Duke University

NSF Awards · FY 2025 · 2025-08

Nontechnical summary: Recent advances in optics have enabled scientists to create and control "twisted light," a type of light that propagates in a spiral, carrying orbital angular momentum. Unlike ordinary light, twisted light can interact with matter in entirely new ways, allowing researchers to probe and manipulate systems at the nanoscale and quantum level. This unique form of light is showing great promise in emerging technologies, including quantum computing, secure communications, advanced imaging, and sensing. The workshop "Twisted Light in Nanophotonic and Quantum Systems" will bring together researchers from diverse fields, including physics, engineering, materials science, and computational modeling, to explore how twisted light can be generated, controlled, and applied in modern scientific and technological contexts. While twisted light has traditionally been studied in large-scale systems, its integration with nanoscale structures, such as metamaterials and optical cavities, is enabling new types of lasers and optical devices. At the same time, experiments with atoms, molecules, and condensed matter systems are uncovering new physical effects, such as chiral sensitivity and access to otherwise forbidden quantum transitions. The goal of the workshop is to identify the most critical challenges and opportunities in this fast-growing area and to foster collaborations that will help shape the future of twisted light research. Technical Summary: This interdisciplinary workshop will address emerging challenges and opportunities in the science and technology of twisted light (TL), electromagnetic fields carrying structured orbital angular momentum (OAM), as applied to nanophotonic and quantum systems. The program will bring together researchers focused on TL generation and detection using advanced nanostructures such as metasurfaces, nonlinear metamaterials, and photonic cavities. Recent developments have demonstrated TL-based micro- and nanoscale light sources, as well as their use in imaging through nonlinear colloidal media and in probing chiral molecular responses. The workshop will also highlight experimental advances in TL-induced atomic and molecular transitions, including quantum selection rules in ion traps and TL-induced photocurrents in solids. Theoretical sessions will explore light-matter interactions beyond the dipole approximation, addressing complex electronic structures and non-dipole contributions relevant to atomic clocks, laser cooling, and quantum sensing. Additional topics include orbital angular momentum multiplexing for optical and quantum communication, spatio-temporal vortex beams, and accelerator-based TL sources. By integrating expertise from quantum optics, condensed matter physics, high-energy physics, optical engineering, and computational modeling (including machine learning), the workshop will outline a strategic roadmap for advancing the fundamental understanding and practical applications of TL. Particular emphasis will be placed on interdisciplinary collaboration, bridging traditionally separate research communities to accelerate progress in structured light science. 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 Over half a million infants and children are admitted to an intensive care unit (ICU) each year. Existing data suggest that the number, complexity, and cost of neonatal and pediatric ICU admissions is increasing and that a growing proportion of children admitted to the ICU use life-sustaining technology. Our group and others have demonstrated that shared decision-making in this setting is incomplete and that parents may experience decisional conflict, poor quality communication, and unmet information needs. To address these gaps in care, we worked with community advisors to develop and refine the Building Relationship, Improving Dialogue, and Growing Empathy (BRIDGE) intervention. The BRIDGE intervention provides parents with a brief tool that includes an introduction to health care decision-making, a values clarification exercise, and a question prompt list. Open-ended prompts additionally invite parents to describe how they define concepts like quality of life and suffering. Parents can choose to share their responses with the health care team. We propose to test the impact of the BRIDGE intervention on decision-making and communication in a 3-site randomized controlled trial, with embedded analyses to identify facilitators and barriers to BRIDGE implementation. In Aim 1, we will test the BRIDGE intervention’s impact on the quality of decision-making and communication. We will enroll parents (n=up to 300) of critically ill children (n=150) < 2 years of age for whom a decision about life-sustaining treatment or major intervention is anticipated. Parents will complete baseline surveys and will be randomized 1:1 at the level of the child to receive the BRIDGE intervention or usual care. Parents in the intervention arm will complete the BRIDGE intervention within 5 days of enrollment. All participants will complete in-hospital follow-up surveys measuring preparedness for decision-making, decisional conflict, shared decision-making, and communication quality. In Aim 2, we will evaluate the intervention’s impact on parent decisional regret, parent self-efficacy, and the evolution of parent values at 6 months. Parents will complete measures of self- efficacy and decisional regret at 6 months following hospital discharge. We will conduct semi-structured interviews with a purposively sampled group of parents (n=60) to characterize how their decision-relevant values evolved over the course of their child’s care trajectory. In Aim 3, we will characterize clinician-perceived barriers and facilitators to the implementation of the BRIDGE intervention. Using a mixed methods approach, we will survey and interview clinicians (n=45) about factors that helped or hindered BRIDGE efficacy and that may contribute to future implementation. We will integrate qualitative findings with parent acceptability metrics and characterize differences across ICU units and clinician roles. Our work will be completed in partnership with a Community Advisory Board, who will help guide study conduct, data analysis, and dissemination of results. The data acquired from this award will directly inform future effectiveness testing of the BRIDGE intervention and ongoing work to support children and families impacted by critical illness.

