University Of California, San Diego

NIH Research Projects · FY 2025 · 2023-09

Project Summary Head and neck squamous cell carcinoma (HNSCC) is driven by tobacco, ethanol and other carcinogens as well as oncogenic human papilloma virus (HPV). In particular, HPV negative HNSCC has a high rate of mortality and the main curative treatment options for local and regional disease, including surgery, radiation, and chemotherapy, incur significant morbidity. PD-1 inhibitors are approved for recurrent/metastatic HNSCC yet have low response rates of 14-20%. Furthermore, a recent Phase III trial demonstrated no benefit when a PD-1 inhibitor was combined with chemoradiation using large radiation fields targeting tumor and lymph nodes. While the tumor immune microenvironment is key to the activity of immunotherapy, the role of draining lymph nodes in the efficacy of immunotherapy is poorly understood and the impact of conventional therapies anti-tumor immunity deserves further investigation. Our preliminary data demonstrate nodal irradiation or surgical removal of draining lymph nodes completely blocks the anti-tumor activity of PD-1 inhibitors, and surgical disruption of lymphatic channels alone while maintaining intact draining lymph nodes also blocks immunotherapy responses. Mechanistically, we have identified cDC1 and B-cell antigen presenting cells in draining nodes as key immune effectors coordinating anti-tumor immune responses. Further, a Phase I trial of immunoradiotherapy using PD-1 inhibitors combined with lymphatic sparing stereotactic radiation (SBRT) demonstrates a remarkable 67% complete pathologic response rate in HNSCC patients. Our central hypothesis is that intact, functional draining lymphatics and lymph nodes are critical for anti-tumor immunity and that lymphatic preserving IRT in HNSCC will maximize anti-tumor responses. To explore this hypothesis, we will use animal models of HPV negative HNSCC to 1) determine the role of the draining sentinel lymph nodes in generating and coordinating immune responses during immunotherapy and SBRT based immunoradiotherapy in HPV negative HNSCC, and 2) maximize immunotherapy responses in HNSCC by optimizing treatment sequencing, radiation targeting, and enhancing antigen presentation in draining lymph nodes. To validate this hypothesis in patients, we will define immune phenotypes that correlate with major pathologic responses from a clinical trial of neoadjuvant immunoradiotherapy in HPV negative HNSCC patients. Completion of this project will elucidate the role of draining sentinel lymph nodes in coordinating anti-tumor immune responses, identify optimized sequencing and novel combinatorial immune therapies in HNSCC, and define immune signatures in patients with complete responses to immunoradiotherapy in HSNCC. These insights will guide and improve the design of therapeutic strategies that leverage draining lymph nodes in coordinating anti-tumor immune response and improve outcomes in HNSCC and other solid tumor patients.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Interstitial fibrosis is a common finding on kidney biopsy, and strongly predicts future decline in kidney function irrespective of the underlying etiology of kidney disease. Unfortunately, interstitial fibrosis is poorly captured by the current clinical biomarkers of kidney function (eGFR and albuminuria). Thus, interstitial fibrosis is common, holds substantial prognostic importance, and yet clinicians are blind to its presence or severity except in rare instances when kidney biopsies are performed. Concurrently, new drugs are being tested to limit kidney interstitial fibrosis, but there are no non-invasive methods to assess changes in fibrosis over time. Interstitial fibrosis is currently estimated from histopathological examination of a kidney biopsy, which are rarely done. A non-invasive test to estimate interstitial fibrosis is not currently available. Our exciting preliminary data demonstrated that use of routine ultrasonography (USG) of the kidney, interpreted by deep learning/artificial intelligence can non-invasively assess the presence and severity of interstitial fibrosis. The overarching goal of this study is to further develop, and internally and externally validate a deep learning-based algorithm to estimate interstitial fibrosis from USG images of the kidney relative to the kidney biopsy gold standard. We hypothesize that, embedded within a kidney USG image are interstitial fibrosis corelates that can be extracted by deep learning and quantitatively analyzed to estimate interstitial fibrosis with high precision, and will improve prediction of longitudinal decline in kidney function. If so, given the widespread availability of kidney USG world-wide, this non-invasive estimate of interstitial fibrosis would have immediate clinical implications with improved prognostication, and ability to serially monitor interstitial fibrosis in response to therapy. The proposed program of research will address three specific aims: Aim 1. To further develop and internally validate a deep learning- based system for interstitial fibrosis quantification from kidney USG image. In Aim 2, we will externally validate the performance of the deep learning model using an independent cohort of USG images and kidney biopsies, and evaluate performance across strata of age, gender, and body size. Finally, in Aim 3, we will determine if the USG deep learning-based interstitial fibrosis score is associated with kidney disease progression with similar strengths relative to kidney biopsy assessment of interstitial fibrosis. Upon completion of this program of research, we envision development of an app. / plug-in for ultrasound reading modules that would facilitate widespread dissemination of the deep-learning tool, such that USG-based fibrosis scoring is widely available to treating clinicians.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Background. Sex-based differences, largely controlled by sex hormones, affect the natural and treated history of HIV infection and HIV-specific immune responses. Our previous work has shown that estrogen potently represses HIV transcription, thus decreasing cellular HIV RNA in women compared to men. Unexpectedly, women undergoing reproductive aging have a progressive increase in levels of inducible HIV reservoir, while estrogen declines. This observed expansion of the reservoir as women age is in sharp contrast to the steady decline in the reservoir size observed in men. Given the increasing number of women aging with HIV, it is critical to determine the interplay of HIV persistence and declining sex hormones during reproductive aging to design effective HIV cure strategies. Our goal. Our study is specifically designed with samples from both cisgender men and women across the reproductive aging spectrum. We will first define the impact of reproductive aging on multiple features of the reservoir including size, transcriptional activity, along with a novel exploration of clonal expansion (Aim 1). Next, we will precisely define the immunologic changes over the course of reproductive aging, using single cell sequencing combined with immunophenotyping using DNA-barcoded antibodies (Aim 2). The data will be integrated, and key features established using advanced statistical analyses. Study Cohort: Longitudinal samples (viable cells, plasma), collected, processed, and stored using standardized protocols in the multi-site Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS) cohorts will be utilized for all proposed experiments. First, we will carefully select 25 cisgender WWH on suppressive combination antiretroviral therapy (ART) with biologic samples representing four reproductive stages (reproductive/pre-menopause, menopausal transition/early and late perimenopause, post-menopause). Then, we will identify 25 MWH as controls using a multivariate propensity score based matching algorithm. After matching, stored samples collected between 2009 and 2019 will be selected based on similar time-intervals across both groups. How will we advance the field? To date, the majority of HIV cure research has used male participants and therefore a significant knowledge gap exists between men and women. We do not know if the same immune- modulatory interventions will be effective in promoting HIV RNA transcription in men and women and how declining sex hormones will impact their efficacy. Agents that are designed for “kick and kill” strategies may be impacted by estradiol-mediated mechanisms as women undergo reproductive aging. A better understanding of these differences will assist in the design of future cure approaches that can be applied across sexes.