University Of California Los Angeles

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Human Papillomavirus (HPV) is the major cause of head and neck squamous cell carcinomas; most oropharyngeal (75%) and other head and neck cancers are caused by chronic HPV infection. Metastatic HPV- associated cancers are minimally responsive to current treatments and uniformly fatal. The most recent American Cancer Society annual statistics for oral/oropharyngeal cancers in the U.S. indicate 54,540 new diagnoses and 11,540 deaths. Novel therapies are therefore sorely needed. HPV-associated cancer cells require direct dysregulation of cells through viral E6 and E7 oncoproteins, which are indispensable for tumorigenesis. These proteins are essential for ongoing tumor cell survival, and therefore serve as ideal therapeutic targets. Knockdown of E6 or E7 using siRNA in HPV-transformed cells results in apoptosis. This pilot R21 project describes plans to screen for druggable small molecule antagonists of HPV E6 or E7 oncoproteins. The overall strategy will be to screen small molecule libraries for compounds that cause specific death of tongue cancer squamous cell lines with HPV, but not those without HPV: o Aim 1: To create tongue carcinoma cell clones differing in HPV status and fluorescence color. o Aim 2: To screen small molecule libraries for drug candidates causing HPV-specific cell death. o Aim 3: To test the function of drug candidates to induce death of other HPV-transformed cells. Successful completion of this project would identify drug candidates that induce apoptosis of HPV-transformed oral cancer cells through interference with E6 or E7.

NIH Research Projects · FY 2025 · 2025-08

Project Summary / Abstract The US is in the midst of a housing affordability crisis, which fuels health inequities for children in low-income families including high rates of obesity and asthma exacerbations. To combat housing crisis, cities across the United States have turned to transit-oriented development, a type of urban planning that incentivizes developers to build dense, affordable housing in urban cores, near jobs and public transit. Transit-oriented development could improve obesity and asthma outcomes for low-income children by expanding access to affordable housing, transit, and healthy neighborhoods. Despite this promise, few studies have rigorously evaluated the impact of transit-oriented development on children's health outcomes. Los Angeles, California's Transit-Oriented Communities (TOC) program, which has led to the production of nearly 10,000 affordable housing units, offers an opportunity to study health implications of transit-oriented development. Our project will leverage TOC as a natural experiment, comparing change in obesity and asthma over time among children in neighborhoods eligible vs. ineligible for TOC (Aim 1). Secondary outcomes for Aim 1 include caregiver mental health and child physical activity. Second, we will explore potential mechanisms underlying Aim 1 associations, by measuring TOC's impact on more proximal outcomes, including housing affordability, transit use, and neighborhood environments (Aim 2). Finally, we will conduct qualitative interviews with caregivers living in TOCs as well as TOC developers and policymakers to contextualize quantitative findings and better understand peoples' lived experience with the program (Aim 3). Together, these aims will allow us to retrospectively measure TOC's impact on wellbeing, while also identifying opportunities to change the program to better promote health going forward. Results will be relevant to decisionmakers in Los Angeles and peer cities pursuing transit-oriented development. Research proposed under this K01 award will support Dr. Leifheit's mentored career development by providing opportunities for practical application of her training goals. Specifically, she will receive training in: (1) child obesity and asthma epidemiology, (2) geospatial analysis, (3) qualitative research, and (4) policy translation. A team of expert mentors will oversee Dr. Leifheit's training in these methods, content areas, and overall career development. This award will launch Dr. Leifheit's career as an independent investigator, providing her with the skills to collect mixed-methods data on child health implications of urban planning decisions. The project will also yield valuable preliminary data for future, R01-funded research measuring TOC's impact on children's longitudinal health trajectories.

