIV-1, including 160,000 children who were newly infected (UNAIDS), thus pediatric HIV-1 remains a global health concern. However, there is a gap in our knowledge of B cell development in early-life that prevents us from implementing the full potential of pediatric HIV-1 vaccines. Understanding the mechanisms of early-life immunity that can establish and maintain vaccine-induced responses to HIV-1 immunogens in pediatric populations will contribute to this knowledge gap. A primary goal of a prophylactic HIV-1 vaccine is induction of broadly neutralizing antibodies (bNAbs) that target the envelope (Env) surface protein and prevent infection of different circulating HIV-1 strains. Infants and children living with HIV-1 develop HIV-1 Env-reactive bNAbs, and often develop bNAbs more rapidly than adults. Young rhesus macaques (RMs) that were simian-HIV (SHIV)-infected as infants generated heterologous HIV-1 NAbs with bNAb characteristics in association with enhanced germinal center (GC) activity, including elevated antigen (Ag)-specific GC B cells—a mechanism for bNAb induction in humans. Natural killer (NK) cells have also been postulated to act as rheostats regulating GC-dependent anti-viral B cell responses. However, the permissive immunological environment for vaccine-induced HIV-1 Env-reactive bNAb development in early-life are vastly understudied. In this proposal, we will immunize infant RMs with an innovative pediatric vaccine regimen of bNAb lineage-inducing HIV-1 Env immunogens and a clinically- approved Hepatitis (Hep) B childhood vaccine known to elicit durable memory B cell responses. We will perform immunologic studies with cells from different B cell compartments (peripheral blood (PBMCs), lymph node (LN), and bone marrow (BM)) in neonatal RMs immunized with the multicomponent cocktail HIV-1 and clinically-approved childhood vaccines in an innovative study design to establish the mechanisms of early-life HIV-1 Env immunity that elicit NAbs, a subset of which has the capacity to develop breadth. The specific aims for this proposal are as follows: Aim 1. Define the B cell repertoires elicited by a cocktail pediatric immunization strategy in infant RMs Aim 2: Define the dynamics and functions of vaccine-induced GC B and T cell subsets in LN, and plasma cells in BM, of infant RMs Aim 3. Define the mechanisms of NK cell immunoregulation on the quality of vaccine-induced memory B cells in infant RMs

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Our goal is to understand how the lung microbiome regulates influenza virus infection response by developing a 3D in vitro bioprinted platform to study host-microbiome-influenza interactions in the lung alveolar space. The respiratory microbiome, encompassing hundreds of different bacterial and fungal species, has essential roles in the development of tissue-specific immunity and colonization resistance to pathogens, including viral infection. The lung and alveolar space undergo constant microbial exposure from the inhalation of oropharyngeal contents. Notably, sequencing-based studies have identified a low biomass but diverse microbial signature in healthy individuals. However, a detailed mechanistic understanding of how these diverse microbes interact with host cells to maintain lung health and contribute to viral infection susceptibility is currently lacking. Major knowledge gaps exist due to 1) the substantial biodiversity of the lung microbiome, 2) difficulties in modeling the complexity of the human lung environment, and 3) limited information about where in the lung epithelium these interactions take place and what are the cell-type specific host responses. Additionally, Current approaches lack the capacity to model host-microbe interactions in the lung at transcriptional and spatial resolution. We will overcome these limitations by developing two new technologies – a 3D bioprinted alveolar sac model and dual host-microbe spatial transcriptomics (ST) – to enhance our understanding of the host response to microbial colonization in an advanced, anatomically relevant lung model. The ability to examine which and how specific microbes interact with the lung epithelium and the effect these interactions on influenza infection would be valuable to investigate the microbiome’s role in lung health and infection response. In Aim 1, we will develop and characterize a 3D bioprinted ventilated alveolar sac model. We will then evaluate its influenza infection response using ST and single-cell RNA-sequencing. In Aim 2, we will examine how diverse respiratory microbiota condition the alveolar epithelium to affect influenza infection response. We will develop a dual ST method to simultaneously profile host transcriptional response and microbial/viral localization. We will then use this method to examine how microbial conditioning of the epithelium affects influenza infection dynamics. Together, these aims will allow us to address fundamental questions on the underlying biology of the lung microbiome and its effect on influenza response. Our success would result in two new technologies facilitating the construction of a high-resolution spatial map of the microbiome-host interactions. This advancement would enable in-depth investigations into the mechanisms of interstrain interactions, virulence regulation, and their impact on lung immune homeostasis and infection response.