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Visualizing metabolic activities in situ is critical to understanding many biological processes. It is the metabolism which carries out the genetic blue print and maintain life. Sugar such as glucose is an essential nutrient for human being and animals, not only provides energy, but also is building blocks for synthesizing new biomass such as protein, lipid, RNA/DNA, and glycogen. Our proposed study is to develop and optimize a new generation of deuterated glucose ([D]-glucose) probed 3D volumetric multiplex stimulated Raman scattering (SRS) imaging platform. In aim I, various types of [D]-glucose including [D1], [D2], [D5], [D7], and [D12]- glucose will be studied and optimized for visualizing metabolic dynamics and heterogeneity in animals. The carbon-deuterium (C-D) chemical bond in the newly synthesized molecules such as C-D labeled proteins, lipids, DNA/RNA, carbohydrates will be imaged in the “cell silent region” of Raman spectra. In addition, based on diverse spectral patterns of metabolites derived from different isotopologues, metabolite synthesis in multiple time points will be visualized in a single image. In Aim II, a new generation of enhanced tissue clearing recipe will be screened and designed for large scale 3D volumetric imaging (20x deeper penetration) of [D]-glucose probed metabolic activities and heterogeneity in animal models. In Aim III, custom designed spectral unmixing algorithm and protocol will be established to maximize the potential of detecting more than 20 newly synthesized C-D labeled molecules and minimize the background signal. Our computational resources and algorithms will optimize numerous variables in complicated hyperspectral imaging datasets for studying organ specific metabolic dynamics and heterogeneity. Using the resources and algorithms, we will optimize a platform to unmix multiple old and newly synthesized molecules and quantitatively dissect the in situ detritions. Completion of the proposed study will potentially reveal mechanistic fundamentals of multiple molecular pathways related to glucose metabolism in different organs.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY / ABSTRACT Peripheral artery disease, an atherosclerotic disorder typically of the lower extremities, is a life threatening and debilitating condition affecting millions of Americans. Once diagnosed, medical management including initiation of antiplatelet therapy, lipid lowering medications, and behavioral therapy such as supervised exercise and smoking cessation have all been shown to significantly improve health outcomes for those with PAD. However, diagnosis of PAD can be difficult due to poor patient and provider awareness of the disease, a high prevalence of atypical symptoms and conflicting guideline recommendations on screening. Furthermore, despite having similar to higher prevalence of disease, Blacks, females and individuals in lower socioeconomic groups are diagnosed later in the disease process, contributing to poorer outcomes. To address low diagnosis rates we developed an artificial intelligence (AI)-based model to detect PAD prior to clinician diagnosis using vast amounts of electronic health record (EHR) data and advanced machine learning algorithms. However, for our technology to have real-world impact, there is a clear need to: 1) Validate performance of our AI-based PAD detection model across diverse clinical settings and populations (Aim 1), 2), Evaluate clinical utility of using an AI-based PAD screening tool and design effective clinical workflows to enhance net benefit and adoption (Aim 2), and 3) Evaluate the effect of an AI-based PAD screening tool on rates of PAD diagnosis and medical management patterns (Aim 3). Aim 1 will be conducted using EHR data from 3 clinical sites with distinctly different patient populations. Our final model will be validated using the unique American Family Cohort registry, a rich outpatient-based EHR dataset made up of patients from all 50 states, including nearly 1,000,000 rural residents and over 600,000 racial/ethnic minorities. We will perform rigorous evaluation of AI model bias using algorithmic fairness metrics. Using decision analysis we will evaluate model utility to ensure our models demonstrate positive net benefit prior to deployment and we will also employ a unique quality improvement and mixed methods approach to work with providers to develop clinical workflows that foster the use of AI for PAD detection and maximize model benefit. Lastly, using a stepped wedge clinical trial design we will perform a pragmatic analysis of the effect of an AI-based PAD screening tool on rates of PAD diagnosis and treatment. At the conclusion of this study, we will have developed an understanding of how an AI-based PAD screening tool can be used to improve PAD detection, reduce disparities in diagnosis rates, and improve medical management.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract The human placenta plays a major role in maintaining the proper environment for fetal growth, but remains a poorly-understood organ, particular during early gestation. Over the past few years, advances in single cell analysis and stem cell derivation have finally been applied to this organ, resulting in significant expansion, both of knowledge of cellular heterogeneity as well as of cell-based modeling, of trophoblast, the epithelial cells of the placenta. Specifically, multiple groups have established protocols for derivation of trophoblast stem cells (TSC) and trophoblast organoids from early gestation human placenta, which allow for study of differentiation into functional syncytiotrophoblast (STB) and extravillous trophoblast (EVT). Other groups, including our own, have established reproducible protocols for conversion of human pluripotent stem cells (hPSC) into bona fide TSC, allowing for modeling of both normal and abnormal trophoblast differentiation. However, recent data suggest that primary TSC have a more limited differentiation potential than originally described, with a profile that is most consistent with precursors to EVT, rather than a truly bipotential “TSC.” In fact, while human trophectoderm (TE) cells and early gestation villous CTB (vCTB) co-express TP63 and CDX2, primary TSC lack CDX2, and hPSC-derived TSC lose CDX2 during the transition from TE to TSC. In addition, placentas from Trisomy 21 (T21)-affected pregnancies show a persistent vCTB layer, with a significant proportion retaining CDX2 expression beyond first trimester; this is accompanied by an abnormality of T21-CTB to form STB in vitro, a phenotype which we have recapitulated using T21-affected hPSC. We hypothesize that CDX2+ vCTB represents a distinct trophoblast progenitor state, one that is possibly more primitive, and/or has altered differentiation potential. The goal of this application is to identify the role of CDX2 in establishment of TE, maintenance of a trophoblast progenitor state, and TSC differentiation potential, and characterize the cellular defects associated with its abnormal persistence in T21-affected placentae and the accompanying placental dysfunction. To this end, we propose to use a combination of CTB, TSC, and trophoblast organoids, derived directly from normal and T21-affected placentas or pluripotent stem cells, along with state-of-the-art single cell/single nucleus transcriptome profiling and complementary functional assays to address these goals. Successful completion of this proposal will provide a comprehensive molecular and functional assessment of cytotrophoblast heterogeneity in early gestation placenta, identify capacities and limitations of different in vitro human trophoblast model systems, and offer insights into mechanisms of placental dysfunction in pregnancies affected by Trisomy 21.