NIH Research Projects · FY 2025 · 2025-08

Postoperative Delirium (POD) is the most common complication after surgery in older adults, and is associated with increased mortality, cognitive decline, and loss of independence. As the United States (US) population ages and more older adults undergo surgery, POD and cognitive decline after surgery are becoming a public health emergency. Dr. Canales has developed the Perioperative Care Partner Program (PCPP), that combines established strategies for risk reduction and early diagnosis with improved communication and community engagement to diminish the risk of POD within this vulnerable population. This initiative pairs older adults at high risk for POD with a care partner throughout the perioperative period. The primary objective of this proposed K76 Beeson Career Development Award is to equip Dr. Canales with the necessary training and hands-on mentored research experience to emerge as a leader in perioperative aging research. The career development and mentorship plans were crafted to fill gaps in current knowledge and experience. With the support of her mentors and collaborators, career development goals are to:(A) become proficient in pragmatic clinical trials in older adults in the perioperative setting;(B) gain skills in implementation science and (C) study communication and community engagement in the aging surgical population. The overarching goal of this proposal is to conduct a pilot pragmatic Hybrid Type 1 Effectiveness-Implementation randomized controlled trial of the PCPP program in older adults undergoing major surgery. The aims of the proposal are: Aim 1. Using state of the art implementation science methods, iteratively refine PCPP for older adults at high-risk of POD; Aim 2. Conduct a pilot pragmatic randomized controlled Hybrid Type 1 Effectiveness-Implementation trial of PCPP vs standard care (n= 80) in older adults undergoing surgery; Aim 3. Define and standardize the core protocols, guidelines and materials needed to create a PCPP implementation bundle that can be tailored for different languages and health settings.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Hyperinsulinemia precedes the development of Type 2 Diabetes (T2D) and is thought to play a key role in β-cell failure by increasing secretory workload. While hyperinsulinemia is thought to act strictly as a compensatory response to peripheral insulin resistance, recent evidence supports a pathological role by promoting obesity, hyperlipidemia and hepatic steatosis. Numerous studies demonstrate that dysregulated secretion is intrinsic to the beta cell since increased levels of secretion at fasting glucose concentrations persist in islets isolated from obese animals and human. During normoglycemic fasting, an increase in insulin release can occur independently of glucose, to cause an insidious desensitization to insulin actions. Previous studies in obese mice and new studies in pre-diabetic humans reveal that islets can acquire a new form of insulin secretion that is driven by fat, rather than glucose, thereby permitting insulin secretion at fasting glucose concentrations. This form of malfunction is known as Fatty Acid Induced Insulin Secretion (FASIS): the ability of fatty acids to stimulate insulin secretion at non-stimulatory glucose. The molecular determinants of FASIS and its contribution to T2D development are uncharacterized. We hypothesize that mitochondrial fragmentation in beta-cells induced by exposure to high fat is the major event inducing FASIS. Our preliminary data show that fragmentation elevates fat oxidation (FAO) in beta-cell mitochondria, by unleashing fatty-acid import into mitochondria, revealing a new role of mitochondrial architecture in fuel preference. We provide new evidence that high fat exposure induces fragmentation by destabilizing Mitofusin 2 (Mfn2), via a decrease in Ubiquitin C-Terminal Hydrolase L1 (UCHL1) activity. This project will provide the unprecedented molecular mechanism by which FASIS occurs, as well as determining the major effector downstream of decreased UCHL1 activity in T2D. Our aims will: A) Determine the role of mitochondrial fragmentation in the acquisition of FASIS. We will use genetic and pharmacological tools to elongate or fragment mitochondria, and determine the effect on FASIS. B) Determine how mitochondrial shape controls fatty acid utilization in beta cells. We will delineate whether a genetic and metabolic induction of fragmentation is sufficient to allow for uncontrolled CPT1 activity, while forced elongation decreases CPT1-dependent FAO. We will further establish whether FASIS depends on unregulated CPT1 activity and FAO that are induced by mitochondrial fragmentation. And C) Establish the mechanism by which high fat induces mitochondrial fragmentation in beta cells. We will investigate the effect of excess fat and glucose on mitofusin-2 turnover, and follow our preliminary data showing that exposure of beta cells to fatty acids result in decreased levels of UCH-L1, a de-ubiquitinase that controls Mfn2 ubiquitination and turnover, whereby restoring UCH-L1 activity restores Mfn2 levels.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Heart failure (HF), spanning from HF with preserved ejection fraction (HFpEF) to HF with reduced ejection fraction (HFrEF), is a leading cause of death worldwide, and among Americans, accounts for 14% of deaths at present. Various pathophysiologic stresses have been clinically and experimentally identified to contribute to HF via distinct molecular mechanisms. However, our limited understanding of the pathogenesis of HF and the poor prognosis of HF strongly underscores the need for further mechanistic investigation and additional therapeutic strategies. Many studies have identified NAD+ deficiency as a central defect in HF of various etiologies. NAD+ deficiency has been attributed to decreased NAD+ salvage resulting from impaired expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway, recycling nicotinamide (NAM) back into NAD+. Our recent studies and preliminary data establish a novel mechanism underlying NAD+ deficiency in failing hearts, namely catabolism of NAM to methyl- nicotinamide (1-MNA) via induction of the enzyme, Nicotinamide N-Methyltransferase (NNMT). NNMT is induced in multiple murine models of HFrEF secondary to hemodynamic stress or genetic defects in autophagy. NNMT is also induced in a murine model of HFpEF and in end-stage failing human hearts. These observations form the basis of our central hypothesis, that NNMT induction results in NAD+ deficiency, in HFpEF and HFrEF and NNMT inhibition could be harnessed to prevent or treat HF. To test these hypotheses and to rigorously evaluate the feasibility of this novel therapeutic approach, we present two aims. Aim 1 will determine if NNMT induction is central to the pathophysiology of HFpEF and HFrEF. By evaluating NAD+ metabolites, NAD+ flux, and the progression of HF, we will determine if NAD+ deficiency attributable to increased NAM catabolism via NNMT induction is a conserved molecular event in HFrEF and HFpEF and determine the contribution of this pathway in modulating existing strategies based on administering NAD+ pool precursors for preventing or treating HF. Aim 2 will determine if genetic or pharmacological inhibition of NNMT will prevent or reverse HFrEF and HFpEF. By genetically deleting or pharmacologically inhibiting NNMT, we will determine the relevance of NNMT induction in the development of HFrEF or HFpEF, and identify molecular mechanisms by which 1-MNA could contribute to HF. The successful completion of these two aims will identify NNMT as a central mechanism underlying the development of HFpEF and HFrEF. Successful completion of this project will provide insight into the pathophysiology of HF and provide pre-clinical evidence for NNMT as a potential target for the prevention and treatment of HF.

NSF Awards · FY 2025 · 2025-08

Plasmas — hot, electrically charged gases that make up most of the visible universe — play a central role in many areas of science and technology, from forecasting space weather to developing revolutionary energy systems like fusion reactors. Laboratory experiments are essential for understanding how plasma behaves, but measuring it in full is extremely difficult. Plasma's high temperature and fast-changing nature mean that only a portion of what is happening can usually be captured, leaving many pieces of the picture missing. This project aims to develop new machine learning (ML) tools that are guided by the laws of physics to help complete that picture. By combining limited measurements from experiments with theoretical models, these tools aim to reconstruct hidden or hard-to-measure aspects of plasma behavior. If successful, this approach will lead to better understanding of plasma dynamics, transforming our ability to extract insight from cutting-edge experiments. The ML tools may also be applied to future multi-satellite space missions, where scattered satellite measurements need to be stitched together into a cohesive view. The project will train the next generation of researchers at the intersection of physics, computation, and machine learning. The Large Plasma Device (LAPD) at UCLA is a unique experimental platform for basic plasma science, enabling studies relevant to space physics, astrophysics, and controlled nuclear fusion. Its high reproducibility, 1 Hz repetition rate, and comprehensive suite of diagnostics allow for detailed spatiotemporal measurements of complex, nonlinear plasma dynamics. Despite these capabilities, the inherent nature of plasmas — characterized by high dimensionality and multiscale behavior — means that experimental measurements of the underlying physics are inevitably incomplete. To bridge this gap, this project aims to develop and apply novel techniques from the emerging field of physics-informed machine learning. These tools will integrate partial measurements from multiple diagnostics with theoretical plasma models to reconstruct quantities that are unmeasured or difficult to observe in dynamically evolving plasmas. The approach will first be developed and validated using nonlinear plasma dynamics data from fully-kinetic first principles simulations, serving as controlled “numerical experiments.” It will then be applied to real experimental data from the LAPD, using it as a testbed to demonstrate the methodology on Alfvén wave dynamics. This validation will serve as a critical stepping stone toward future applications of the method to more complex laboratory experiments, such as studies of collisionless shocks and magnetic reconnection. Moreover, these techniques are expected to have broader applicability to space plasma observations and fusion reactor diagnostics, where sparse measurements must be synthesized into coherent global reconstructions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-08