NIH Research Projects · FY 2026 · 2025-08

ABSTRACT Though the cerebellum has long been known to play a key role in motor control and motor learning, we have yet to establish a cohesive model for cerebellar learning. In large part, this is due to a lack of information about the in vivo activity of discrete cerebellar cell types and their interactions during behavior. In particular, despite their large numbers and extensive connectivity within the cerebellar circuit, little is known about how inhibitory interneurons influence cerebellar processing and learning in awake animals. Molecular layer interneurons (MLIs) represent a large class of cerebellar inhibitory interneurons, and are known to provide GABAergic inhibition to the primary output cells of the cerebellum, the Purkinje cells (PCs). Recent single cell RNAseq experiments have revealed that there are two types of genetically defined MLIs, so called MLI1s and MLI2s. Based on their unique connectivity and firing patterns, we have recently established methods to identify these two subtypes of MLIs in vivo using high density silicon probes (Neuropixels), and discovered that the MLI1s inhibit Purkinje cells while MLI2s disinhibit them. This newly discovered circuit motif provides a major revision to our understanding of cerebellar processing and suggests critical yet distinct roles for these interneuron subtypes in behavior and learning. In this proposal, we will test the hypothesis that MLI2 driven disinhibition and MLI1 driven inhibition are recruited by distinct circuit mechanisms to enable learning and behavior. Specifically, in Aim 1 we will test whether MLI2s can be preferentially recruited by climbing fiber activity to disinhibit PCs and facilitate both LTD and learning. We will use in vivo recordings cell-type specific pharmacology to evaluate the role of disinhibition during learning, and an in vitro brain slice preparation to measure synaptic plasticity in tissue from trained animals. In Aim 2, we will test the hypothesis that learning related changes in the cerebellar cortical circuitry enable preferential recruitment of MLI1-mediated inhibition of PCs to drive behavioral responses after learning, and in particular to regulate the timing of learned movements. We will again use a combination of in vivo and in vitro approaches to determine how the circuit transitions from disinhibition to inhibition across learning. Together these experiments will reveal how specific subtypes of interneurons are engaged to promote learning and proper execution of cerebellar-dependent motor behaviors.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/ Abstract Lower respiratory tract infection (LRTI) is one of the most common reasons for hospitalization globally. Viral and bacterial LRTI present similarly, leading clinicians to overprescribe antibacterials for fear of missing a lethal bacterial infection or superinfection. However, emerging data from global cohorts indicate that viral LRTI is frequently more prevalent than bacterial LRTI in both children and adults. In low- or middle-income countries (LMICs), antibacterial overuse for viral LRTI is often worse given limited diagnostic capacity. Access to point- of-care (POC) diagnostic tests, which do not require laboratory infrastructure, may decrease antibacterial overuse for LRTI in LMICs. Locally relevant, evidence-based, cost-effective diagnostic algorithms for LRTI have not been systematically developed in LMICs. The objective of this proposal is to integrate multiple low- cost diagnostic tools (clinical predictors, POC pathogen tests, and POC biomarker tests) to develop and evaluate an LRTI diagnostic and treatment algorithm in a LMIC setting. We will use a large, existing, setting- specific biorepository of patients with LRTI to guide algorithm development. The following aims are proposed: 1) create an evidence-based algorithm for LRTI management by integrating clinical predictors, POC pathogen tests, and POC biomarker tests; 2) establish understanding, acceptability, and barriers to implementation of clinical algorithms for LRTI management among local physicians; and 3) evaluate an LRTI management algorithm in a stepped-wedge, cluster randomized trial at a single hospital in a LMIC. We will complete gold- standard testing and clinical adjudications of samples in our biorepository to identify etiology of infection. We will then construct decision trees by inputting 1) clinical predictors, 2) POC pathogen tests, and 3) POC biomarker tests to identify a potentially cost-effective algorithm that would reduce inappropriate antibacterial prescriptions. We will conduct focus group discussions with local physicians to identify barriers and facilitators to using clinical algorithms. Following algorithm development, we will reconvene focus groups to iterate on the algorithm and to determine appropriate methods for communicating and implementing the algorithm. We will then conduct a stepped-wedge cluster randomized trial to evaluate the algorithm. Patients admitted with LRTI will receive either 1) algorithm-directed care, or 2) usual care. To assess clinical outcomes and antibacterial duration concurrently in this trial, we will use the innovative Response Adjusted for Duration of Antibiotic Risk (RADAR) clinical trial design developed by the Antibacterial Resistance Leadership Group (ARLG). The expected outcome of this work is the development and evaluation of a LRTI diagnostic algorithm that uses local evidence and integrates multiple low-cost diagnostic tools. The long-term goal of this work is to translate these methods to other low-resource settings to combat the growing global crisis of antimicrobial resistance.

NIH Research Projects · FY 2025 · 2025-08

Abstract The xenotransplantation field has achieved commendable success through the utilization of the non-human primate (NHP) model. Studies to date serve as a proof-of-concept, demonstrating that pig-to-NHP or human transplantation can be achieved without hyperacute rejection and providing insights regarding the human immune response to a xenograft. Xenotransplantation survival in nonhuman primate recipients has markedly improved in the past decade due to 1) the use of genetically modified pig donors, and 2) the treatment of recipients with costimulation blockade, in particular targeting CD40-CD154 signaling pathway. Recently, a pig- to-NHP xenokidney transplantation model employing a TKO pig with additional human proteins under anti- CD154mAb immunosuppression showed the longest graft survival close to 2 years. However, it is imperative to not overlook the outcomes of animals that did not attain long-term graft survival. In this study, 40% of NHP recipients (6 out of 15 animals) did not survive beyond 2 months. The consistent occurrence of early xenograft failures in virtually all NHP xenotransplantation studies is a matter of concern. Considering the two cases of clinical cardiac xenotransplantation outcomes (patient survival of 61 and 40 days) are coincide with the early failure shown in NHP model, clear mechanistic explanation and intervention for this phenomenon is urgently required prior to clinical xenokidney transplantation. Interestingly, we and others observed a clear antibody- mediated rejection (AMR) in early xenograft rejection with high levels of preformed and de novo xenoreactive IgG/IgM. Removal of preformed IgG antibodies with cleaving enzyme such as IdeS (Imlifidase) has shown therapeutic promise in organ transplantation for sensitized recipients. However, strategies to selectively remove IgM, which precedes IgG in triggering immune dysfunction are lacking. Especially, preformed and de novo polyreactive IgM antibodies against porcine glycans were considered detrimental in pig-to-human and pig-to-NHP xenotransplantation. Therefore, in the present study, our focus is on targeting both xenoreactive IgG and IgM using novel endopeptidase(s), IceMG, to eliminate early antibody-mediated injuries. We hypothesize that mitigating the early injuries caused by preformed and/or de novo xenoreactive IgG/IgM prolongs xenograft survival by preventing AMR. This study will validate the role of xenoreactive IgG and IgM in early xenograft rejection, identify potential xenograft injuries independent of AMR, and assess the efficacy of the novel endopeptidase as a therapeutic option for xenotransplantation.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT During human pregnancy the interface between the maternal and fetal vasculature is a tissue-sized multinucleate cell termed the syncytiotrophoblast (STB). The STB is essential for transport, fetal immunoprotection, metabolic functions, and is the primary producer of placenta hormones. Surrounded by maternal blood, the STB must maintain these diverse functions while responding to extracellular stresses like hypoxia, oxidative stress, and inflammation to maintain a healthy pregnancy. In fact, systemic STB stress is a key driver of maternal pathology in preeclampsia, a leading cause of maternal and fetal mortality that affects 5-10% of pregnancies. The objective of my long-term research program is to dissect how a single giant cell supports these diverse functions while simultaneously reacting to stress. In fact, my research has revealed that individual nuclei in the STB express different sets of genes and therefore adopt distinct nuclear subtype identities. These nuclear subtypes shift in proportion throughout gestation and in response to environmental cues, suggesting the STB can adapt its distribution of nuclear subtypes to the fluctuating maternal environment. How are unique nuclear subtypes created and modified in a shared cytoplasm? Ultrastructure analyses of nuclei in the STB reveal diverse sizes, shapes, and degrees of chromatin compaction, suggesting the transcriptional diversity among STB subtypes could arise from distinct epigenetic landscapes. Further, I have identified candidate chromatin remodelers and transcription factors whose expression is specific to individual STB subtypes and could regulate their unique transcriptional identities. Therefore, I hypothesize that epigenetic regulation facilitates the formation of distinct nuclear subtypes and drives STB adaptation to stress. My research goals to test these hypotheses are 1- determine the mechanism of nuclear subtype adaptation during stress and 2- map the unique epigenetic regulation of each STB nuclear subtype. I will complete this training in Dr. Amy Gladfelter’s lab, a supportive and inspiring mentor who has ensured I have all resources necessary to achieve the proposed Aims. However, to obtain my research goals I require additional experimental and intellectual training in lineage tracing and epigenomic profiling. This will be accomplished with a world-class advisory committee at Duke University. To test how STB nuclear subtypes adapt to stress, I will work with work with Dr. Purushothama Rao Tata to master cutting-edge CRISPR lineage tracing experiments. To map the epigenetic regulation of STB nuclear subtypes, I will work with leaders in cutting-edge chromatin techniques including Dr. Anoop Patel, Dr. David MacAlpine, and Dr. Greg Wang. This training will lay the groundwork for my independent research program that dissects the epigenetic mechanisms by which a giant STB cell can support diverse cell functions while adapting to stress. Ultimately, I aim to use these molecular studies to identify therapeutic targets that mitigate STB stress during pregnancy disease. This K99/R00 award will enable me build collaborations with experts in plasticity and epigenomics and master these new fields with focused training, seminars, workshops, and conferences.