NIH Research Projects · FY 2025 · 2023-09

Abstract Staphylococcus aureus is a leading cause of infection worldwide and a major driver of antibiotic resistance. Although many experimental staphylococcal vaccines have been reported, all vaccines tested to date in human trials have failed for unclear reasons. Unlike mice, humans are exposed to S. aureus beginning early in life, leading to generation of antibodies to S. aureus antigens. In preliminary experiments, we have shown that select human anti-S. aureus antibodies are protective, but many are not. In mice exposed to S. aureus, vaccination against protective antigens leads to immunity against S. aureus whereas vaccination against non-protective antigens induced recall of non-protective immunity which further interferes with protective antibodies by direct competition. Based on these findings, we generated a model of how pre-existing antibodies shape vaccine responses and how this predicts novel ways to develop effective vaccines against S. aureus. To query the validity of our model, in Aim 1, we will recruit children and old adults with invasive S. aureus infections, survey the anti-S. aureus antibody profile and define functionally protective antibody responses to S. aureus antigens. In Aim 2, we will identify and characterize protective and non-protective anti-S. aureus antibodies from candidate samples acquired in Aim 1, and assess structural and functional features of the specific antibodies that confer protection or non-protection. In Aim 3, we will study these antibodies and their target in the context of naïve mice and mice previously exposed to S. aureus. We will evaluate mechanisms whereby non-protective memory shapes vaccine efficacy and test strategies that circumvent interference. Overall, using the novel model systems, we aim to develop a more predictive framework for explaining staphylococcal vaccine failures and developing novel strategies for effective vaccination against S. aureus.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Excessive alcohol use and alcohol-associated liver disease are two of the leading causes of morbidity and mortality worldwide. The gut microbiome can modify an individual’s risk for progression of alcohol-associated liver disease via microbe-derived metabolites such as ethanol. Patients with Autobrewery Syndrome (ABS), a condition where dysregulated gut microbiota produce high levels of ethanol that is then absorbed into the bloodstream leading to symptoms of intoxication, are a unique and ideal population for studying the host effects of gut microbial ethanol production. My preliminary data confirms that gut microbiota from ABS patients produce more ethanol in culture than that of their controls. Because chronic alcohol consumption can increase gut permeability, which is associated with persistent psychological symptoms of alcohol withdrawal and increased bacterial translocation to the liver resulting in liver disease progression, we hypothesized that endogenous gut microbial ethanol production could cause similar effects. Indeed, my additional preliminary data demonstrates that gnotobiotic mice humanized with high ethanol-producing gut microbiota from ABS patients demonstrated increased voluntary alcohol use behavior compared with control-humanized mice and increased hepatic inflammatory gene expression. I then confirmed that the gut microbiota of a subset of patients with alcohol use disorder also produce significant amounts of ethanol in culture. These observations have led to my central hypothesis that pathologic gut microbial ethanol production is an independent risk factor for increased alcohol consumption and exacerbation of liver disease. Hence, the aims of this application are to 1) characterize the gut microbiota of patients with ABS and identify microbes responsible for high levels of ethanol production, 2) examine how pathologic gut microbial ethanol production affects host alcohol use and liver disease progression and test antimicrobials as a therapeutic strategy, and 3) establish gut-microbial ethanol production as an independent risk factor for a subset of patients with alcohol use disorder and alcohol-associated liver disease. My proposed studies will advance our understanding of the biological mechanisms that drive ABS and predisposition for increased alcohol use and liver disease progression, and test potential therapies. The proposed research and career development plan, along with my mentors, advisory committee, and resources at the University of California, San Diego, will provide the support and additional training necessary for me to become an independent physician scientist studying the gut-liver-brain axis in an academic research environment.

NIH Research Projects · FY 2025 · 2023-09

Up to 40% of patients with pancreatic cancer present with locally advanced pancreas cancer (LAPC), defined as localized (non-metastatic) but unresectable. Treatment of this patient subset is a particularly glaring unmet need. Irreversible electroporation (IRE) is a technique that is being used increasingly for ablation of persistent LAPC after systemic therapy. Our group has demonstrated that IRE can function as an "in situ vaccine" by releasing tumor neoantigens in the setting of inflammation and thereby promoting recognition of the tumor by the innate immune system. CD40 is an immune receptor located on antigen-presenting cells that serves as a bridge between the innate immune system and the host’s specific response to neoantigens (the adaptive immune system). Using immunocompetent orthotopic mouse models of pancreatic cancer, we have shown that the combination of IRE with local delivery of a CD40 agonistic antibody (CD40 Ab), can both improve the local effects of IRE and decrease metastatic disease in the liver. ADC-1013 (mitazalimab) is a CD40 antibody that is currently being studied in clinical trials as a systemic therapy for metastatic pancreatic cancer. It has also been delivered by local (intratumoral) injection into a variety of superficial and deep tumors. Local (intratumoral) delivery is appealing in that it has potential to be more effective while decreasing systemic side effects. Intratumoral injection is also feasible at the time of IRE, which is generally performed via an open surgical approach. We hypothesize that local delivery of a CD40 agonist at the time of IRE in patients with LAPC will augment the systemic immune effects of IRE, enhance local disease control, and ultimately decrease distant recurrence. We propose to conduct a phase I study of intratumoral mitazalimab injection at the time of surgical IRE to determine a recommended Phase 2 dose and establish preliminary efficacy for future studies. In parallel, we will perform correlative studies to determine if this combination can generate immune responses to neoantigens identified using an unbiased bioinformatic analysis pipeline of tumor biopsies. Our multi-disciplinary team is uniquely qualified to conduct the proposed studies. Dr. White is a surgical oncologist at UCSD with clinical expertise in IRE and whose laboratory generated the preliminary data. Dr. Wainberg is a medical oncologist at UCLA with expertise in immuno-oncology clinical trials and specifically CD40 agonists. Subjects will be recruited from all five of the University of California Pancreatic Cancer Consortium centers. Dr. Schoenberger, at the La Jolla Institute for Immunology, will assist with neoantigen identification from human tumor samples and measurement of immune responses in post-treatment blood samples. We hypothesize that this novel approach to the treatment of LAPC will prove to be safe, and result in progression-free survival superior to that of patients previously treated with IRE alone. With these data in hand, Drs. White and Wainberg will be well-positioned to design a larger multi- center efficacy study for this large subgroup of understudied pancreatic cancer patients.

NIH Research Projects · FY 2024 · 2023-09

Project Summary The burden of Alzheimer’s Disease and Related Dementias (ADRD) is projected to increase by 150% by the year 2060 to affect 14 million Americans, with four- and seven-fold increases anticipated among Black and Hispanic/Latino older adults. To better understand the accumulation of risk throughout the life course and the disparities that exist in ADRD, studying social and structural determinants of health and employing a life course perspective have been emphasized. Research on the role of early life stressors and adversity on ADRD is emerging, but still limited. Older adults who experienced more childhood adversities had greater likelihood of incident dementia in three international aging cohorts; U.S.-based studies have been largely cross-sectional in design, mixed results have been observed, and only one examined racial/ethnic differences. However, greater understanding of the role these factors play is imperative if we aim to mitigate the risk of ADRD with a health equity lens. Identifying early life risk factors for ADRD and the primary pathways through which childhood adversity is operating will allow for more targeted interventions to reduce risk of ADRD in later life for the most vulnerable in our population. In addition, the role of neighborhood deprivation in these relationships remains understudied, despite known ramifications of environmental factors on health behaviors and outcomes. Understanding structural determinants of health and how they impact risk of ADRD will provide valuable insight for identifying the most vulnerable communities for targeting effective prevention strategies and motive for structural changes and policies that aim to improve these environments and the overall health of those individuals at greatest risk. To have the greatest impact on reducing the risk of ADRD, the role of the environment must be considered. In the F99-phase of this proposed research, Adrienne Lee will conduct three novel studies of these complex associations. Specifically, Adrienne will use the Health and Retirement Study to evaluate the associations of childhood adversity with neighborhood deprivation, cognitive trajectories, and dementia outcomes within racial/ethnic subgroups. She will link the study sample to the area deprivation index in midlife to further understand the role of environment and structural determinants of health on these associations, and to identify population-specific mechanisms by which we can tailor interventions throughout the life course. In the K00-phase of this proposed research, Adrienne will build off her dissertation research to identify early life resilience factors that promote healthy cognitive aging and that may counteract ACE exposure, and she will examine the associations of ACE exposure, in combination with neighborhood deprivation in relation to other hallmarks of aging. This research will inform equitable interventions.