Min-max optimization underpins technologies ranging from generative Artificial Intelligence (AI) to large-scale reinforcement learning, yet today’s methods remain slow and unreliable for many real-world tasks. This suboptimality stems from the traditional approach of adapting minimization techniques to the min-max setup, which necessarily overlooks the unique complexities inherent in min-max problems. This project fundamentally revises this approach, developing specialized theoretical frameworks and efficient algorithms tailored explicitly to min-max optimization. By establishing a deeper understanding of these unique characteristics, the proposed research will significantly enhance the efficiency and robustness of min-max optimization, directly impacting practical applications in machine learning and artificial intelligence. Technically, this project will first explore core theoretical foundations under idealized convex-concave conditions, emphasizing accelerated convergence through anchor-type algorithms and enhanced stochastic methods with relaxed assumptions. Building upon this, the project will also develop practical algorithms that are robust to realistic, non-ideal conditions, including methods for nonconvex problems, efficient sampling strategies for stochastic settings, and adaptive update rules. Additionally, the research will investigate efficient alternating-update strategies, proximal gradient-type methods, and applications to training deep neural networks. These efforts are anticipated to greatly enrich the mathematical tools of min-max optimization and to lead to the discovery of more practically efficient algorithms. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Chronic pain is present in nearly one-third of Veterans and is frequently accompanied by comorbid trauma and mental health symptoms. Emotional awareness and expression therapy (EAET) is an evidence-based psychological treatment for chronic pain that was developed to directly target comorbid trauma and mental health symptoms with the goal of reducing or eliminating chronic pain. Eleven controlled and uncontrolled efficacy trials of EAET in Veterans and civilians have shown EAET can produce robust effects on improving outcomes that include pain severity, pain interference, depression, anxiety, and post-traumatic stress disorder (PTSD) symptoms. Consequently, EAET was recommended as a Pain Management Best Practice by the U.S. Department of Health & Human Services in 2019. Moreover, in two single-site efficacy trials conducted at VA Greater Los Angeles Healthcare System, EAET was found to be superior on several outcomes to gold- standard cognitive behavioral therapy for chronic pain (CBT-CP) among older Veterans with chronic pain. Yet these more tightly controlled trials may not reflect the true effectiveness of EAET when implemented by diverse clinicians. The overall goal of the proposed project is to conduct a rigorous and comprehensive evaluation of EAET delivered in usual care settings. The project will proceed in two phases. During a 1-year UG3 phase, clinicians at 7 geographically diverse VA healthcare systems will be trained in EAET via an EAET learning collaborative, and an open pilot of EAET will be performed at each site to confirm feasibility. In addition, a formative evaluation will be conducted to engage clinicians, administrators, and Veterans and to identify barriers and facilitators to implementation. During a 4-year UH3 phase, a multisite pragmatic randomized controlled superiority trial of group-based EAET compared to group-based CBT-CP will be conducted among 672 Veterans with chronic musculoskeletal pain. The aims are to determine whether Veterans randomized to EAET versus CBT-CP experience improved pain severity (primary outcome), pain interference, functioning, quality of life, depression, anxiety, PTSD symptoms, and sleep; and decreased use of opioid pain medications and unhealthy substance use from baseline to 10 weeks (primary endpoint), 6 months, and 12 months after enrollment. Outcomes will also be compared for those who do or do not have comorbid mental health diagnoses (i.e., VA service-connection for depressive disorders, anxiety disorders, and PTSD) and for men compared to women Veterans. In addition, a longitudinal process evaluation will support the development of an implementation toolkit for scaling, and the effects of EAET and CBT-CP will be compared on healthcare use and costs, including a cost-effectiveness evaluation from the VA healthcare system perspective. Findings may promote a paradigm shift in the treatment of chronic pain that could influence policy and guidelines.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Richard Watson, MD, PhD, is a Clinical Instructor of Medicine in the Division of Pulmonary and Critical Care Medicine at the University of California, Los Angeles (UCLA). His clinical and research interest is in idiopathic pulmonary fibrosis (IPF), a disease that results in the progressive, irreversible scarring of the lung and has no curative treatment. A five-year research career development plan is proposed, focused on determining the mechanisms of lipid metabolism in IPF, which will serve to establish Dr. Watson’s independent translational research program. This proposal builds upon his strong basic science background and provides new training in epithelial biology, next-generation sequencing techniques, bioinformatics, and translational research utilizing human patient samples. During the award term, Dr. Watson will be mentored by Dr. Steven Bensinger, a leader in the field of immunometabolism and lipid biology with a track record of mentoring over 15 graduate students, post-doctoral fellows, and junior faculty to independent careers in biomedical research. He will have additional support from co-mentor Dr. Steven Dubinett, a world-renowned lung cancer immunologist, and a strong team of advisors with diverse but complementary areas of expertise. During his post-doctoral training, Dr. Watson established an innovative research platform that leverages advanced mass spectrometry-based techniques with a series of loss-of-function genetic murine models. Using this unique system, Dr. Watson has begun to mechanistically dissect the intricate, lipid-rich metabolic circuit represented by the distal airway. Dr. Watson has demonstrated that the lipid metabolic state, or lipidome, of the alveolar macrophage (AM) is dramatically reprogrammed during IPF pathogenesis. This is characterized by the generation of monounsaturated fatty acids (MUFAs) through the upregulation of the lipogenic enzyme stearoyl- CoA desaturase (SCD), which serves as a protective factor against pulmonary fibrosis. In this proposal, Dr. Watson aims to study the complex metabolic relationship between AMs and alveolar epithelial type II cells (AT2s). Aims 1.1 & 1.2 build upon preliminary in vitro data indicating that SCD functions through cREL and NFκB to modulate proinflammatory signaling and seek to determine how changes in macrophage lipid composition relay information to the cell’s epigenome and transcriptome. Aim 1.3 utilizes human IPF biospecimens and multiplex immunofluorescence technology to determine the spatiotemporal regulation of macrophage SCD in IPF pathogenesis. Aim 2.1 of the proposal leverages a novel in vitro co-culture organoid system that can recapitulate much of the complexity of the alveolar space, allowing rapid screening of small- molecule inhibitors that may have therapeutic potential for treating IPF. Aims 2.2 & 2.3 will utilize a series of lineage-specific genetic murine models to mechanistically dissect the fatty acid biosynthetic pathway in AMs and AT2s and their symbiotic relationship in the airway. Completion of these aims will mechanistically advance our understanding of the lipid metabolic circuitry of AMs and AT2s in IPF.