NIH Research Projects · FY 2025 · 2025-08

Like many microbes, S. cerevisiae cells will grow in liquid culture until they utilize all the nutrients, when they cease dividing as unbudded cells in G1 and enter stationary phase. The pathogenic budding yeast, Cryptococcus neoformans also arrests when cells grow to high density, but the cells arrest as unbudded G2 cells with fully replicated DNA. This is an unusual arrest point for stationary phase, and experiments demonstrate the C. neoformans cells arrest in response to low [O2] rather than depletion of nutrients. Cells reproducibly arrest at the same [O2] levels (approximately 6%) regardless of the starting conditions. As cells approach the saturation arrest and deplete O2, bud emergence is inhibited in early S phase and cells don’t bud until G2 phase. This arrest point is reminiscent of a checkpoint arrest observed in S. cerevisiae cells when budding is inhibited. The morphogenesis checkpoint prevents unbudded cells from undergoing mitosis and generating polyploid, multinucleate cells. We hypothesize that in saturated cultures of C. neoformans, low [O2] inhibits budding and triggers a morphogenesis checkpoint or directly activates a checkpoint that arrests cells in G2. In response to various intracellular signals, some checkpoints, including the morphogenesis checkpoint, act to inhibit mitotic cyclin/CDK complexes to prevent entry into mitosis. Inhibition of these complexes is regulated by the Wee1 kinase that phosphorylates inhibitory residues on CDK, and the Cdc25 phosphatase which dephosphorylates these sites. The short-term goals of this proposal are: i) to characterize changes in cell-cycle events during transition from log-phase growth to saturation arrest to provide clues to what defects might be associated with triggering a checkpoint arrest; ii) identify changes in the cell-cycle machinery that might impact bud emergence and checkpoint arrest in G2; iii) evaluate deletion mutants of the C. neoformans orthologs, WEE1 and CDC25, as well as orthologs of other known checkpoint kinases for their role in the saturation/hypoxia arrest. These initial studies will set the stage for the long-term goal of identifying the complete molecular mechanism for the hypoxia checkpoint from the initial molecules that sense low [02] to the machinery controlling bud emergence and mitotic arrest. As checkpoints normally protect cells from dividing when cell-cycle events or the genome is perturbed, these studies are key for understanding how C. neoformans cells proliferate in low oxygen environments. Moreover, understanding the complete molecular pathways that drive cell-cycle arrest may provide ideas for novel antifungal strategies that target checkpoint components.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Despite the advent of highly active anti-retroviral therapy, there are ~1 million new HIV infections and hundreds of thousands of deaths annually. Thus, HIV is still a global health concern, and there remains an unmet critical need for an effective vaccine to prevent HIV-1 acquisition. One strategy for an effective HIV vaccine is to elicit broadly neutralizing antibodies (bnAbs) that target conserved epitopes on Envelope (Env) of diverse HIV strains of different subtypes. Recent studies have shown that subtype C HIV-1 Env diversification over time has resulted in greater resistance to nAbs and Fc-mediated antiviral activities, thus highlighting the need for bnAb-inducing vaccine strategies to target recent subtype C viruses. However, there remains a gap in our knowledge regarding the induction of bnAbs, including those that can target subtype C HIV Envs. A common vaccination strategy for the development of bnAbs is the initial priming and subsequent boosting or maturation of B cells that have the capacity to develop bnAb status with heterologous HIV neutralization breadth. In this proposal, I will use a single priming Env immunogen followed by multivalent Env boosts to mature V2-apex nAbs to bnAb status in a NHP model. My central hypothesis is that a V2-apex precursor B cell engaging prime and multivalent boosting with computationally selected immunogens that captures the diversity in the V2 region of recently circulating subtype C HIV, will engage and mature B cell lineages capable of generating robust polyfunctional Env V2-targeting Abs that can neutralize heterologous HIV, including subtype C Envs. The scientific premise for this project is that identifying vaccine immunogens capable of inducing V2- targeting polyfunctional Abs that can recognize recently circulating viruses, including subtype C will provide a much-needed component of a successful vaccine that can prevent HIV-1 acquisition. At the completion of the proposed research, my expected outcomes are two-fold and related to: 1) scientific achievements: development of an HIV-1 vaccine that elicits robust polyfunctional anti-V2 Ab responses against subtype C Envs in an NHP model; and 2) career development: to gain knowledge and skills for leading a preclinical and translational research program using NHP models to develop and test vaccines and immunoprophylaxis strategies for HIV and other emerging/established pathogens.

NIH Research Projects · FY 2025 · 2025-08

This supplement will follow the approved Abstract under the ECHO CC U2COD023375-08. Child health is determined by multiple environmental forces; however, surprisingly little is known about the interactions of these forces. In addition, despite an emerging consensus that numerous gene-environment interactions determine child health, much remains unknown about how genetic and environmental factors combine to promote or prevent adverse outcomes. This Environmental influences on Child Health Outcomes (ECHO) Coordinating Center (CC) proposal seeks to further strengthen the broad children’s health research community to increase the body of knowledge about these complicated effects by fostering collaboration among internal and external stakeholders and supporting the research of the ECHO Program to enhance the health of children for generations to come. The Duke Clinical Research Institute (DCRI) is uniquely positioned to serve as the ECHO CC after successfully serving as the ECHO CC for the last seven years. In addition, DCRI manages >30 active network and administrative coordinating centers and has emerged as a leader in pediatric research. Unique features of the proposed ECHO CC include: 1) extensive experience and track record of the leadership team in the support of the initial ECHO Program and conduct of multiple pediatric studies; 2) pediatric operational expertise of the DCRI; and 3) existing, robust administrative infrastructure necessary to effectively and efficiently manage responsibilities for coordinating the ambitious efforts of the ECHO Program. The team is led by Drs. P. Brian Smith and Linda Adair. The specific aims for the ECHO CC are to: 1) provide organizational infrastructure to coordinate and oversee ECHO Program’s research activities; 2) support ECHO Cohort Committees and communication among all ECHO Program Components and stakeholders; 3) manage the ECHO OIF and foster training of early investigators through a comprehensive research environment. The ECHO CC will establish and oversee the required infrastructure to coordinate the multiple levels of membership in the ECHO Program. This infrastructure will focus on methods of learning valuable information about environmental exposures through aggregation of massive amounts of data from ECHO Cohort Study Sites. The ECHO CC will make scientific efforts faster and more efficient while protecting human subjects. This infrastructure is possible because of the expertise of DCRI, which not only has extensive experience in coordinating pediatric studies but also has the essential platforms ready.