NIH Research Projects · FY 2025 · 2023-09

Project Summary HPV mediated oropharynx cancer (HPVOPC) is projected to increase in incidence in the United States over the next 20 years. Attempts to de-escalate nonsurgical treatment for HPVOPC have not been successful and current treatment regimens incur significant long-term morbidity. Recently, PD-1 inhibitors received approval as first line therapy for recurrent/metastatic head and neck squamous cell carcinoma (r/mHNSCC), achieving ~15-20% overall response rates. However, PD-1 inhibition has demonstrated no benefit in patients with previously untreated, locally advanced HPVOPC/HNSCC, and emerging neoadjuvant window of opportunity trials examining PD-1 inhibition have documented only modest response. Targeting stereotactic body radiation (SBRT) to the tumor while sparing the tumor draining lymphatics may increase the response to PD-1 inhibition as part of a novel rational therapeutic strategy. In support of this hypothesis, we have shown that ablating tumor- draining lymphatics blocks the response to PD-1 inhibition and that elective nodal irradiation attenuates antitumor immunity and T cell infiltration in multiple experimental HNSCC model systems. In addition, we found that early, but not delayed, lymphatic ablation blocks the response to combined SBRT and PD-1 inhibition, indicating that an immunologically competent draining lymph node bed is critical to mount effective antitumor immunity after PD-1 inhibition. We explored this premise in our recent Phase 1 clinical trial in resectable HNSCC patients who received nivolumab in combination with SBRT to gross tumor volume (GTV), followed by definitive surgical resection (NCT03247712). Astonishingly, the pathologic complete response rate in HPV+ patients was 90% and no patient required adjuvant radiation or chemoradiation. In addition, the combination of a CD47 inhibitor (evorpacept) with PD-1 inhibition shows enhanced response compared to PD-1 inhibition alone in both preclinical models and in r/mHNSCC. Our overall hypothesis is that preserving the immune-lymphatic axis during neoadjuvant immunoradiotherapy (NIRT) for HPVOPC will promote anti-tumor immunity, potentiate checkpoint blockade therapy and reinstate effective cancer immunosurveillance. Therefore, we propose a phase IIb, single arm clinical trial of neoadjuvant 8Gy x 3 SBRT to GTV followed by combination evorpacept and pembrolizumab in patients with previously untreated locally advanced, resectable HPVOPC, followed by risk adapted adjuvant therapy. We specifically hypothesize that combination neoadjuvant SBRT and evorpacept + pembrolizumab will 1) provide >80% complete/major pathologic response in patients with resectable HPVOPC, 2) is safe and will result in functional and quality of life metrics that are similar or better to those for patients treated with standard therapy, and 3) enhance cytotoxic CD8 T cell antitumor immunity by driving the priming and expansion of tumor- reactive T cells along the tumor-immune-lymphatic axis. A high pathologic response rate and favorable toxicity profile in the proposed trial will support a subsequent paradigm-shifting, randomized phase II trial comparing nonsurgical treatment with SBRT to GTV followed by immunotherapy versus standard of care radiation with concurrent cytotoxic chemotherapy.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Globally, more than 900,000 people are diagnosed with head and neck squamous cell carcinoma (HNSCC) each year, with more that 250,000 dying annually from this cancer. Infection with human papilloma virus (HPV), a known risk factor for developing HNSCC, significantly impacts clinical prognostication. Specifically, for HPV- negative HNSCC, the most lethal subtype of head and neck cancer, less than 30% of those diagnosed survive for more than five years. The most common and lethal HPV-negative HNSCC subtype is oral cavity squamous cell carcinoma (OSCC). Importantly, most OSCCs are preceded by morphologically distinguishable pre- cancerous lesions which are readily accessible for histological and molecular evaluation. This provides a unique opportunity for intercepting this deadly cancer in the earliest stages of its development by halting the conversion of oral precancer into invasive OSCC. Oral leukoplakia, the focus of this application, represents the most frequent type of oral premalignancy, with one in every fifty people is expected to develop OL in their lifetime. OL’s low malignant transformation rate of ~3.3% progressing to oral cancer and its highly variable natural history poses a major challenge for surveying OLs and for intercepting their malignant conversion into invasive oral cancers. To address this challenge, we hypothesize that the evolutionary transition from an OL into an OSCC is due to the immuno-genomic interactions encompassing the acquisition of somatic driver events, the gain of chromosomal instability, and the loss of effective immunosurveillance. We further hypothesize that the genomic and immune landscapes of OL in patients who subsequently develop oral cancer (progressors) will differ from those that do not develop oral cancer (non-progressors). The overall objective of this project is to elucidate the molecular and immune mechanisms by which OLs progress to OSCCs, and to develop actionable and predictive biomarkers. To achieve this objective, we will leverage well-annotated OL cohorts to generate the largest whole- exome and whole-transcriptome atlas encompassing 300 OLs, including at least 100 cancer progressors and 100 non-progressors. Further, by utilizing a spatial multiplex immuno-fluorescence platform and an unbiased RNA-sequencing approach for immuno-profiling, we will comprehensively map the immune landscapes of these 300 OLs and associate distinct immuno-genetic features with likely progression to OSCC. Lastly, our state-of- the-art oral carcinogenesis mouse model will be used to model the transition of OL to OSCC at the single cell resolution in order to understand the role of common genomic alterations and immune surveillance in this process. Overall, this project will reveal the compendium of immuno-genetic changes that drive the evolutionary transition from an OL to an OSCC and elucidate a set of targetable immune cell population(s) and novel immune surveillance mechanisms, which can likely halt this malignant transformation.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Pancreatic cystic neoplasm (PCN) represents a common incidental finding in the population. Branch-duct intraductal papillary mucinous neoplasms (IPMN), the most common incidentally discovered PCN, have a risk of malignancy approaching 15%within 15 years of diagnosis. The performance of existing guidelines for identifying early cancer is poor, and results in both surgical overtreatment and missed opportunities for early diagnosis. Effective screening biomarkers are needed to accurately differentiate high-risk PCN that require close surveillance from low risk lesions with little chance to progress. In this proposal, we will test and validate of three novel blood-based biomarkers and one cyst fluid biomarker for the detection of early PDAC in patients with PCN. The proposed markers, developed in both academic and industry settings, show promise in preliminary studies, with sensitivity and specificity sufficiently high to warrant further evaluation. We will incorporate prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) standards to rigorously test the performance of these biomarkers with samples collected from three cohorts: 1) stage I/II PDAC and controls; 2) Patients with PCN who undergo surgical resection; 3) Patients with PCN ≥ 2.5 cm or main pancreatic duct ≥ 5 mm under surveillance with serial imaging and sample collection. We will test performance of the biomarkers individually, and as part of multi-variable models in combination with each other, with the added information of germline testing and clinical laboratory values (CA19 -9, HbA1c), and with specific PDAC risk factors (smoking status, alcohol consumption, diabetes, pancreatitis history). Key components of our research strategy to tackle this recalcitrant problem include: 1) rigorous testing of several promising blood-based biomarkers, individually and in combination, through a unique collaboration between industry and academic partners; 2) testing of a novel platform for advanced cyst fluid analysis for early detection of PDAC and comparison of its performance to blood-based biomarkers; 3) a large number of retrospective and prospective samples interrogated using the PRoBE design, with statistical rigor for biomarker validation; 4) resources leveraged from the established Pancreatic Cancer Early Detection (PRECEDE) Consortium including standardized collection of germline genetic testing, clinical, and laboratory data with blood and cyst fluid biosampling in accordance with PCDC protocols; 6) collection of a large set of de-identified partnering pancreatic images (MRI/MRCP, CT and EUS) and digitized pathology slides on a funded cloud-based platform for collaborative opportunities using artificial intelligence and machine learning strategies, and 7) multimodal data integration for model development. Longitudinal biospecimens will be shared with the PCDC to support the Signature Cohorts, and de-identified stored images (MRI, EUS, digitized pathology) will be available for collaborative consortium efforts.