NSF Awards · FY 2025 · 2025-08

Large earthquakes can cause devastating ground shaking and tsunamis, but understanding their rupture behavior in real time remains a major scientific challenge. This project aims to improve imaging and interpretation of the rupture processes of large earthquakes around the world. By improving an analysis method that uses waves recorded by seismic array called "back-projection," it is possible to visualize an earthquake rupture in time and space. The outcome of this research will produce more accurate measurements of how fast and how far earthquake ruptures travel. The results will help scientists identify unusual behaviors of large earthquakes like so called ‘super-shear ruptures’, which radiate unusually intense shaking. The findings of this study may lead to better earthquake early warning and hazard mitigation strategies. This research also provides valuable training to graduate students and includes science outreach efforts to engage K–12 students and the broader public through hands-on activities and educational field trips. The outcomes will support public safety by advancing our fundamental knowledge of how earthquakes happen. This project aims to systematically investigate the rupture characteristics of global large earthquakes (M ≥ 7.0) from 2000 to 2022 using advanced seismic back-projection (BP) techniques. Applying the Slowness-Enhanced Back-Projection method to correct spatial errors caused by 3D Earth structures will allow more accurate estimates of rupture speed, extent, and segmentation. This work will expand the geographical reach of BP by incorporating core-phase BP techniques that utilize PKIKP and PKP phases to image events from near-antipodal distances. A key goal is to build a comprehensive global database of rupture histories, which will be made publicly available. The investigators will perform synthetic tests using Incoherent Green’s Functions to quantify uncertainties and identify artifacts such as shadowing and tailing effects in BP imaging. The database will serve as a foundation for analyzing complex rupture behaviors, including the prevalence and dynamics of super-shear ruptures and the potential for ruptures to extend beyond the down-dip limit of the seismogenic zone. We will test hypotheses related to dynamic weakening mechanisms through earthquake cycle simulations using 2.5-dimensional spectral element modeling. These observations and models will be compared to determine the physical conditions that promote super-shear rupture and rupture depth extension. Ultimately, this research will improve the fidelity of rupture imaging, provide benchmark datasets for theoretical modeling, and enhance the ability to interpret the physics governing earthquake rupture processes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Cysteine-reactive drugs are an exciting class of therapeutics that offer the benefits of high potency, occupancy and increased selectivity. Motivated by the clinical success of recent cancer therapeutics that engage specific cysteines, including neratinib and ibrutinib, the discovery of additional targets amenable to covalency is a burgeoning area for drug development. One strategy to find such targets is cysteine chemoproteomics, which uses mass spectrometry-based proteomics to mine the cellular proteome for potentially targetable cysteine residues. While cysteine chemoproteomic platforms are increasingly adopted for target discovery and mode of action studies, two unmet needs remain that together will increase the utility of this technology for cancer drug discovery applications: (1) improved sample throughput and (2) enhanced discovery of actionable cysteines, for which covalent labeling will clearly impact protein function. To this end, our team has already made substantial inroads into both of these challenges by establishing high throughput and low cost screening platforms and novel multi-dimensional chemoproteomic platforms that report cysteine-dependent changes in protein thermal stability, which provides a high throughput metric of likely cysteine functionality. Here we will build on this exciting proof- of-concept data by establishing enhanced sample preparation reagents that will further increase screening throughput by enhancing multiplexing capabilities compared to state of the art technology. Enabled by these custom reagents, we will establish a custom proteomics platform to pinpoint covalent labeling sites that alter protein thermal stability, which will provide a roadmap for prioritizing high value targets for further mode of action studies. To ensure the rigor of our technology, the proposed methods will be assessed relative to the state of the art, using rigorous performance metrics. Thus, our work will solve the bottleneck of cysteine prioritization, which will increase the conversion of initial hits to leads. More broadly, our unprecedented ultra-high coverage chemoproteomic platform will be paradigm shifting both for cysteine chemoproteomic sample processing, and more broadly for many proteomic applications that require analysis of many samples in parallel.

NIH Research Projects · FY 2025 · 2025-08

Summary The diagnosis of atypical parkinsonian disorders is difficult due to symptom overlap, especially at early stages. As a result, these diseases often are misdiagnosed first as Parkinson’s disease or as another parkinsonian disorder. Misdiagnosis not only causes high stress and anxiety to patients, families, and caregivers, but also is a major impediment to developing effective therapy for these diseases. Some of the most challenging diagnoses are those of the 4R-tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Although the original definitions of these diseases were relatively easy to distinguish, later pathological studies showed that each has many subtypes with a large overlap, both with each other and with other movement disorders and dementias. Though PSP and CBD (corticobasal degeneration, the pathological counterpart of CBS) are distinct pathologically, biomarker studies have generally been unsuccessful in distinguishing between them. However, a recent study (Horie et al., Nat. Med., 2022) has shown that mass-spectrometry detection of two peptides derived from the second repeat in the microtubule-binding region (MTBR) of tau, called MTBR- tau275 and MTBR-tau282, separated PSP from CBD with high sensitivity and specificity. These are exciting results that could support future studies, including our ongoing biomarker studies of parkinsonian disorders, yet mass- spectrometry is not ideal for routine biomarker analysis. Therefore, we propose to develop new assays using aptamers specific for the two peptides, that will allow their detection in an ELISA-like assay format. To that end, the Co-PI, Dr. Murakami, who is an aptamer expert will produce the needed aptamers and modify them to allow sensitive detection of the minute amounts expected to be found in patient brain and CSF. We will then test the assay using matching brain and CSF samples from patients diagnosed pathologically with PSP or CBD and compare them with controls without a neurological disease. If successful, the new assay will provide the first streamlined biomarker measurement for PSP and CBD/CBS, facilitating future diagnosis and clinical trials for these diseases.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Infection of Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), is estimated to account for 34,000 new cancer cases each year, presenting a significant healthcare challenge globally. Typically, KSHV infection in healthy infected individuals results in weak neutralizing antibody responses and low T cell immunity. This modest immunity during natural infection calls for a vaccine that can circumvent the immune evasion mechanisms of KSHV, effectively priming the immune system to generate robust and reliable immunity across individuals. Such a vaccine would not only protect against initial infections but also help individuals maintain better control over persistent infection, thereby reducing the risk of developing KSHV- associated diseases. This is particularly vital for high-risk populations, including individuals with an increased likelihood of HIV-1 infection, transplant patients receiving immunosuppressive therapy, and people living in resource-limited endemic regions of Africa. Our proposal addresses this critical medical need. Our proposal outlines a comprehensive and innovative vaccine strategy against KSHV, harnessing antibody and T cells to establish strong antiviral immunity. Aim 1 focuses on generating potent humoral antibody responses through structure-guided immunogen design, leading to neutralizing and non-neutralizing activities that block infection and mediate the immune clearance of infected cells. Aim 2 is dedicated to enhancing vaccine- induced T cell immunity targeting latently infected cells by utilizing innovative RNA-based adjuvants. These RNA- adjuvanted T cell responses are designed to complement antibody-mediated antiviral effects. Aim 3 seeks to integrate these strategies by combining vaccine components that simulate both antibody and T cell responses while maintaining the immunogenicity of each antigen. This aim will also address species differences in terms of dendritic cell activation and inflammatory responses after receiving our combined vaccine. Overall, through this multidisciplinary effort, we aspire to develop a prototype vaccine for KSHV that provides broad and effective immunity.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT The purpose of this proposed K01 Mentored Research Career Development Award is to support the applicant in advancing and maximizing her research skills in order to launch an independent research career in the dissemination and implementation of evidence-based substance use treatment for safety net populations. Safety net populations, especially individuals who are publicly insured by Medicaid and the Children’s Health Insurance Program (CHIP), have been disproportionately impacted by the U.S. opioid epidemic. Despite a significant need for treatment, lifesaving medications for opioid use disorder (MOUD) are underused by this population. Low MOUD use is driven by a myriad of misaligned federal, state, Medicaid/CHIP agency and managed care organization benefit and utilization management policies informed by varying levels of evidence. Federal policy requires all three MOUD (i.e., buprenorphine, methadone, naltrexone) be included as mandatory Medicaid state plan benefits, but not all states have complied, and the Centers for Medicare and Medicaid Services acknowledges that enforcing coverage is not feasible. Even when Medicaid/CHIP agencies cover all three MOUD, they can restrict access via preferred drug lists, fail-first, prior and re-authorization requirements – thus imposing potentially life-threatening care delays on beneficiaries. Managed care organizations (MCOs) that many state agencies contract to administer benefits can enact additional utilization management policies that limit MOUD access. Research is needed to promote Medicaid/CHIP and MCO policymakers’ use of scientific evidence when designing MOUD benefits. Under the mentorship of Dr. Gregory Aarons (sponsor and mentor) and an expert mentoring team, the applicant will pursue training in: (1) survey design, (2) multivariate statistical analysis, including latent class analysis and finite mixture modeling, (3) policy dissemination strategy development, including packaging and communicating evidence for policymakers, and (4) developing research partnerships with policy-relevant decision-makers. These training goals will facilitate accomplishing research aims to: (1) develop and administer a national survey to Medicaid/CHIP agency and MCO policymakers to identify determinants, mechanisms, and intermediaries that influence their evidence use behaviors; (2) empirically identify and describe distinct subgroups of Medicaid/CHIP agencies and MCOs based on their evidence use behaviors when designing MOUD benefits; (3) design and pilot test the acceptability, appropriateness and feasibility of dissemination strategies, tailored to each latent class, for promoting policymakers’ evidence-based decision-making regarding MOUD benefits. This proposal is aligned with NIDA’s strategic objectives to assess the impact of substance use disorder-related federal, state and systems policies on public health, and to identify strategic intermediaries and policy implementation strategies aimed at improving evidence use in policy. The planned K01 activities will effectively position the applicant to achieve an independent research career focused on improving access to evidence-based substance use treatment.