NIH Research Projects · FY 2026 · 2025-08

ABSTRACT The vertebral column or spine is a segmented support structure composed of alternating vertebrae and intervertebral domains. In zebrafish, the notochord sheath segments into cartilage-like (col9a2+) and mineralizing (entpd5a+) domains in a Notch dependent process. Osteoblasts are then specifically recruited to the mineralized domains, producing highly regular and symmetrical vertebrae. Notochord segmentation occurs sequentially along the anterior-posterior (AP) axis, much like somite formation, which takes place alongside the notochord several days earlier in development. However, unlike somitogenesis, notochord segmentation is not associated with oscillations in Notch signaling, suggesting that different signaling mechanisms control notochord and somite segmentation. The goal of this proposal is to integrate genetics, cell biology, and quantitative imaging methods to investigate the signaling processes that drive notochord segmentation. Specifically, we will elucidate both the clock mechanism that times the addition of new mineralizing segments at a rate of about 2-3 segments per day and the mechanisms that ensure that segments form in the correct spatial location. Finally, we will investigate how after segments are formed their boundaries are sharpened via self-organizing cellular and mechanical interactions. The mechanisms elucidated by our studies will build a new paradigm of periodic pattern formation. Our studies will also help understand the formation and organization of gene expression domains within biological tubes, which may underlie the regionalization and specialization of functional domains within organs.

NIH Research Projects · FY 2025 · 2025-08

Recent work suggests that infection with the B-lymphotropic herpesvirus, Epstein-Barr virus (EBV), is a key early event in the etiology of multiple sclerosis (MS). However, the molecular basis for how EBV promotes MS is currently unknown. EBV infects most human in the first decade of life and by adulthood, nearly 95% are latently infected. Given this very high prevalence of EBV in the general population, it is unclear why only 1:300 people in the US are afflicted with MS. Despite the well-studied, yet heterogeneous, genetic risk factors associated with MS, this apparent disconnect might be explained by a mechanism whereby EBV infects a particular B cell subset that accumulates in individuals at high genetic risk for MS. The expansion of such a pathogenic, potentially autoreactive and pro-inflammatory B cell subset has been described, yet little is known about the mechanism of how EBV plays a role in the expansion or activity of these cells. It is our ultimate goal to define the role of EBV in MS pathogenesis. In this proposal, we aim to characterize the temporal and spatial expression of EBV and EBV-regulated genes within a unique B cell subset. It is our central hypothesis that EBV persists in atypical memory B cells which display markers consistent with CNS trafficking ability and pro-inflammatory cytokine production. We have formulated our central hypothesis based on extensive preliminary data characterizing an EBV de novo infection signature in T-bet+/CXCR3+ B cells and observing this EBV-associated signature in clinically isolated syndrome (CIS) and MS patient samples. However, the capture of EBV-specific transcripts are outstanding in these clinical samples, which is a critical need to determine the putative role of EBV in MS pathogenesis. The rationale for this proposed research is that defining the role of EBV and its effects in B cells of CIS/MS patients will provide important insight into MS pathogenesis as well as new diagnostic and prognostic indicators of disease. Our laboratories are well positioned to pursue these studies as they have complementary expertise in EBV and MS biology and immunology as well as access to and experience with cutting edge single cell resolution techniques for studying viral and host gene expression in clinical samples. We plan to test our hypothesis and complete the objectives outlined in this proposal through the following two specific aims: 1) Validate and extend an EBV-associated peripheral atypical B cell gene expression signature in CIS/MS patients and 2) In situ transcriptomic analysis of ABC and EBV status in MS CNS tissue. The proposed study constitutes a comprehensive approach to precisely define the peripheral and CNS-resident cells that harbor EBV in patients with MS. In conjunction with our prior work, the data generated herein will yield invaluable insight into EBV- mediated loss of immune tolerance associated with CNS pathology. Completion of this project will directly guide future mechanistic studies of EBV involvement in neuroimmune dysregulation and inform clinically actionable biomarkers and therapeutic targets for the treatment and management of MS, thereby providing a springboard for a more expansive proposal.

NIH Research Projects · FY 2025 · 2025-08

Abstract C-terminus of HSC70 Interacting Protein (CHIP) is a neuroprotective protein that is beneficial in many different neurodegenerative diseases. More recently mutations in CHIP have been identified as the cause of two neurodegenerative diseases. Recessive mutations in CHIP cause Spinocerebellar ataxia autosomal recessive type 16 (SCAR16), while dominant mutations cause Spinocerebellar ataxia type 48 (SCA48). While SCAR16 is a very rare disease, SCA48 is a more common form of ataxia. Many mutations that cause SCA48 exist in the tetratricopeptide repeat domain of CHIP and map to a single interface between the first and second TPR repeat of CHIP. That led us to investigate the importance of this domain. Our findings indicate that mutations in this domain cause SCA48 by inducing a structural change that partially unfolds the TPR domain of CHIP. Importantly this unfolding event can be reversed by addition of excess ligand suggesting that mutations that cause SCA48 do not terminally unfold the TPR domain of CHIP. Importantly these results also suggest that one could identify small molecules that stabilize this domain and thus may be therapeutic for patients with SCA48. Here we propose to optimize and miniaturize a series of assays. These assays will then be utilized to screen for small molecules that restore the proper fold and function to the TPR domain of CHIP. Compounds from the screen will then be evaluated with secondary and tertiary assays to identify hits. These hits will then be tested in cell culture models of SCA48 to see if they reverse disease phenotypes. Together the work proposed in this application will put us on the road to developing small molecules that may one day be therapeutically useful.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Halting the spread of HIV-1 infection with a protective vaccine continues to be a global health priority. Passive immunotherapy with broadly neutralizing antibodies (bnAbs), and vaccine-induced autologous tier 2 nAbs, have proven effective in preventing simian-human immunodeficiency virus (SHIV) infection in non-human primates (NHPs). Thus, eliciting nAbs, preferably bnAbs, is thought to be required for a protective vaccine against HIV-1 infection, but inducing high titers of nAbs that persist for long period of time is a difficult task. Our group has developed both HIV-1 and SIV-based Integrase-Defective Lentiviral Vectors (IDLVs) to deliver a broad range of antigens (Ag) for induction of durable antigen (Ag)-specific immune responses in both mice and NHPs. IDLVs offer significant advantages in addressing limitations shown by other vaccine platforms. IDLV persistently expresses the encoded-Ag, and induces higher magnitude antibody responses with extended durability compared to other common vaccine platforms, including DNA, protein and mRNA. To elicit protective, durable immune responses with vaccination, we will optimize two crucial aspects toward an effective HIV vaccine: the vaccine delivery platform and a multi-antigen Gag-Env strategy to elicit durable neutralizing antibodies and T cell responses. The overall hypothesis to be tested in these studies is that a vaccination strategy where a trimeric stabilized HIV-1 Env is persistently expressed by IDLV will lead to initiation and affinity maturation of nAb B cell lineages in Rhesus Macaques (RMs). Furthermore, we hypothesize that the presentation of these stabilized Env trimers by IDLV in a membrane tethered conformation will enhance immunogenicity. Additionally, the inclusion of SIV-Gag will stimulate strong CD4 and CD8 T cell responses that will enhance protection from SHIV challenge. The overall strategy will be to use the RM model systems to elucidate the mechanisms driving IDLV’s persistent immunogenicity by performing in depth immune responses analysis in longitudinal blood, lymph nodes and bone marrow samples. We will combine transcriptomics with flow cytometry functional assays to study the landscape of immune cells in IDLV vaccinated RMs that is associated with vaccine-induced nAb responses. We will also study the ontogeny and dynamics of B cells using BCR sequencing over time to look for evidence of increased mutation rates and clonal expansion. Results from this project will significantly advance our understanding of how the delivery modality and immunogen strategy contribute to durability and efficacy of vaccine induced immune responses.