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT – OVERALL The Cancer Research and Education to Advance HealTh Equity (CREATE) Partnership’s overarching goals are to further increase SDSU’s cancer research capacities and expand SDSU’s and UCSD’s emphasis on cancer health disparities research. Bi-directional community engagement is also a principal feature that is integrated across every organizational component in the CREATE Partnership and is a strength that SDSU has built over the last 30 years. Additional goals include developing cancer research opportunities and pathways for undergraduate, graduate, and medical students, as well as early-stage investigators (ESIs), which will lead to a future workforce that is more diverse and reflective of the catchment-area population. To meet these overarching goals, the following Specific Aims are proposed: 1) Recruit and support diverse ESIs who have chosen an intentional career goal to become independent, cancer-focused researchers (Administrative Core and Transforming fAcuLty dEvelopmeNT for Equity [TALENT] Shared Resource); 2) Conduct catchment-area relevant research and pilot research projects aligned with identified cancer priorities for the underserved communities in the region (Research and Research Pilot Projects and Planning and Evaluation Core); 3) Expand and implement cancer, cancer disparities, and community-engaged research education with a focus on under-represented students across SDSU and UCSD undergraduate, graduate programs, and medical students (Research Education Core); and 4) Integrate community engagement into all CREATE Partnership activities (Outreach Core). To achieve these aims, the CREATE Partnership requests the initial support for two Full Research Projects and one Pilot Research Project designed to provide insight into the mechanisms (or behaviors) underlying cancer health disparities. All three projects will be jointly led by SDSU and UCSD Co-Leads; Project 2 is co-led by two under-represented researchers. The Research Projects will be integrated with the Research Education Core, providing expanded research experiences in cancer, cancer disparities, and community-engaged research to under-represented undergraduate, graduate, and medical students. A TALENT Shared Resource will foster the career development of Partnership ESIs. The Outreach Core will develop new and strengthen existing community-academic partnerships to foster cancer research, education, and tailored outreach efforts with a focus on the dissemination and implementation of evidence-based interventions that can reduce the cancer burden. The Partnership is notably bolstered by strong institutional commitment, an Administrative Core composed of investigators with demonstrated leadership and organizational capabilities, and a strong Planning and Evaluation Core guided by an external Program Steering Committee, an Internal Advisory Board, and a Community Advisory Board.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY/ABSTRACT Growing evidence reports that women show a more aggressive profile of Alzheimer's disease (AD) than men with greater pathological tau burden and steeper cognitive decline; yet the reasons for these sex differences are poorly understood. Sex differences in AD point to sex-disparate causal pathways as well as sex-specific therapeutic targets. Neuroinflammation (N-Inf) is one candidate casual pathway that shows sex disparities and plays a central role in AD pathogenesis with close ties to both tau and cognitive decline. Women tend to have a more robust immune/inflammatory response and comprise 80% of autoimmune disease cases. Moreover, our own preliminary work in the Alzheimer's Disease Neuroimaging Initiative indicated that women may be more susceptible than men to the adverse effect of N-Inf, particularly the markers of TNFα, IL6 and their receptors on cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and cognitive function. There are also lifestyle factors such as physical activity and obstructive sleep apnea (OSA) known to influence N- Inf and relate to tau and cognitive decline and to do so differently in women versus men. Our own preliminary data highlight sedentary behavior and obstructive sleep apnea as two modifiable risk factors that show strong associations with N-Inf, tau and/or cognitive function in older women, and thus stress the need to further understand how and to what degree these lifestyle interventions could reduce AD risk. Together, these findings led us to this proposed observational study that will examine how N-Inf markers (specifically TNFα, TNFR2, IL6 and IL6R) and the modifiable risk factors that influence N-Inf relate to tau accumulation and cognitive decline in older women at-risk for AD by way of mild cognitive deficits and genetic risk. Moreover, we will explore how sex hormones, particularly testosterone, contribute to these relationships given their anti-inflammatory and central nervous system effects and often contributing role to sex differences. To achieve this, we propose to measure CSF N-Inf markers, physical activity, OSA, and circulating sex hormones in a sample of 100 older women at-risk for AD and relate these measures to changes in cognitive function and accumulation of tau, measured via positron emission tomography (PET), over a two-year period. This study will build upon a state-funded, pilot study by increasing the sample size and adding longitudinal assessments in order to conduct a rigorous examination of our hypotheses. In keeping with NIH research priorities, after 5 years of potential funding, this project will help to close critical gaps in our understanding of sex differences in AD by examining under-explored yet highly-relevant mechanisms that may contribute to the greater pathology and steeper cognitive decline in women on the AD trajectory. Furthermore, our findings will inform risk reduction strategies that influence these mechanisms – an important focus given current the lack of disease-modifying treatments.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT The opioid crisis is a major public health problem in the United States. Over the past two decades, opioid use and abuse have increased dramatically, with over 5 million people in the United States using prescription analgesics without medical need or prescription. This has resulted in a significant increase in opioid-related deaths and addiction rates, with the crisis having a profound impact on individuals, families, and communities. The proposal aims to develop machine learning-based predictive models for opioid use disorder (OUD) leveraging genomic, social, and clinical factors. The project will utilize the diverse and equitable AllOfUs database to identify novel genomic markers associated with OUD in patients with and without co-existing pain conditions. A significant advantage of the AllOfUs database is the diversity of the patient population and clinical samples – over 50% of the population is considered underrepresented. This will be achieved through genome- wide association analysis to identify novel single nucleotide variants, copy number variants, and/or structural variants. The project will also use machine learning techniques to develop predictive models that classify the risk of OUD, integrating various data types such as clinical factors, social factors, and genomic data. The project aims to identify key features that aid in the development of improved models for predicting the risk of OUD. The first specific aim of the proposal is to identify associations between genomic profiles and OUD. The project will focus on patients with or without co-existing pain conditions and identify novel genetic markers associated with OUD in each of these unique patient populations. The second specific aim is to develop predictive models using machine learning techniques to classify the risk of OUD. The models will integrate social, clinical, and genomic data to provide clinicians with a tool to risk stratify their patients. The project aims to develop robust machine learning-based models predicting OUD and visualize the individual features' impacts on model performance to provide understanding of which factors are most impactful to predicting the outcome.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Nucleic acid therapies provide a promising pathway for the treatment of diseases that are not amenable to target- ing by traditional small molecule drugs. Reduction in toxicity and improvements in delivery and specificity have been achieved through covalent modifications to naturally occurring RNAs, and these advances have recently led to the regulatory approval of several nucleic acid therapies. For example, small interfering RNA (siRNA) silences the expression of disease-causing messenger RNAs (mRNAs). However, this strategy can cause deleterious silencing of off-target mRNAs with partial complementarity to the siRNA guide strand. A strategy for mitigation of off-target silencing is destabilization of base pairing in one end of the duplex by substitution of the siRNA guide strand by glycol nucleic acid (GNA), a nucleic acid analogue with an acyclic backbone. The precise mecha- nisms of many covalent modifications, as well as their dependence on features such as sequence position and structural motifs, are still poorly understood. Physics-based atomistic simulations can interrogate the impact of these modifications on the conformational ensembles of nucleic acids and expedite the trial-and-error process for molecules that are difficult to synthesize in the laboratory. The success of such simulations relies on the accuracy of the force field, a parameterized function that uses classical physics to estimate potential energies from atomic coordinates. A major obstacle to the application of physics-based simulations to therapeutic nucleic acids is the difficulty in developing accurate force field parameters for covalently modified nucleotides. This proposal aims to advance the role of simulations in the design and mechanistic understanding of therapeutic RNAs with covalent modifications by developing an open source workflow to derive force field parameters and run simulations of duplex hybridization for realistic therapeutic siRNAs. In Aim 1, a force field for nucleic acids with arbitrary covalent modifications and backbone chemistry will be parameterized using a systematic and reproducible workflow based on open source software infrastructure maintained by the Open Force Field Initia- tive. In Aim 2, the force field parameters will be validated against experimental measurements of duplex melting temperatures by performing melting simulations for RNA duplexes containing substitutions of GNA. In Aim 3, the weighted ensemble enhanced sampling method will be applied to study the duplex association process for guide siRNAs containing GNA substitutions pairing with target and off-target mRNAs. The proposed research will enable reliable atomistic simulations of therapeutic RNAs, expanding the available toolkit for rational design of such therapies. The systematic workflow for developing and validating nucleic acid force field parameters will be easily generalizable to other covalent modifications beyond those in the siRNAs studied here, facilitating similar studies of other therapeutic platforms. This research plan will prepare the applicant for a productive indepen- dent research career by developing technical and management skills appropriate for leadership of an academic computational chemistry lab studying biophysical and pharmacological properties of therapeutic RNAs.