NIH Research Projects · FY 2025 · 2025-08

Project Summary This is an application for a K23 award for Adam J Brownstein, MD, MS, a Pulmonary and Critical Care physician at the University of California, Los Angeles. The goal of this proposal is for Dr. Brownstein to establish himself as independent investigator in patient-oriented research in the field of pulmonary hypertension, with a focus on pulmonary fibrosis-associated pulmonary hypertension (PF-PH). This K23 award will provide Dr. Brownstein with the support to (1) develop proficiency with prospective clinical study design for future multi-institutional studies and clinical trials, (2) develop expertise in the application of multi-omics approaches to PH detection, risk-stratification, and evaluation for lung transplantation in PF-PH, (3) determine the feasibility and utility of developing peripheral blood biomarkers that reflect pulmonary vascular disease severity in PF, (4) become an expert in large data analysis integrating clinical data with omics analyses and advanced statistical modeling, including machine learning approaches, and (5) become an independent translational researcher. Dr. Brownstein is supported by an excellent multidisciplinary mentoring team. Dr. Xia Yang and Dr. Airie Kim, the two primary mentors of this K award, will provide complementary guidance regarding applying multi-omics approaches and translational research design. Dr. Brownstein will also work closely with Dr. Rajan Saggar, a leader in the PH field with expertise in clinical trials and observational cohort studies and Dr. David Elashoff, the leader for the Biostatistics, Epidemiology and Research Design program for the UCLA CTSI. PF is often complicated by the development of PH, leading to significantly reduced survival and increased morbidity. Our preliminary data, which leveraged transcriptomic analysis of explanted lung tissue from patients with PF, has identified a module of genes (referred to as the “tan” module) as potentially pathogenic in PF-PH. However, a better understanding of the cell-specific pathways altered in PF-PH is required to predict those at risk of progressing to clinically significant PF-PH and identify novel therapeutics and biomarkers of disease. This proposal will investigate the PF-PH lung and blood transcriptome by using lung and blood samples collected as part of the UCLA PF and PH biorepository, which includes prospectively collected biospecimens, hemodynamics, echocardiography and other clinical markers of PH. We will also use the PF Foundation Registry to identify a blood transcriptomic signature of PF-PH using machine learning approaches. The specific aims are: 1) Define cell-specific transcriptional changes in lung tissue of PF-PH patients compared to PF-NoPH and PAH, and correlate these findings with clinical markers of disease severity and 2) Evaluate the blood transcriptomic signature of PF-PH patients in order to identify and develop blood biomarkers and predictors of disease. The proposed studies will enable Dr. Brownstein to develop into an independent investigator focusing on PH translational research.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Understanding how genetic variants impact protein function is essential for unraveling the mechanisms underlying both basic biology and disease, particularly for rare genetic variants. Of the 4.6 million missense variants found in large population studies, only about 2% have clinical interpretations. Due to their rarity, these variants are exceptionally challenging to study through observational methods. However, Deep Mutational Scanning (DMS) offers a high-throughput method for testing thousands of protein variants by generating a mutant library and obtaining a phenotypic readout for each mutation in one sequencing assay. Initially focused on fitness-based readouts, DMS has expanded to include fluorescence-based methods for protein profiling, binding assays, and more. It has been crucial for studying proteins like SARS-CoV-2, BRCA1, and drug-metabolism transporters like OCT1. With over 1,000 protein datasets publicly available, a recent study highlights technical advances by independently assaying over 500 additional proteins in one study. Unfortunately, the development of statistical methods to interpret and analyze these technologies has not kept pace. For example, DMS with fluorescence-activated cell sorting (DMS-FACS), which has been used for nearly a decade to measure protein abundance and other functional phenotypes, still lacks dedicated analysis methods. As a result, analyses are often ad hoc, and small sample sizes (typically three replicates) make standard statistical methods unsuitable. Our recent work demonstrates that naive approaches miss many real effects and lead to many false discoveries. We propose three statistical areas to improve DMS analysis and interpretation through accurate sample comparisons, epistasis analysis, and causal inference. First, we will develop methods to analyze DMS-FACS for assessing how genetic variants affect molecular phenotype targeted by FACS, and enabling precise comparisons between experimental conditions. Second, we will develop methods to improve genetic interaction (epistasis) analysis and interpretation within proteins, and thus ask which protein regions are acting in concert. Third, we open a new area of research for DMS, aiming to identify the causal impact of variants through measured pathways, including complex traits. In summary, we will solve the analysis gap for DMS-FACS, epistasis DMS, and causally link DMS data through structural causal models by leveraging our expertise in DMS data and small sample statistics. Leveraging our expertise in DMS data and small sample statistics, we will create reliable, robust tools for common workflows while also enabling new types of analyses that improve the interpretation of DMS, epistasis, and phenotypic relationships. With strong collaborations with assay developers and DMS experts, along with a proven track record in developing tools for high-throughput sequencing in small sample contexts, we are well-positioned to lead this effort.