NIH Research Projects · FY 2025 · 2025-08

Abstract The same intensity applied to identifying molecular targets, investing in research, and running clinical trials that is occurring now for adult cancers has not extended to the pediatric population, despite evidence that doing so in pediatric cancers will improve patient outcomes. An amenable context for targeted therapies is fusion- driven cancers, which are characterized by relatively quiet genomes with recurrent, balanced translocations that create fusion oncoproteins that drive oncogenesis. CIC::DUX4 sarcoma, a common member of the Ewing sarcoma family of pediatric and young adult cancers, is defined by a transcription factor fusion of the CIC and DUX4 genes. This is an especially aggressive disease and bears a significantly worse prognosis than classic Ewing sarcoma. A major limitation as to why no targeted therapies exist for this cancer is relatively little is known about the mechanisms by which CIC::DUX4 drives disease progression. In response, my team has developed and assembled the largest known collection of CIC::DUX4-driven human and mouse sarcoma models. I am working on studies combining these models with genomic and proteomic technologies to define, for the first time, the altered gene expression driven by this oncoprotein, how it alters cellular signaling, proliferation, survival, and differentiation state, and the network of proteins within the cell that regulate its oncogenic functions and associated survival dependencies. The purpose of this work is to shed light on consensus functions of the CIC::DUX4 fusion oncoprotein to better understand its molecular pathophysiology.

NIH Research Projects · FY 2025 · 2025-08

Abstract Lung cancer continues to be the leading cause of cancer-related deaths globally, marked by a high incidence of metastatic disease and the development of resistance to treatment. Existing therapies for metastatic lung cancer lack an ability to elicit durable responses. Our laboratory has demonstrated that the Abelson (ABL) family of non- receptor tyrosine kinases promotes metastatic outgrowth of lung cancer cells in mouse models, and that inhibition of the ABL kinases disrupts metabolism and decreases tumor burden in vivo. To identify pathways that might synergize with ABL kinase inhibition to impede the growth of metastatic lung cancer cells, we performed a metabolically-focused CRISPR/Cas9 loss-of-function screen. This screen revealed that disrupting regulators of cholesterol homeostasis significantly sensitized metastatic lung cancer cells to cell death when combined with sub-therapeutic doses of allosteric ABL kinase inhibitors. The goal of this proposal is to investigate the role of ABL kinase signaling in cholesterol homeostasis in metastatic lung cancer, thereby uncovering novel exploitable vulnerabilities to improve treatment strategies. I will use CRISPR technology, pharmacological inhibitors, and mouse models of metastasis to evaluate the effectiveness of targeting cholesterol pathways in combination with the ABL kinases to impair lung cancer growth and metastasis.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitor (ICI)-based therapy revolutionized cancer treatment; however, prostate cancer (PCa) is known to be generally immune-cold and refractory to ICI in non-selective patients. A lack of cytotoxic T lymphocyte (CTL) infiltration and the enrichment of myeloid-derived suppressor cells (MDSCs) contribute to immune evasion in PCa. Exact mechanisms that shape PCa’s tumor immune microenvironment (TIME) remain poorly understood. Recent studies point to critical involvement of epigenetic regulators. ~8% of the human genome are endogenous retrotransposons (ERVs), which are normally silenced by epigenetic mechanisms, notably, histone H3 lysine 9 trimethylation (H3K9me3). We recently identify TNRC18, an under-studied epigenetic factor, to be a new H3K9me3 reader that mediates ERV silencing. TNRC18 directly binds H3K9me3 via a C-terminal BAH domain and uses its N-terminal segment for recruiting corepressor such as HDAC. In the TCGA PCa patient dataset, we observe a significant negative correlation between TNRC18 expression and anti-tumor immune response, which indicates TNRC18 epigenetically modulates immunity. Our preliminary results collected from both human and mouse PCa cell models now show that TNRC18 knockout (KO) or loss- of-function (LOF) mutation activates ERVs and immune activation-related genes (such as CXCL10), which induces viral mimicry and immune activation. Combined scRNA-seq and flow cytometry-based analyses of immune cells in a murine PCa model further show that TNRC18 loss causes dramatic changes of TIME, notably, decrease of MDSCs and increase of CTLs; and in the same mouse PCa model, TNRC18 inactivation significantly sensitizes PCa to anti-PD1 treatment. Our hypotheses are that (i) in PCa, TNRC18 epigenetically silences the immune activation-related transcripts and immunogenic ERVs to promote immune evasion and that, (ii) conversely, TNRC18 LOF induces an ‘inflamed’ TIME, enabling the ICI-based therapy. To test these innovative hypotheses, we propose to use representative preclinic models to elucidate TNRC18’s tumor- intrinsic functions in regulating transcriptome and immunogenicity of PCa (aim 1); here, we use genome-wide profiling to dissect involvement of TNRC18 and associated Sin3/HDAC complex for epigenomic modulation and for silencing of immune activation pathways. We will also assess the TNRC18 LOF-induced viral mimicry effects on inducing interferon response and suppressing PCa growth. On a separate line of research (aim 2), we will define tumor-extrinsic effects of TNRC18 LOF on inducing an immuno-‘hot’ TIME, re-sensitizing PCa to ICIs; here, we will also examine the chemokine signaling pathways that mediate recruitment/infiltration of CTLs and MDSCs to PCa. The completion of the proposed research will not only gain novel mechanistic insights into epigenetic regulation of PCa’s immuno-‘cold’ characteristics but importantly will provide new therapeutic strategies that may be translated to the clinic in the future. The potential impact of the project is high.