NSF Awards · FY 2025 · 2025-08

This project introduces novel nanobodies, or VHHs, as cost-effective, reproducible and tunable alternatives to traditional growth factors in cell culture media. Cell culture is fundamental to modern biotechnology, supporting applications from regenerative medicine to cultured meat production, yet current methods often rely on expensive and inconsistent animal-derived growth factors. VHHs, which are small antibody fragments, can be precisely designed to activate cell growth receptors, mimicking natural proteins at a significantly lower cost. Leveraging a novel microbial production system, we can drastically improve growth factor prototyping, reduce manufacturing costs and eliminate batch-to-batch variability common with conventional growth factors. Project outcomes will lead to advances in cell culture methods with broad impacts on human health, sustainable food production, and U.S. biomanufacturing competitiveness. This project aims to engineer novel VHH-peptide fusions as next-generation growth factor alternatives for synthetic cell culture media. Our core innovation involves creating bispecific molecules that combine a receptor-binding VHH with activating peptides. Specifically in this work we will target growth factor alternatives which activate the FGF receptor (FGFR) and the epidermal growth factor receptor (EGFR). These VHHs will be produced using a two-stage bacterial expression system in E. coli, which enables soluble expression, proper disulfide bond formation, and simplified purification, significantly reducing production costs (projected from $15,000/g to $100-500/g). Our approach is systematic, beginning with the design and validation of FGF receptor-activating VHH fusions using cell-based reporter assays and surface plasmon resonance to assess binding kinetics and activation. Subsequently, we will leverage Design of Experiments methodology to optimize complete synthetic media formulations for pluripotent stem cells and bovine satellite cells, ensuring robust proliferation and maintenance of cellular identity. A multi-omics strategy, encompassing RNA-seq transcriptomics, proteomics, phosphoproteomics, and targeted metabolomics, will provide a systems-level characterization of cellular responses to the VHH-fusions, comparing them to natural growth factors across multiple temporal points to capture signaling dynamics and validate functional equivalence. The platform will then be expanded to engineer EGFR-activating VHH-fusions for mesenchymal stem cell culture. This research will generate comprehensive molecular signatures and optimized media formulations, addressing critical challenges in cost, reproducibility, and scalability of cell culture. The integrated academic-industrial collaboration with Roke Biotechnologies provides a clear commercialization pathway, enhancing U.S. biomanufacturing competitiveness. This project is being jointly supported by the Division of Molecular and Cellular Biosciences at NSF and the BioMADE Manufacturing Innovation Institute. 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 mission of the Duke Clinical and Translational Science Institute (CTSI), home to the Clinical and Translational Science Award (CTSA) since 2006, is to catalyze translational science in ways that effectively and efficiently bring medical discoveries to society. In the next phase of our CTSA, we are poised to build on established programs and capabilities to markedly increase our impact. However, we are acutely aware of the challenges posed by the increasing doubts about the credibility of medical science. In response to diminished trust in science and medical institutions and driven by our fierce commitment to improve health for all, we will focus the next phase of our CTSA on “Trustworthy Partnerships to Improve Health Through Translational Science.” To ensure that the benefits of clinical and translational research (CTR) are accessible to all, we will center our programs on the foundational principles of trustworthiness and meaningful engagement of partners and the community that include bidirectional communication, shared resources and decision making, attention to balancing power dynamics, and respect for broad expertise and experiences. Together, with our partners and collaborators, we will: (1) catalyze innovations that advance clinical and translational science, (2) cultivate and disseminate a suite of best- in-class research services and resources that enables investigators and partners to conduct efficient, effective research across the translational spectrum, (3) create, nurture, and advance community-partnered research to improve health for all across the lifespan, (4) train and develop an interprofessional clinical and translational research workforce prepared to implement trustworthy research programs that rapidly translate discoveries to practice, and (5) propagate an informatics framework that enhances data access, data transparency, and the trustworthy application of biostatistics, data science, and artificial intelligence. We will study the impact of our efforts and identify effective approaches to facilitate the achievement of improved health for all. We will also implement new procedures for measuring health in our community. We will disseminate generalizable novel approaches and practices throughout the CTSA consortium and beyond, catalyzing efforts to improve health across our nation.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a highly fatal disease characterized by irreversible destruction of lung tissue and a median survival well below 5 years. The pathologic effector cells in IPF are collagen-secreting fibroblasts driven by transforming growth factor beta (TGF-β). Despite the promise of TGF-β inhibition as a treatment for pulmonary fibrosis, global blockade has been associated with severe side effects, necessitating the identification of strategic therapeutic targets within this pathway. Harnessing the candidate's formal training in biochemistry and innovative expertise in protein post-translational modifications, proteomics, and machine learning, a previously unknown site of lipid modification (S-palmitoylation) on the TGF-β receptor (TGFβR1) has been discovered that appears to regulate its activity. Additionally, evidence of global S-palmitoyl perturbation in IPF has been identified. Based on preliminary data, the candidate hypothesizes that S- palmitoylation of the TGFβR1 receptor represents a reversible pro-fibrotic regulatory mechanism, whose enzymatic regulators may represent novel anti-fibrotic targets. The proposal’s three aims interrogate the roles of S-palmitoylation at three distinct levels: molecular, cellular, and regulatory. Aim 1 utilizes cultured fibroblasts to probe the molecular implications of S-palmitoylation on ligand-induced TGFβR1 phosphorylation and immediate effectors such as Smads, MAP and Src kinase. Aim 2 uses adeno-associated viral (AAV)-based fibroblast expression of TGFβR1 to examine the role(s) of S-palmitoylation within two distinct fibrotic mouse models. Finally, Aim 3 utilizes AAV-based CRISPR deletion to investigate the fibrotic contributions of two enzymatic S-palmitoyl regulators – palmitoyl transferase Dhhc20 and depalmitoylase Abhd17a – that are selectively induced in pathologic fibroblasts and may represent novel antifibrotic targets. These aims allow for the candidate's skill development in cell biology and animal models, while simultaneously supporting a career development plan that fosters expertise in AAV tools, quantitative microscopy, flow cytometry, mouse handling, and advanced bioinformatics. The proposed aims and training plan will delineate the role(s) of S-palmitoylation in IPF and potentially generate a novel therapeutic angle to target pathologic fibroblast signaling and reduce fibrosis. The mentorship team, led by Dr. Purushothama Rao Tata, includes experts in lung biology, fibrosis, TGF-β signaling, and proteomics, ensuring comprehensive training and guidance throughout the award period. This K08 award will pave the road toward the candidate's overarching career goal of anti-fibrotic discovery by focusing on fibrosis-oriented post-translational protein modifications, ultimately aiming to improve outcomes for patients with IPF and other fibrotic lung diseases.