NIH Research Projects · FY 2025 · 2023-09

Summary The U.S. has the highest maternal mortality rate of all industrialized nations, a trend that has been steadily increasing for two decades. Nearly 2 in 3 maternal deaths are preventable, with cardiovascular disease (CVD) being the leading cause. Preeclampsia (PE) and other hypertensive disorders of pregnancy (HDP) are major sources of maternal and fetal morbidity and mortality. Notably, half of pregnancy-associated maternal deaths occur in the year after delivery. Although maternal morbidity is increasing across all racial and ethnic groups, Black, Hispanic, and Native American women are disproportionately affected. We, and others, have demonstrated a strong association between PE/HDP and postpartum CVD, but it remains unclear whether these links stem from an underlying genetic, environmental, and physiologic state that precedes pregnancy or is a direct effect of PE/HDP. The heterogeneity and complexity of PE/HDP demands an approach that intentionally studies a range of clinical phenotypes, and integrates phenotypic, environmental exposure (EE), and multi-omic data using computational modeling and machine learning to build multi-component signatures of the different PE/HDP subtypes and unravel their relationships with maternal health outcomes, ultimately allowing us to develop a precision approach to optimize postpartum maternal health. The central goal of the Multi-Omics for Maternal Health after PE (MOM-Health) Disease Study Site is to use multi-omic analyses of biofluids and placental tissue linked with comprehensive phenotypic and EE measures in a diverse population to uncover mechanisms leading from PE/HDP to intervenable postpartum maternal health outcomes. We will recruit 680 participants (180 high-risk and 500 low-risk) in the 2nd trimester of pregnancy and follow them through pregnancy with serial collections of phenotypic and EE data and maternal biosamples, yielding 200 cases with PE/HDP and 480 controls. At delivery, placental tissue and cord blood samples will be collected from all 680 participants. All 200 cases and a subset of 100 controls will be followed for one year postpartum, with collection of serial phenotypic (including functional CV testing) and EE measurements and maternal biosamples. We anticipate collaborating closely with the OPCs that will be generating multi-omic data from the collected biosamples, as well as the DACC, on integrated analysis and interpretation of the multi-omic, phenotypic, and EE data. Our sites are led by investigators with extensive experience in recruitment and retention of diverse populations through novel community-engagement resources, as well as experience in NIH consortia using omic data for disease subtyping and biobanking of diverse biosamples. In addition, we will leverage ongoing NIH-funded efforts in our group in which placental single cell/single nucleus and spatial transcriptomics is being performed to prioritize circulating targets in the current study. This project has the potential to inform methods to integrate longitudinal multi-component and multi-omic data and contribute to improved mechanistic understanding of PE/HDP and risk stratification of women with PE/HDP.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Visual attention differences are a promising diagnostic marker for autism spectrum conditions (ASC). Yet, despite mounting evidence for group-level differences in visual attention, particularly for visual attention directed toward socially relevant information (i.e., “social gaze”) between autistic and non-autistic individuals, the source of gaze differences in autism remains unclear. Prominent theories of social gaze differences focus heavily on a particular category of visual stimuli, namely: faces. What these theories leave unanswered is whether reduced social attention is, in fact, best explained by atypical attention to a specific stimulus class or whether it reflects an underlying reduction in attention to distributed (face and non-face) sources of important social information in complex environments. In other words, social information may not be limited to a single visual category, and it may not be categorical in nature at all. Yet, by focusing on object categories, eyetracking analyses have failed to capture the richness and complexity of real-world environments in which visual attention supports an individual’s behavior. In order to leverage visual attention as a clinically actionable tool, a critical knowledge gap must be addressed: are social gaze differences in autism driven by information at the level of visual categories, or instead, by higher-order conceptual information beyond the visual domain? The objective of this project is to examine the impact of both categorical and conceptual levels of information on individual and autistic group differences in visual attention. The central hypothesis is that visual attention differences in autism stem from conceptual-level, rather than categorical-level, differences in mental processing. To test this hypothesis, I have developed a novel approach that uses tools from computer vision (computational neural networks; CNNs) and natural language processing (NLP) to characterize individually unique patterns of visual attention. First, Specific Aim 1a will test whether gaze patterns reflect high-dimensional conceptual priorities that are unique to individual participants (N = 62 non-autistic adults). Specific Aim 1b will test whether conceptual priorities reliably guide autistic individuals’ (N = 28) gaze and can be used to classify individuals by diagnostic status (autistic vs. non-autistic). Specific Aim 2, the postdoctoral research direction, will extend the focus of my dissertation research, on conceptual priorities that drive visual attention, to conceptual priorities outside the visual domain, such as language. These aims have been articulated as part of a structured training plan designed to facilitate the transition to a postdoctoral position and independent research career. This training plan emphasizes skill development in multivariate statistical analysis, experimental design, and scientific communication. This training plan is sponsored by Dr. Caroline Robertson, whose expertise in autism, visual processing, and novel experimental techniques (e.g., virtual reality) is ideally complemented by the technical and computational strengths in the Psychological and Brain Sciences Department at Dartmouth.