NIH Research Projects · FY 2026 · 2025-08

ABSTRACT Glioblastoma is a uniformly lethal brain tumor despite aggressive and toxic standard of care treatments including surgery, radiation, and chemotherapy. One of the main barriers to understanding glioblastoma tumor biology and developing more effective therapies is the dependence on invasive surgical procedures for diagnosis. The need to obtain tumor tissue for initial diagnosis in patients with glioblastoma is limited by 1) intratumoral heterogeneity (genomic and epigenomic), 2) temporal heterogeneity, 3) sampling error, and 4) surgical eligibility. Additionally, surveillance of glioblastoma remains a diagnostic challenge since recurrent disease is often indistinguishable from treatment-induced inflammation, termed pseudoprogression, on conventional imaging, which contributes to diagnostic ambiguity and treatment delays. The identification of a non-invasive, prognostic biomarker for longitudinal molecular profiling of glioblastoma could overcome these challenges, improving risk stratification, clinical trial design, surveillance, and standard of care. Our prior work revealed that changes in peripheral immune cell populations from whole-blood samples of patients with primary and recurrent glioblastoma correlate with treatment response and overall survival, thus supporting the concept of a local and systemic tumor microenvironment. In non-CNS tumors, circulating tumor DNA (ctDNA) has received considerable attention to assess tumor burden, predict treatment response, and select therapies. However, classical ctDNA approaches using somatic mutation analysis are limited in glioblastoma due to the lack of recurrent somatic mutations, significant intertumoral heterogeneity, and low detectability of somatic mutations in blood. We hypothesize that methylation profiling of cell-free DNA (cfDNA) can overcome these limitations, as epigenetic modifications are detectable in cfDNA, correspond to the cell of origin and cell state, are stable and detectable with a low input of genomic DNA (<250 ng), and offer a greater breadth of information about the state of the cell of origin and differential responses of clonal lineages to treatment. To our knowledge, cfDNA methylation has not been evaluated in a prospective clinical trial as a biomarker for brain tumor biology or correlated with clinical outcomes. To test this hypothesis, we will employ prospective blood sample from patients with glioblastoma enrolled in the completed randomized Phase II VERTU trial (NCT02152982) to determine whether cfDNA methylation patterns cluster with specific tumor tissue DNA methylation patterns (Aim 1). We will then characterize the impact of changes in cfDNA methylation patterns on clinical outcomes, including survival (Aim 2). Finally, we will evaluate whether the activation state of circulating immune cell populations, inferred from cfDNA methylation patterns, can be used to non-invasively distinguish pseudoprogression from recurrent disease (Aim 3). These translational aims have the potential to guide the development of non-invasive diagnostic and surveillance platforms for patients with glioblastoma, which could impact treatment selection and clinical trial design.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT One in five US adolescents have obesity, making pediatric obesity a significant public health problem. Safe and effective treatment options exist for adolescents with obesity including motivational interviewing, intensive health behavior and lifestyle therapy, pharmacotherapy, and metabolic and bariatric surgery. Recently, several anti- obesity medications (AOMs) have been approved for use in adolescents, showing great promise for reducing obesity. However, to date, these AOMs have only been studied in tightly controlled clinical trials. While clinical trials have high internal validity and provide evidence for efficacy of pharmacological approaches, they are limited in their external validity and real-world generalizability. This has lead to gaps in our understanding of adolescent AOM use including knowledge of the reach of AOMs in youth, effectiveness within real-world clinical settings, and possible unintended consequences of AOM use. It is imperative that these gaps are addressed to ensure that adolescents receive safe and effective clinical care. Therefore, the objective of this project is to collect real- world evidence that can be used to inform clinical practice, improve health outcomes, and ensure patient safety among adolescents using AOMs. The proposed project will recruit a cohort of adolescents using AOMs (12-17y; n=200) from two pediatric obesity treatment clinics. In Aim 1, we will characterize the population of youth using AOMs by examining demographic characteristics from the electronic health record of cohort youth compared to those who are eligible, but never prescribed AOMs. In Aims 2 & 3, cohort participants will be followed for 18- months, completing four study visits that will include measure of body composition, diet, physical activity, mental health and quality of life. A subset of patients will complete DXA scans to further assess changes in body composition and semi-structured interviews to yield richer contextual information. Data will also be obtained from the electronic health record and assessments of adherence throughout the duration of cohort participation. In Aim 2, effectiveness of AOMs will be evaluated by examining change in relative BMI among cohort youth compared to the youth not utilizing AOMs from Aim 1 using propensity weighting approaches. Additional analyses will examine the relationship between changes in diet, physical activity and study outcomes as well describe adherence to AOM treatment protocols including medication switching and discontinuation. In Aim 3, we will consider the unintended consequences of AOM use including longitudinal changes in mental health, development of disordered eating behavior, and changes in DXA measured body composition and bone mineral density. Overall, this project will provide valuable clinical evidence around AOM use in adolescents by addressing key gaps in our knowledge of access, effectiveness and factors that influence effectiveness, and potential unintended consequences. Successful completion of this project will inform clinical recommendations around adolescent AOM use and has broader implications for implementation of AOMs among specialized obesity treatment centers and general pediatric clinics.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT The ability of mammals to regenerate injured appendages is limited to healing bone fractures and regenerating digit tips. For any future therapies to be useful they must pattern regrowth so that it restores tissue size and function and avoids hypertrophy and dysmorphology. In contrast to mammals, zebrafish regenerate entire appendages following an injury, such as amputation. Notably, regenerated fins reproduce the original size, shape, and function of the injured appendage. While previous work has identified molecules and cellular events required for promoting zebrafish fin regeneration, we still do not fully understand how cells within a regenerating appendage encode size memory or how cells dynamically monitor the progression of regenerative outgrowth to ensure accurate tissue size. This is partly due to the difficulty of rigorously documenting cellular events, such as signaling levels, in vivo in complex tissues at single-cell resolution. This proposal will overcome these difficulties by combining quantitative live imaging approaches, computational analysis, and theoretical modeling to map cell signaling activity with single cell resolution. Specifically, Aim 1 will dissect how the initial conditions encoding size memory are established for fin rays of different lengths. Aim 2 will uncover how size memory is processed in fibroblast tissue, which comprises connective tissue-secreting cells that lie inside and between bony hemirays. Aim 2 will also test the hypothesis that size memory is differentially regulated in fibroblasts and osteoblasts (bone-matrix secreting cells) by distinct upstream Fibroblast Growth Factor (Fgf) ligand expression. The research outlined here will form the intellectual basis of my own independent research program. Together with my advisors, Dr. Stefano Di Talia and Dr. Ken Poss, I have developed a training plan that will enable me to master skills in theoretical approaches and transgenic zebrafish generation as well as gain hands-on lab management experience during the K99 award phase. Furthermore, I have established an exceptional committee of advisors, including expert theorists and experimental biologists, who are committed to helping me develop my independent research program. The research and training described here will uniquely position me to apply this interdisciplinary, quantitative approach to additional signaling pathways, such as Wnt, and other regenerating tissues, including the vasculature and the nervous system. Long-term, I will lead my own research group in generating a wholistic understanding of how size memory is established and dynamically processed during fin regeneration. I expect the insights gained from this research will inform the development of regenerative therapies that promote tissue regrowth in humans without inducing pathogenic overgrowth or dysmorphology.