NIH Research Projects · FY 2025 · 2025-08

from human dementia brains that support an interaction between interneurons, tau toxicity, and cognitive decline. We recently generated hippocampal assembloids in which physiological proportions of interneurons and excitatory neurons — achieved through interneuron migration from the ganglionic eminence — exhibit electrophysiological oscillatory and connectivity properties that mirror those observed in human brain recordings. Mutations in the microtubule-associated protein tau (MAPT), such as R406W and IVS10+16 C>T, cause frontotemporal dementia and result in a spectrum of clinical phenotypes, with a predilection for temporal lobe- dominant syndromes affecting the hippocampus. Human induced pluripotent stem cells (iPSCs) expressing different MAPT mutations exhibit various phenotypes but converge on alterations in genes involved in transsynaptic signaling, including a group of 11 genes enriched in interneurons. Despite these observations, the interaction between MAPT mutations and interneuron subtypes remains poorly understood, due in part to iPSC model systems that lack sufficient numbers of interneurons. By generating human iPSC-derived hippocampal assembloids expressing MAPT mutations, we have developed a unique model of tau mutation-associated toxic phenotypes in a system containing interneurons, excitatory neurons, astrocytes, and simple circuits. This model, once validated, will open opportunities to consider interactions between interneurons, tau toxicity, and circuit-related neuronal dysfunction in mechanistic or drug development applications. We propose to validate this system as a model for studying the interaction of interneurons with MAPT mutation - associated tau toxicity and circuit-related neuronal dysfunction. We will achieve this through reproducibility studies, deeper molecular phenotyping, perturbations of tau mutant expression, and by mapping new phenotypic endpoints achieved by our model to match cellular and physiological data from human MAPT mutation carriers.

NSF Awards · FY 2025 · 2025-08

Symmetry is a fundamental form of order in nature and, for this reason, the systematic study of symmetry plays a basic role in how scientists understand nature. Namely, for a given natural phenomenon, its symmetries constrain the possible laws it can obey, which in turn helps scientists determine the laws and their consequences. Over the past century, these methods have played a transformative role in many areas of science, notably chemistry, number theory, and physics. Representation theory is the mathematical study of symmetries and the constraints they dictate. The local geometric Langlands program is a vast web of conjectures in representation theory that has emerged over the past thirty-five years, with deep ties to, and applications in, both number theory and physics. During the period of support, the PI will tackle some of the basic problems in the local geometric Langlands program and develop some of its applications in nearby areas. In addition, the project provides research training opportunities for graduate students. In more detail, on one front, the PI and coauthors will apply new tools from local geometric Langlands to a set of problems originating from the kinematics of two-dimensional conformal field theories in physics, specifically the complete determination of the simple highest weight characters for affine Lie algebras and W-algebras in characteristic zero. On a second front, the PI and coauthors will verify the local geometric Langlands conjecture with restricted variation and pursue its applications in number theory. Finally, the PI and coauthors will develop the local geometric Langlands program in positive characteristic and investigate its implications in modular representation theory. 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

With its focus on developing and deploying evidence-based strategies into routine practice to optimize healthcare value and population health, implementation science (IS) plays a cross-cutting role in ending the HIV epidemic. Moving substantial investments in HIV research into implementation in rapid, rigorous, and relevant (3R) ways is critical. Now entering its fifth year, the UCLA Rapid, Rigorous, Relevant Implementation Science Hub (UCLA 3R Hub) proposes to provide the NIH and the Coordination, Consultation, and Data Management Center (CCDMC) with IS expertise and, in collaboration with other Regional Consultation Hubs (RCHs), meet the demand for effective and efficient ways to translate HIV research into practice. The goal of the UCLA 3R Hub is to provide leadership, resources, and support for 3R HIV-related implementation research emphasizing pragmatic study designs and community-involved methods and strategies to improve HIV outcomes. Over the next five years, in response to calls to integrate IS with quality improvement (QI, a rapid and iterative approach to change), the UCLA 3R Hub will also build capacity at the intersection of IS and improvement science (the foundational science and methods of QI). Our Specific Aims are to: 1) Provide technical assistance (TA), coaching, and consultation to a defined set of research projects by: a) offering expert guidance and support to inform project planning, execution, evaluation, and dissemination; b) supporting the projects with data harmonization and reporting requirements; c) highlighting best practices that will support implementing agencies; and d) fostering opportunities for collaboration across research teams. 2) Collaborate and coordinate with the CCDMC by: a) collecting specified data from awarded projects; b) conducting a systematic review of promising strategies identified in previous projects and developing evidence-based policy/practice recommendations; and c) engaging in cross-network activities. 3) Enhance IS capacity in the institutional, local, regional, and national HIV research communities by: a) delivering Beachside Chats and high-quality workshops on pragmatic methods and strategies; b) fostering multidisciplinary, multi-institutional research teams; and c) building a centralized infrastructure at UCLA to advance high-impact implementation research focused on ending the HIV epidemic and related conditions. 4) Enable locally driven solutions to implementation challenges through integrating improvement science into our IS capacity-building efforts by: a) providing training and mentoring on improvement science methods, including evidence-based QI (EBQI); and b) working with practitioners and healthcare partners to identify opportunities for, and to demonstrate, application of these methods.

NIH Research Projects · FY 2025 · 2025-08

Abstract As part of the basal ganglia circuitry, the striatum is a large, evolutionarily conserved brain nucleus that serves multiple essential functions throughout the lifespan, including precise information encoding necessary for a range of motor behaviors and skills. Normal aging disrupts striatal function, resulting in degradation of motor learning and susceptibility to age-related neurodegenerative diseases such as Huntington’s disease (HD) and Parkinson’s disease (PD). Glial cells are abundant within the striatum and are known to exhibit age-related decline. For example, human single-nucleus RNA sequencing (snRNAseq) of several brain regions, including the striatum, demonstrated that age degrades the molecular signatures of glia more than those of neurons. Astrocytes are a type of glia and are found throughout the mammalian brain, interacting spatially and functionally with neurons, blood vessels, and other glia. They serve multiple homeostatic and active functions and are involved in neuroinflammation, synapse formation, removal, and regulation. A long standing and open question concerns how astrocytes change during aging. One recent study employing postmortem human tissue found synaptic gene expression changes are coordinated in neurons and astrocytes, and another showed astrocytes lose their complex morphology with aging. In mice, several transcriptomic approaches show that glia display more pronounced changes in gene expression and density than neurons with age. Gene expression analyses of astrocytes across several brain regions of mice also demonstrated marked age-induced shifts in their transcriptomes, with separable patterns of decline that were apparent within individual brain regions. However, the striatum was not included in the evaluations and consequently despite progress how striatal astrocytes change with age in mice remains unknown. Since normal brain aging is a multicellular process, we seek to provide astrocyte-specific proteomic, transcriptomic, and functional data for how astrocytes change with age in the striatum of mice. The availability of these data, along with already available postmortem human gene expression studies, will permit specific mechanistic hypotheses in mouse models to ultimately aid in understanding normal aging and aging-related diseases such as HD and PD that affect the basal ganglia. We will test the hypothesis that striatal astrocytes undergo molecular, cellular, and functional changes with aging that can be assessed rigorously with state-of-the-art methods and understood in molecular terms. Specific Aim 1 will determine striatal astrocyte subproteomes and transcriptome in 18-month-old mice in relation to 2-month-old mice. Specific Aim 2 will evaluate functional and cellular properties of striatal astrocytes in 2- and 18-month-old mice. Our exploratory studies could have widespread applications in striatal and age-related astrocyte research, enabling development of hypothesis driven mechanistic studies in follow up R01 applications.