NIH Research Projects · FY 2026 · 2023-09

Project Summary/Abstract Recruitment and retention of women and underrepresented minorities into academic gastroenterology (GI) has been a major challenge for decades (Merchant, 2010). Indeed, as of 2017, only 3.2% of gastroenterology fellows were African American and 8.5% were Hispanic (Quezada, 2017). To address these challenges NIDDK has funded initiatives by the American Gastroenterology Association (AGA) since 2012: R25 DK096968 Investing in the Future to Promote Diversity in GI Training (9/10/2012 – 8/31/2017) and R25 DK118761 AGA - Fostering Opportunities Resulting in Workforce and Research Diversity (FORWARD, R25 DK118761 7/1/2018 – 4/30/2023). FORWARD is a structured curriculum that has been successful in helping junior GI faculty from URM backgrounds (twenty so far) to succeed in academia. Its renewal for the next 5 years has received a favorable score. For the past ten years this PI and others at AGA, who are passionate about diversity, have volunteered their time to compete for funding, organize, coordinate and supervise the progress of these NIDDK-funded initiatives. This K26 award will provide dedicated salary support to allow this investigator to decrease his clinical load and reallocate salary support to hire a senior scientist to assist the PI with the day-to-day operation of his research program. These measures will for the first time allow the PI the dedicated time that might better guarantee the success of these national initiatives. At the institutional level, these funds will free time to continue mentoring URM students at the undergraduate and graduate levels and newly hired junior GI faculty.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY /ABSTRACT The Centers for Disease Control and Prevention estimates that 1 in 44 children have autism. Implementing evidence-based practices (EBPs) is crucial for their meeting their needs. However, there are challenges to delivering EBPs for autistic children in routine services. This proposal leverages data from the TEAMS (Translating Evidence-based Interventions for Autism: A Multi-Level Implementation Strategy) Hybrid Type III trials. TEAMS aimed to improve implementation of EBPs by testing multi-level implementation strategies in children’s mental health services (Study 1 PI: Brookman-Frazee, R01-MH111950) and schools (Study 2 PI: Stahmer, R01-MH111981). Specifically, the TEAMS trials applied the Exploration, Preparation, Implementation, Sustainment (EPIS) framework and utilized the Leadership and Organizational Change for Implementation (LOCI) strategy to test the effectiveness of two multi-component implementation strategies. TEAMS targeted organizational and provider level mechanisms. The organization level implementation strategy (TEAMS Leadership Institute, TLI), an adapted version of the Leadership and Organizational Change for Implementation (LOCI) strategy, targeted organizational implementation leadership and climate as mechanisms. The proposed study will supplement the primary study aims by exploring a new potential mechanism of TLI – climate embedding mechanisms (CEM). The construct of CEM refers to tools that leaders utilize to teach their organizations how to perceive, think, feel, and behave. This study aims to identify which individual CEM are most impactful to promote successful implementation and whether use of specific CEM mediates the associations between TLI and implementation and child outcomes. The objective of this NRSA application is to foster my development as an implementation scientist with a focus on organizational implementation factors and autism services research. The proposed project will examine climate embedding mechanisms as potential mechanisms of action of an organizational implementation strategy within two linked randomized controlled trials. Specifically, Aim 1 will identify individual climate embedding mechanisms associated with implementation (provider) and clinical (child) outcomes. Aim 2 will utilize quantitative methods to examine whether the individual climate embedding mechanisms identified in Aim 1 mediate the effects of TLI on implementation and clinical outcomes. Lastly, Aim 3 will use qualitative and mixed methods to complement and expand quantitative findings on additional climate embedding mechanisms and explain how individual mechanisms facilitated implementation of autism EBPs. The present proposal represents an important step in further understanding mechanisms of organizational implementation strategies. With support of my mentoring team, this proposal will launch my development toward a career as an independent implementation scientist focusing on organizational level strategies and mechanisms to improve EBP implementation in autism services settings.