NIH Research Projects · FY 2025 · 2025-08

Despite the known benefits of regular physical activity (PA), adherence to recommended PA guidelines remains alarmingly low, with marked variation observed across the population. PA behavior is influenced by genetic, behavioral, environmental, and social factors. In particular, the built environment—where people are born, live, learn, work, play, worship, and age—has become an increasingly important focus for interventions aimed at promoting healthy PA behaviors. However, understanding the role of the built environment in shaping PA behaviors has been limited due to incomprehensive measures of PA and the infeasibility of randomized controlled trials. Our project aims to address this gap by leveraging the large, longitudinal wearable device data from the All of Us Research Program (AoURP). We propose a novel approach to represent PA behaviors and a machine learning framework to uncover the mechanisms through which the built environment factors influence PA and, by extension, health outcomes. We will utilize minute-level intraday step data from the AoURP to generate PA behavior profiles—a data-driven representation for quantifying daily patterns of PA. This high-frequency data from wearable devices offers detailed insights into each individual’s daily interactions with the built environment, offering greater temporal specificity than conventional summary metrics, such as average daily steps or minutes of moderate-to-vigorous activity. We hypothesize that PA will be strongly associated with a variety of factors, including the built environment, and that these associations will be more pronounced using PA behavior profiles than traditional summary measures. We also aim to study the indirect effects of the built environment on health outcomes through a machine learning framework that incorporates counterfactual analysis. Through this framework, we will examine how hypothetical modifications in the built environment could "flip" health outcomes by altering an individual's PA behavior. In addition, stratified post-hoc analyses will be conducted to explore the differential impacts of environmental changes across various subpopulations. This proposed project will advance our scientific understanding of population-level health outcomes through the development of a new approach for representing PA behaviors from wearable device data. By proposing a novel framework for counterfactual analysis, the project will demonstrate how observational data can be used to understand the underlying etiologic factors and mechanisms that contribute to variation in health outcomes.

NSF Awards · FY 2025 · 2025-08

Simulation of quantum dynamics, also known as Hamiltonian simulation, served as the original motivation for quantum computers and remains a core task in quantum computing today. It has wide-ranging potential in fields such as quantum physics, quantum chemistry, and biological molecular dynamics. This project aims to advance quantum simulation by addressing challenges posed by so-called unbounded operators, which frequently arise in scientific and engineering context due to the discretization of differential operators. By tackling these issues, the project seeks to enhance computational techniques, deepen theoretical understanding, and broaden the practical impact of quantum computing while strengthening its connections with mathematics. Graduate and undergraduate students involved will gain valuable interdisciplinary training at the intersection of mathematics and quantum information science. This project focuses on developing innovative quantum algorithms and advancing mathematical frameworks for quantum simulation with unbounded Hamiltonians. Key contributions include the development of quantum algorithms based on techniques such as Trotterization, randomization, Linear Combination of Unitaries, and Magnus expansion. These methods aim to overcome computational challenges and significantly accelerate the application of quantum simulation across various fields. Rigorous numerical analysis will be integrated to estimate the quantum complexity and provide performance guarantees for these algorithms. Special attention will be given to understanding and constructing superconvergence, particularly in relation to spatial discretization, leveraging mathematical tools from continuous and discrete microlocal analysis. By applying these advancements to real-world applications, this project will contribute to scalable quantum computing solutions and establish new benchmarks for algorithmic efficiency and accuracy. 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

ABSTRACT: Young adults with juvenile systemic lupus erythematosus (JSLE) and dermatomyositis (JDM) have greater risk of cardiovascular disease (CVD) than the general population. Increased CVD risk in JSLE/JDM starts in childhood. Suboptimal cardiovascular health (CVH), defined by the American Heart Association (AHA) as protective factors against CVD, is common in adolescents and young adults with JSLE/JDM (AYA-JSLE/JDM), with >95% non-ideal CVH behaviors (i.e. physical activity, diet, sleep). Psychological stress further increases long-term CVD risk via associations with worse CVH behaviors and elevated inflammation. Roughly 50% of JSLE/JDM patients report moderate-to-severe stress even when disease activity is low, yet most do not receive formal treatment due to treatment access barriers. Given the prevalence of unmitigated stress and CVD risk, there is a critical need to develop accessible JSLE/JDM-tailored interventions for stress reduction and CVH behavior promotion. The overall research objective of this proposal is to use a culturally sensitive intervention adaptation framework (Formative Method for Adapting Psychotherapy [FMAP]) to engage AYA- JSLE/JDM as partners in developing, piloting, and refining an online, self-administered intervention for stress reduction and CVH behavior promotion in AYA-JSLE/JDM, i.e. Teams Engaged in Accessible Mental Health Interventions for Lupus Erythematosus and Dermatomyositis Stress (TEAM-LEADS) intervention. Dr. Ardalan’s long-term career goal is to develop interventions to improve mental and physical health outcomes in JSLE/JDM and other rheumatic diseases. His mentoring team has expertise in clinical trials, CVD, and stress (Dr. Schanberg), pediatric mental health and remote pediatric behavioral interventions (Dr. Connelly), trial design and biostatistics (Dr. Hornik), and the application of health behavior change theory and partner engagement methods for behavioral intervention adaptation (Dr. Gierisch), facilitating Dr. Ardalan’s acquisition of skills in partner-engaged research methods, pediatric mental health and health behavior change, contemporary clinical trial design, and remotely delivered behavioral interventions. The following aims are proposed: Aim 1) Partner with AYA-JSLE/JDM patients, parents, and health care providers to develop TEAM-LEADS via co-design sessions; Aim 2) Determine feasibility, acceptability, adherence, and impact on stress and CVH behaviors of the initial TEAM-LEADS intervention for AYA-JSLE/JDM in an open-label, single-arm successive cohort design pilot trial; Aim 3) Refine the TEAM-LEADS intervention by addressing facilitators and barriers identified by AYA-JSLE/JDM pilot trial participants in exit interviews. Completion of these aims and training goals will lead to an R01 application to conduct a larger efficacy trial of TEAM-LEADS. Future research directions include determination of optimal combinations and sequences of TEAM-LEADS components via novel trial designs and adaptation of TEAM-LEADS for other chronic pediatric and adult conditions.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract: Excess cardiovascular disease (CVD) mortality among Black Americans with chronic kidney disease (CKD) is a significant US public health disparity. Compared to their White counterparts, Black Americans develop kidney disease earlier in life, are 3.5-fold more likely to develop kidney failure, and are 1.5-fold more likely to die prematurely from CVD. Uncontrolled hypertension, which is also more prevalent and more severe in Black adults with CKD compared to Whites, is a major risk determinant of CKD progression and CVD mortality. Therefore, improving hypertension control rates in Black adults with CKD could have a profound positive impact on an important minority health challenge. Multi-component lifestyle modification, including healthful dietary changes, increased physical activity and weight management, is proven to lower BP in adults with normal kidney function. However, the impact of multi-component lifestyle modification on BP in adults with CKD is yet to be determined. The quality of evidence from the few existing randomized controlled lifestyle intervention trials involving patients with CKD is poor due to a lack of power to detect changes in BP and kidney function. Moreover, Black adults and patients with advanced CKD have been historically under- represented in such trials despite each sharing an excess burden of poor kidney and CVD outcomes. It cannot be assumed that lifestyle modification will effectively lower BP in patients with advanced CKD considering they have a pathophysiology that causes their BP to be more severely elevated and less responsive to standard anti-hypertensive medications than patients with normal kidney function. Culturally-adapted strategies may also be necessary to improve hypertension and kidney health disparities among Black adults. The goal of this study is to conduct an adequately powered randomized controlled trial to determine whether a multi- component lifestyle intervention improves BP in Black adults with advanced CKD. We will randomize 152 adults with an estimated glomerular filtration rate of 15-44 ml/min/1.73m2 to either: 1) a 4-month lifestyle intervention involving weekly culturally-adapted, low-sodium DASH diet counseling, thrice-weekly supervised exercise, and weight management delivered in a cardiac rehabilitation setting, or 2) a usual care control condition involving a one-time 30-minute low sodium diet consultation plus an exercise prescription to self- implement without study support. Our primary outcome will be change in clinic systolic BP (SBP) from baseline at 4 months. Our secondary outcomes will be changes at 4 months in 24-hour ambulatory SBP, DASH diet score, urinary sodium-to-potassium ratio, peak oxygen consumption, and 24-hour urine albumin excretion. We will also assess sustainability of the intervention effect 12 months post-randomization and explore the effect of individual level and engagement level factors on variability in response at 4 months and 12 months. Findings from our study will have important implications for expanding BP management options for an understudied racial subgroup and a CKD sub-population using a strategy that is feasible for future implementation.