NIH Research Projects · FY 2026 · 2025-08

Project Summary The long-term goal of our laboratory is tackling a fundamental question in the field of Genetics: How do genetic variants drive functional changes at the molecular, cellular, and phenotypic levels? In essence, we aim to unravel the intricate consequences of genomic variation on genome function and phenotypes. This undertaking is particularly challenging, primarily because most variants associated with phenotypes or diseases are located in non-coding regions, indicating their likely involvement in the regulation of gene expression. The noncoding nature of most loci introduces another layer of complexity, characterized by cell-type specificity, developmental dynamism, residence at considerable distances from their target genes, and often a lack of conservation across different model systems. Additional challenges arise from allelic heterogeneity and linkage disequilibrium. This complexity forms a bottleneck, hindering progress in understanding the genetic basis of dynamic gene expression programs crucial for specifying distinct cell types, modulating tissue homeostasis, and influencing diseases. Our proposal builds upon past research achievements and adopts a multidisciplinary approach that integrates cutting-edge technologies, including computational analysis, single-cell analysis, iPSC system, and genetic screening. The objective is to create an integrative platform for systematically investigating the genetic architecture of complex traits and the impact of genomic variation on function. Over the next five years, we plan to thoroughly and mechanistically characterize the effects of genomic variation on genome function and phenotypes. We will define and systematically characterize genetic dynamics profiling to explore the impact of allelic heterogeneity on complex traits. Additionally, our proposal aims to characterize the role of genetic variants in cellular programs relevant to human diseases by using high-content microscopy imaging. Our research holds the promise of providing valuable insights into the dynamic landscape of genetic regulation and its profound impact on human health and disease.

NSF Awards · FY 2025 · 2025-08

The fluids we interact with on a daily basis (for example, air and water) display a wide variety of multi-scale phenomena, that is, interesting and important dynamics occurring at very different scales in space and time. For example, the thin boundary layer of fluid along the wing of an aircraft or a moving car can be only a few millimeters thick, and yet the dynamics of this thin layer can have a dramatic effect on the flight characteristics of the aircraft in terms of maneuverability, speed, and fuel efficiency. These so-called viscous boundary layers are one very important small scale in fluids. Another example are the complicated set of whorls and vortices one observes when the fluid is undergoing turbulence, like for example in the wake of a vehicle. In this situation there are many different active scales and the statistics of these patterns has a profound effect on the overall behavior of the fluid, for example, often creating a great deal of additional air drag on the vehicle. A third more subtle example is in the interaction between wave-like motion and a background flow, for example surface water waves traveling across a large gyre. While the small scales may not be immediately visible, in fact they play an important role in determining the interaction between the waves and large scale vortex structures. Accurate understanding of boundary layers, turbulence, and other such small scales, are crucial in a variety of scientific and industrial applications, including in the design of air, land, and sea vehicles and in the understanding of more complicated fluid-like systems such as the weather or confined fusion plasmas. The principal investigator (PI) will work to build firm mathematical foundations for understanding these phenomena more precisely, which could help other applied researchers obtain deeper insights, lead to better modeling, and better computational methods for these problems. Further, a better understanding of these extremes helps pave the way for a better understanding of the interactions and intermediate situations, for example, flows that have a mix of structure and chaos. Finally, overcoming the inherent mathematical challenges to these questions will require multiple innovations that will be of interest to the wider mathematical and scientific community. The research projects are also integrated with the training and mentorship of graduate students, post-doctoral scholars, and younger scientists in mathematics and STEM at large in order to help build and maintain a strong scientific and engineering expertise in the United States. The PI will work to develop a more mathematically rigorous understanding of three behaviors observed in incompressible fluids at high Reynolds numbers and in similar systems: (A) chaos and turbulence in statistically stationary models subjected to random forcing; (B) the structure and stability of sharp transition layers, such as boundary layers and shock layers; (C) the interaction of large scale waves (such as atmospheric Rossby waves) with the small-scale filamentation created by disturbing a large background shear flow or vortex. The primary long term goal motivating Program (A) is to provide a proof for the observed positive Lyapunov exponents and anomalous dissipation (e.g. as the celebrated Kolmogorov 4/5 law) from the stochastically-forced three-dimensional (3D) Navier-Stokes equations or other similar turbulent models. For program (B) it is to determine the dynamics of laminar boundary layers over long times in the presence of large scale flows. For program (C), it is to provide mathematical analysis of filamentation/inviscid damping dynamics interacting with large-scales waves in a nonlinear system, as this frequently arises in many applications, such as in weather dynamics and plasma physics. The PI has chosen several specific problems that will advance the theory towards significant insights while being ambitious yet achievable in the near term. Projects have been selected to train and integrate graduate students and post-doctoral scholars into the research, including the PI's current and future mentees. The PI and his collaborators have planned a number of activities to integrate the professional development of younger scientists, including participating seminars, conferences, and lectures series. 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