NIH Research Projects · FY 2025 · 2023-09

I am a board-certified radiation oncologist and Professor in the Department of Radiation Medicine at the University of California, San Diego. My clinical and research work spans the entire spectrum of gynecologic oncology clinical trials, with a strong emphasis on translational science and national leadership within the NRG Oncology cooperative group. Over the past 16 years, I have held several leadership roles within NRG Oncology. I began as a core member of the Radiation Oncology Committee for GOG (2009–2015) and subsequently served on the Phase I Developmental Therapeutics and Cervical Cancer Committees. From 2015 to 2018, I was Co-Chair of the GYN Developmental Therapeutics Committee and received a National Service Award from NRG Oncology in 2018 for my leadership as Co-Chair of the Phase I Committee. Since 2018, I have served as Co-Chair of the NRG Cervical Cancer Committee, where I lead national efforts in trial development, strategic prioritization, patient accrual, and dissemination of findings. I have played a principal role in 16 NRG proposals since 2018, serving as a lead investigator, mentor, or key study team member. I am deeply committed to mentoring early-stage investigators and building clinical trial capacity both nationally and at my home institution. At UC San Diego, I serve as Co-Leader of the Gynecologic Oncology Disease Team at the Moores Cancer Center (MCC) and as UCSD’s Co-PI for the VICKtOrY Early Clinical Trials Consortium (UM1CA186689), a component of the NCI ETCTN network. I collaborate closely with the clinical trials office and the Community Outreach and Engagement team to broaden access to NCI clinical trials. My own research focuses on advancing therapies for high-risk, node-positive cervical cancer. I have developed and led a series of NCI-funded trials as principal investigator, including GOG 9929, a Phase I study of sequential ipilimumab after chemoradiotherapy, and NRG GY017, a Phase I study of atezolizumab as an immune primer in combination with chemoradiation. In November 2024, I became named national PI of NCI funded NRG GY037, a Phase III trial evaluating induction pembrolizumab and chemotherapy prior to chemoradiation and immunotherapy in locally advanced cervical cancer. With the support of the R50 Research Specialist Award, I will: 1) Provide national leadership in clinical trial development within the NRG Oncology network; 2) Design and submit novel, biomarker-driven clinical trials; 3) Mentor early-career investigators in trial development and implementation;4) Lead translational science efforts using biospecimens from NRG trials; and 5) Enhance access to and enrollment in NCI-funded clinical trials.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Hematopoietic stem cells (HSCs) regenerate all blood and immune cells throughout life. Aging HSCs exhibit diminished regenerative function, reduced lymphoid potential, and clonal outgrowth that is associated with compromised immunity as well as an increased incidence of anemia, bone marrow failure, and hematological malignancies in older adults. The regulation of protein homeostasis (proteostasis) has recently emerged as a fundamental process required to promote HSC self-renewal. Loss of proteostasis is considered one of the hallmarks of aging, but to what extent it contributes to stem cell aging is largely unknown. An essential pathway in maintaining proteostasis is the Heat Shock Response, which is regulated by the master transcription factor Heat shock factor 1 (Hsf1). Hsf1 induces expression of heat shock proteins that aid in proper protein folding, trafficking, and degradation. At steady state, Hsf1 is typically sequestered in the cytoplasm, but translocates into the nucleus in response to cellular and proteotoxic stress. Previously, we demonstrated that HSCs undergo cellular stress when cultured ex vivo and Hsf1 activation can alleviate this stress to maintain HSC regenerative activity. Hsf1 is highly expressed in young and old adult HSCs but is specifically activated during aging in middle- aged and old adult HSCs. Aging is a notably stressful process associated with the accumulation of genetic mutations, inflammation, and oxidative stress. Based on these preliminary results, the central hypothesis of this proposal is that Hsf1 activation promotes HSC function and proteostasis during aging. To test this hypothesis, Aim 1 will examine the role of Hsf1 in aging HSC function and proteostasis using conditional Hsf1 knockout mice. HSC function will be assessed in competitive transplantation assays and proteostasis will be assessed by quantifying protein synthesis, proteasome activity, misfolded protein, unfolded protein, and protein aggregate abundance. I expect that there will be less reconstitution in aged Hsf1-deficient HSCs and more protein synthesis, misfolded and unfolded proteins, and aggregates. While Hsf1 activation is hypothesized to be important for HSC function during aging, the mechanism underlying heterochronic Hsf1 activation is unknown. Preliminary RNA-sequencing results revealed that Transglutaminase 2 (Tgm2), involved in Hsf1 activation, is significantly upregulated in old adult HSCs. Thus, Aim 2 will examine if age-related Hsf1 activation depends on Tgm2 upregulation. Hsf1 activation, HSC function, and proteostasis will be assessed in conditional Tgm2 knockout mice. I expect that loss of Tgm2 in aging HSCs will disrupt proteostasis and exhibit an associated decline in fitness and function due to a decrease in Hsf1 activation. Collectively, these studies will provide deeper insights into mechanisms that regulate proteostasis during stem cell aging. These findings will uncover new therapeutic targets to promote HSC fitness during aging.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY/ABSTRACT Physical activity (PA) has been listed as a promising intervention to delay or prevent Alzheimer’s disease (AD) and related dementias (ADRD), however most studies used self-reported PA. Our preliminary data show that, among older women, higher amounts of accelerometer-measured moderate to vigorous intensity PA and steps/day are associated with lower risk of rigorously adjudicated incident mild cognitive impairment (MCI) and ADRD. However, the molecular mechanisms through which PA influences ADRD risk are unclear. The plasma proteome is a promising target for identifying the molecular mechanisms of PA because proteins regulate biological processes, capture disease mechanisms, and may identify intervention targets. Machine learning (ML) methods have been applied to derive PA proteomic signatures, proteomic aging clocks, and ADRD proteomic clocks. However, few studies have systematically applied and compared ML methods to derive PA proteomic signatures. The objective of this research is to enhance our understanding of PA, proteomics, and how they relate to ADRD. I propose leveraging an NIA-funded study (RF1AG079149) that will use the SOMAscan platform to measure ~7,000 clinically relevant plasma proteins and plasma AD biomarkers in a case cohort of 2,836 (n=1,336 incident MCI/ADRD cases) women in the richly phenotyped and racially/ethnically diverse Women’s Health Initiative (WHI) Memory Study (WHIMS) from samples collected in 1995-1998 (n=2,836) and 14-18 years later in 2012-2013 (n=1,000; 500 incident MCI/ADRD cases) and the WHI Objective Physical Activity and Cardiovascular Health (OPACH; R01HL105065) study which collected accelerometry in 2012-2014 among 6,489 women, including the 1,000 WHIMS women in RF1AG079149. WHIMS contains longitudinal annual cognitive assessments and rigorously adjudicated MCI/dementia over 27 years of follow-up. In the R00 phase, I propose obtaining plasma biomarkers of AD pathology from 600 Black and Hispanic/Latina OPACH women. Study results will be replicated in the Atherosclerosis Risk in Communities study to extend findings to men and women. Our Aims are: (1a) Apply and compare ML methods to derive PA proteomic signatures, (1b) Examine the overlap of PA proteomic signatures, proteomic aging clocks, and ADRD proteomic clocks, (1c) Relate PA proteomic signatures with MCI/ADRD and cognitive functioning, (2) Determine the role of PA-associated plasma proteins in our observed PA-MCI/ADRD associations, and (3) Determine the associations of PA (self-reported and accelerometer-measured) and PA- associated plasma proteins with plasma AD biomarkers among Black, Hispanic/Latina, and White women. This research will advance understanding of the molecular mechanisms linking PA, aging, and ADRD. The addition of plasma AD biomarker data to OPACH will have an enduring impact by enabling broader studies of accelerometry and AD pathology in relation to aging-related phenotypes.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT With each inhalation, exhalation and across development, maturation, aging and pathogenesis, the lung is constantly under mechanical tension. How the biophysical force is sensed and responded to remains poorly understood. In the gas exchange region that bears the front of this force, tension is distributed across the vast alveolar surface. In this study, we will investigate the central premise that mechanical tension, sensed by alveolar epithelial cells, triggers a molecular feedback loop that drives the generation and regeneration of the gas exchange surface area. At the center of this feedback loop is Piezo, a large membrane localized channel that is a quintessential mechanosensor. First discovered and studied in neurons, Piezo genes are also widely expressed in the lung. Our preliminary data show that while loss of Piezo genes in the lung mesenchyme or the endothelium did not lead to discernable alveolar structural defects, inactivating these genes, especially Piezo2, in the lung epithelium led to alveolar simplification in the early postnatal lung. In the adult lung, Piezo2 loss in the alveolar epithelium led to drastically increased susceptibility to alveolar damage, leading to fibrosis. In this study, we will investigate the nature of this mechanosensory circuit in development (Aim 1) and injury repair (Aim 2). The findings will advance our knowledge on how mechanosensation could tune the size and composition of the alveolar surface.