NIH Research Projects · FY 2026 · 2025-08

ABSTRACT: During the transition to adolescence, mammalian cardiomyocytes switch from a proliferative phase to a growth phase, primarily achieving expansion through whole genome duplication, also known as polyploidization. Unlike most polyploid tissues, I have found that the Drosophila heart has rigid ploidy limits crucial for optimal function. My postdoctoral work has revealed that the Drosophila cardiac organ has a chamber-specific asymmetry to cardiomyocyte polyploidization, which I found is also conserved in humans. Altering this chamber- specific asymmetry significantly impacts cardiac function in Drosophila, resembling human cardiomyopathies. To identify conserved regulators of cardiomyocyte polyploidization, I used reverse genetics in Drosophila to interrogate human cardiac chamber-specific gene expression differences. This genetic screen, as well as subsequent screens described herein, identified conserved organ-specific and novel cardiac- specific genes important for heart tissue ploidy regulation. This proposal builds on my successful screen to reveal new molecular mechanisms of cardiac ploidy control. Utilizing Drosophila genetics, Optical Coherent Tomography, immunofluorescence imaging and mammalian cardiomyocytes, I propose the following aims during the K99/R00 phase: AIM1: Identify the mechanism of cardiac-specific ploidy regulation by COX7A (K99). I identified cytochrome c oxidase subunit 7A (COX7A) as a heart-specific ploidy regulator. My hypothesis is that COX7A functions as a specific regulator of cardiomyocyte polyploidization through repressing mitochondrial production. AIM2: Identify the mechanism of cardiac-specific ploidy regulation by DZfand (K99/R00). I identified the Zinc Finger Protein DZfand as a novel cardiac-specific ploidy regulator. My hypothesis is that DZfand functions as a transcriptional regulator to negatively regulate cardiomyocyte polyploidization. AIM3: Identify cardiac-specific function of Goliath ubiquitin ligases and other HF-linked GWAS genes in heart diseases (R00). I found an enrichment of ubiquitin ligases in publicly available GWAS data for heart failure (HF), which prompted me to conduct an Optical Coherence Tomography (OCT)-based reverse genetic screen of Drosophila ubiquitin ligase genes. I identified that Goliath (gol/RFN150) ubiquitin ligases regulated cardiac function. Hypothesis: Goliath ubiquitin ligases regulate cardiomyocyte polyploidization during heart failure (HF). Building on the success of the OCT-based screen, I will expand this approach to screen for GWAS- identified genes linked to HF in my independent phase. My work to identify novel cardiac ploidy regulators using accessible Drosophila genetics is unique and crucial for understanding heart diseases, given that cardiovascular diseases rank as the leading global cause of death. To successfully achieve these aims, I have designed a training plan with my advisor, Dr. Don Fox, to acquire the necessary skills for transitioning to an independent research role. Additionally, guidance from my advisory committee and collaborators will further enhance my conceptual, technical, and professional abilities, facilitating this transition.

NIH Research Projects · FY 2025 · 2025-07

Failure to detect and treat atherosclerosis in younger adults worsens cardiovascular morbidity and mortality. Current strategies of assigning preventive therapies are not based on screening for atherosclerosis, but rather on short-term risk scores that heavily weight age and leave most at-risk young and middle-aged adults untreated. A new paradigm of screening for and identifying subclinical atherosclerosis via coronary computed tomography angiography (CCTA) is emerging because subclinical atherosclerosis has prognostic superiority over traditional risk scores. However, it is still unknown how best to screen for and identify younger adults who have subclinical coronary atherosclerosis, and how best to treat them to reduce atherosclerotic burden. Both LDL-C and inflammation are causal in the pathogenesis of atherosclerosis, but it is unknown whether treating either or both processes in younger individuals can effectively and safely reduce atherosclerotic burden. The PREEMPT (Prospective RandomizEd trial of the Evaluation and Management of Premature aTherosclerosis) study will address this urgent public health need by determining optimal strategies to screen for, identify, and treat subclinical coronary atherosclerosis in young and middle-aged adults. Aim 1 will focus on screening younger adults for subclinical coronary atherosclerosis. We will evaluate the effectiveness of three strategies to detect coronary atherosclerosis in young and middle-aged adults (women aged 40−60 and men aged 30−50) at low 10-year, but high lifetime risk. These strategies will include an electronic health record search, outreach to family members of those with premature heart disease, and community outreach/social media. The outcome will be proportion screened with coronary artery calcium (CAC) score >0. An adaptive design will be utilized to modify or eliminate ineffective strategies. Aims 2 and 3 will focus on assessing the efficacy and safety/tolerability of 3 therapeutic strategies to reduce atherosclerotic burden. Individuals who meet clinical eligibility criteria through the screening study, or opportunistically through preexisting imaging evidence of coronary calcification, and have a CAC score of 1−99 will undergo CCTA to confirm presence of measurable non-calcified plaque (NCP) volume, and will then be randomized to a placebo-controlled, double-masked, 2x2 factorial randomized trial of rosuvastatin 20mg, colchicine 0.5mg, or the combination vs. placebo. All participants will also receive a state-of-the-art mHeath behavioral intervention to ensure lifestyle modification for all participants. The primary endpoint will be centrally adjudicated NCP volume on CCTA at 2 years, adjusting for baseline NCP volume. If successful, PREEMPT will reduce the unacceptably high morbidity and mortality of cardiovascular disease by providing randomized trial evidence supporting a paradigm shift away from a 10-year risk-based prevention strategy and towards earlier detection and treatment of subclinical atherosclerosis in younger adults.