NSF Awards · FY 2025 · 2025-08

This research project develops new ways to model the US economy by using the assumption that economic decision makers learn by experience over time about underlying optimal decision rules. Individuals and organizations are faced with complex real world economic decisions and the best decision may not be immediately obvious. Many macroeconomic models assume that these decision makers have full information and always make decisions that best advance their interests. In contrast, this project models economic decision makers by using artificial intelligence in a model of learning through experience, and incorporates this new framework in classic economic cost-benefit tradeoffs. The new framework provides more realistic economic models that can better approximate the actual behavior of people and firms. These models can provide new insights into how U.S. government fiscal and monetary decisions can achieve desired economic outcomes. The project’s starting point is the observation that people and firms in real life typically learn in two ways about optimal behavior. The first one is reasoning: through introspective, abstract deliberations, economic units can better figure out their optimal course of action. The second one is accumulated experiences: the realized outcomes of past actions can update the perceived benefit of these past decisions. These two sources of information are conceptually distinct but limited, as experiences are observed only along the actual path taken by economic participants, while abstract thinking is a scarce cognitive resource. This research project develops a new interdisciplinary framework to learning through both reasoning and experience. There are three main components to the project. The first component develops the theoretical foundations of the framework and studies its deep fundamental properties, both in the short-run and the long-run. Learning can occur through cognition, which is costly, but beneficial in reducing decision makers' uncertainty about the best course of action. Decision makers trade off that benefit and cost of engaging cognitive resources, giving rise to constrained-optimal, or “resource-rational” choice of reasoning. These participants also update beliefs about optimal behavior based on the experienced flow utility each period. Critically, the effective precision of both reasoning and experiences in informing behavior is endogenous, as a function of the participant's beginning of period prior beliefs which evolve dynamically. This research advances the interest in bounded rationality within economics with novel methods that are rigorously grounded in established cognitive science findings. At the same time, the research also introduces several conceptual innovations to Reinforcement Learning literature, primarily by grounding the proposed learning theory in the constrained-optimal framework familiar to economists. In the second and third projects, the research team evaluates specific applications of the new bounded rationality theory in both household and firm settings. In the second project, the team studies the consumption-savings behavior in a rich model with participant heterogeneity, incomplete markets, consumption of durable and non-durable goods, and potentially investment in liquid and illiquid assets. In the last project, the team evaluates firm and investment dynamics, incorporating fixed costs of investment, endogenous entry and exit, and borrowing constraints. These two projects explore how the proposed learning friction could fundamentally alter economic literature's understanding of both demand and supply blocks, while providing novel and rich implications for decision making. 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.