SUMMARY Cellular chaperones are promising targets for therapeutic intervention in neurodegenerative disease due to their ability to limit misfolding and promote degradation of pathological proteins. ProSAAS is among the few brain-specific chaperones that are actively secreted and therefore capable of interacting with toxic proteins in both the extra- and intra-cellular environments, making it particularly attractive as a therapeutic candidate. Moreover, ProSAAS has been identified as a potential biomarker for Parkinson’s disease (PD) and is colocalized with Lewy bodies in post-mortem PD tissue. ProSAAS blocks alpha-synuclein (α-Syn) fibrillation and α-Syn toxicity to rat dopamine (DA) neurons in primary culture and its lentivirus-mediated overexpression in rat substantia nigra (SN) protects DA neurons from AAV- α-Syn toxicity in vivo, even when administered several weeks after the onset of motor deficits, portending therapeutic efficacy in post-symptomatic PD. Overexpression within DA neurons themselves may not be required for neuroprotective benefit since delivery of lentivirus-proSAAS to the striatum is as effective as nigral delivery in protecting against nigral AAV- α-Syn- induced motor deficits. This is significant because it suggests that proSAAS delivery to the DA terminals in the more accessible caudate-putamen is a viable therapeutic strategy for PD. It is currently unknown if the protection afforded at the DA terminal level requires proSAAS release from neuron terminals making synaptic contact with DA terminals or whether a more diffuse delivery of proSAAS would be effective. The translational significance of this question lies in the several benefits offered by a genetically modified astrocytic cell transplantation approach to proSAAS delivery over direct viral inoculation, including: 1) avoidance of insertional mutagenesis; 2) ability to incorporate larger, controlled expression constructs; 3) benefits provided by supportive astrocytes 4) enhanced tissue penetration afforded by cellular ramifications. We have therefore produced human induced pluripotent stem cell (iPSC)-derived neuroprogenitor cells (iNPCs) expressing proSAAS and will test their efficacy in both cell culture and in vivo PD models. Rat primary DA neurons will be co-cultured with iNPC-proSAAS or control iNPCs and exposed to human α-Syn-expressing AAV or α-Syn preformed fibrils, with DA neuron survival and p129-aSyn staining as the output measures (Aim 1a). In parallel, iNPC-proSAAS will be co-cultured with human iPSC-derived DA neurons from patients with young-onset PD (YOPD) to test their effectiveness in attenuating previously demonstrated elevated endogenous soluble α-Syn protein levels (Aim 1b). The effectiveness of iNPC-proSAAS striatal transplantation in providing neuroprotection will be tested using in rat unilateral nigral AAV-haSyn and aSyn preformed fibril PD models. Positive results would confirm that proSAAS offers protection to DA neurons in a non-cell-autonomous fashion and support progression to iNPC-proSAAS IND-enabling studies.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Title of Project: “Regulation of Intravascular Triglyceride Hydrolysis” My objective is to address persistent problems in the intravascular triglyceride (TG) metabolism field. This topic is important because inefficient processing of TG-rich lipoproteins (TRLs) results in higher plasma levels of atherogenic lipoproteins and increased risk of coronary heart disease (CHD). Also, current treatment strategies are limited. My plans are rooted in our laboratory’s discoveries. We discovered an endothelial cell (EC) protein, GPIHBP1, that binds lipoprotein lipase (LPL) and shuttles it into capillaries; we discovered that some of that LPL detaches from GPIHBP1 and enters the EC glycocalyx where it is active in TRL processing; we discovered that LPL is active as a monomer; we solved the structure of the LPL–GPIHBP1 complex; we discovered LPL and GPIHBP1 mutations that cause chylomicronemia by disrupting the GPIHBP1–LPL interface; and we discovered that chylomicronemia can be caused by GPIHBP1 autoantibodies. We have elucidated the regulation of LPL. We showed that GPIHBP1’s acidic domain stabilizes LPL’s catalytic domain; we showed that an LPL regulator, ANGPTL4, catalyzes the unfolding of LPL’s catalytic domain; we showed that APOC2 binds to sequences anchoring LPL’s lid and stabilizes LPL conformation; and we showed that APOA5 preserves LPL levels in capillaries by suppressing the ability of the ANGPTL3/8 complex to detach LPL from capillaries. We uncovered heterogeneity in LPL and GPIHBP1 expression in EC subsets and heterogeneity in LPL binding to the glycocalyx of capillaries and larger blood vessels. Our progress has resulted from NHLBI support, investments in recombinant proteins and monoclonal antibodies, application of advanced biophysical methods, and introducing new scientists to the field and driving productive collaborations. Our discoveries have transformed textbook models for intravascular lipolysis but have also highlighted persistent questions in the field. During the next seven years, we will answer these questions. We will identify APOA5 sequences that are important for suppressing the activity of the ANGPTL3/8 complex and use those findings to create therapeutics to preserve LPL levels in capillaries and reduce plasma levels of atherogenic lipoproteins. We will investigate whether ANGPTL3/8– mediated LPL detachment from cells results from LPL unfolding and whether the ANGPTL3/8 complex preferentially detaches LPL from the glycocalyx of capillary ECs. We will determine, by X-ray crystallography, whether APOC2 activates LPL by opening its lid. We will define the transcriptional basis for heterogeneity in LPL and GPIHBP1 expression in EC subsets, and we will determine why LPL binds avidly to the glycocalyx of heart capillaries but not to the glycocalyx of larger blood vessels or capillaries of the brain. We will investigate whether TRL processing in the choroid plexus plays an accessory role in delivering lipids to the central nervous system. We are uniquely positioned—with recombinant proteins, a trove of mAbs, expertise in biophysical methods and structural biology, and highly experienced collaborators—to address these issues. Addressing persistent questions in intravascular lipolysis will transform the field and uncover new strategies for preventing CHD.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Viruses and their hosts are engaged in a constant, dynamic struggle as part of an ongoing evolutionary arms race. It is well established that viruses continually evolve new offensive strategies, like the production of proteins that disrupt host defenses, while hosts develop countermeasures to detect and neutralize viruses. However, a key question that remains is: how do viruses perceive and respond to host cues in real-time? This ability to sense and adapt to the intracellular environment, akin to real-time "decision-making," which helps them decide when to replicate, assemble, or escape, plays a crucial role in their fitness and ability to spread. To understand how viruses sense and respond to their environment, we will study host-derived post-translational modifications (PTMs) of viral proteins. The overarching hypothesis of this proposal is that viral proteins have evolved as substrates for host enzyme-derived PTMs to equip them with molecular sensors to coordinate viral life cycle transitions. Furthermore, we will study how PTMs enable multifunctionality in viral proteins by creating distinct proteoforms. By understanding the molecular mechanisms of viral biosensors, we expect to pinpoint critical viral dependencies, revealing promising targets for antiviral intervention. PTMs, imposed by the host cell, can dramatically alter the functions of viral proteins, influencing their behavior and ultimately the fate of the virus. Our preliminary mass spectrometry phosphoproteomics analysis of alphavirus infection revealed phosphorylation sites at the capsid-glycoprotein interface, likely regulated by plasma membrane-localized kinases, suggesting a functional switch in glycoproteins at the membrane. We similarly identified phosphorylation sites on herpesvirus latency proteins, which we believe may play a role in allowing the viral genome to replicate alongside the host genome during latency. Lastly, we discovered phosphorylation of a SARS-CoV-2 accessory protein by innate immune kinases, suggesting a feedback mechanism that may modify viral protein function in response to immune activation. Our data have led us to three specific areas of inquiry, each forming a distinct research project being conducted by PhD students, a project scientist, and undergraduate trainees: (1) How do viruses navigate through distinct host subcellular locations during their life cycle? (2) How do viruses coordinate their life cycle with the host cell cycle? (3) How do viruses sense, respond to, and exploit the host innate immune system? The projects and questions outlined in this proposal will serve as the foundation for the primary research in my laboratory over the next five years. Our questions seek to establish a new research area centered on the biochemical mechanisms through which viruses act as biosensors of the host signaling environment, how these biosensors adjust their functionality in response to PTMs, and how targeting these sensors may result in innovative antiviral therapies.