Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2022-05

Project Summary Population cohort studies funded by the National Institute of Health, including the Atherosclerosis Risk in Com- munities (ARIC) Study and Multi-Ethnic Study of Atherosclerosis (MESA), are widely used in cardiovascular research and have provided fundamental knowledge for cardiovascular disease (CVD) prevention strategies and public health policies. Pooling data across multiple cohorts provides a unique opportunity for in-depth investiga- tions of emerging CVD research questions, such as optimal blood pressure threshold values triggering initiation of antihypertensive treatment for young adults, that heretofore would not have been possible. While forming a fertile ground for innovative research, the methodological issues associated with the pooled cohorts data cannot be as effectively addressed by existing statistical methods. There are three main analytic challenges. First, many discrete or continuous longitudinal variables have missing values with various missing data patterns. Existing methods either are susceptible to misspecification biases or do not provide coherent estimates of imputation un- certainty, and cannot handle missing not at random. Second, current causal inference methods either require aligned measurement time points or parametric assumptions about forms of causal pathways, neither of which can be satisfied in complex longitudinal health data. Third, violations of the “sequential ignorability” assumption embedded in causal inference methodology can be a potential source of bias. The sensitivity analysis methods for time-varying confounding with censored survival outcomes are underdeveloped. To overcome these chal- lenges and improve statistical and CVD research, we propose a suite of generalizable statistical methods utilizing machine learning. We propose to develop a scalable Bayesian nonparametric (BNP) framework to impute con- tinuous or discrete missing at random longitudinal covariates while providing coherent uncertainty intervals, and address the missing not at random mechanism via sensitivity analysis. We will apply the developed method to address missing data issues for several longitudinal CVD risk factors such as blood pressure, cholesterol levels (Specific Aim 1); to develop a robust and computationally efficient BNP causal inference method (Specific Aim 2) and a new continuous-time marginal structural survival model from a Bayesian perspective (Specific Aim 3) to study and validate the survival effects of time-varying antihypertensive treatments for young adults and the frail elderly; to develop a flexible and interpretable survival sensitivity analysis method to assess the sensitivity of the causal effect estimates to varying degrees of sequential unmeasured confounding (Specific Aim 4); and to create usable R software packages for all proposed methods and develop tutorial papers and short courses to bridge theoretical and practical knowledge and promote use of our methods (Specific Aim 5).

NIH Research Projects · FY 2025 · 2022-04

Obesity, a long-standing pandemic in the United States, is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common chronic liver disease globally, affecting about one third of adults, for which there is no approved medication. The first stage of NAFLD is steatosis (fatty liver), a condition that can progress to non-alcoholic steatohepatitis (NASH) where fat accumulation in the liver is associated with inflammation, fibrosis and scarring, resulting in the eventual loss of liver function. There is therefore a dire need to understand the molecular mechanisms underlying the development of fatty liver and NASH to create the first identified targets for medication. The liver produces a peptide known as kisspeptin (KP), that signals by binding a G protein-coupled receptor, the kisspeptin 1 receptor (KISS1R) expressed in the liver. The metabolic functions of KISS1R signaling in the liver, however, are not known. We found that hepatic KP/KISS1R expression are upregulated in high fat diet induced mouse model of NAFLD. We also observed that when mice lacking hepatic KISS1R were challenged with high fat diet-feeding, they showed increased hepatic steatosis, insulin resistance, and an upregulation of inflammatory and fibrosis markers, compared to controls on the same diet. Taken together, this data led us to hypothesize that hepatic KISS1R activation suppresses hepatic lipogenesis thus limiting fat accumulation and NASH development. The proposed work will decipher the mechanisms by which KISS1R signaling inhibits fatty liver and NASH. In Aim 1, we will investigate the mechanisms by which hepatic KISS1R signaling modulates hepatic lipid levels by inhibiting lipogenesis. In Aim 2, we will assess the impact of enhancing KISS1R signaling on the development of NAFLD. In Aim 3, we will study the clinical relevance of KP/KISS1R signaling pathway by measuring plasma KP levels in healthy subjects, NAFLD and NASH patients and assess whether plasma KP levels correlate with metabolic disease severity and other anthropometric, laboratory, radiographic and demographic features. Additionally, the expression and localization of hepatic KISS1R in NAFLD/NASH liver biopsies will be examined. Understanding this knowledge is important because it will shed light on using the KISS1R signaling pathway as a potential avenue to develop a novel pharmacological approach to reduce NAFLD and NASH.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Skin cancer is the most common cancer in the United States (US). Melanoma is the deadliest form of skin cancer. In the past two decades, melanoma incidence among Hispanics has risen by 20%. The mortality rate of Hispanics is higher compared to Non-Hispanic whites (NHW). In general, compared to NHW, Hispanics diagnosed with melanoma are younger, have thicker tumors, and have worse survival rates. Skin cancer can be prevented with regular sun protection, and early detection can improve skin cancer outcomes. The Hispanic population is the fastest growing ethnic group in the US. Alarmingly, Hispanics are less aware of the symptoms and harms of skin cancers, tend to have misperceptions regarding the risks and benefits of skin cancer prevention behaviors, engage in less sun protection behaviors than NHW, and only 18% of them reported ever having done a skin self-examination. In addition, due to the increase of acculturation of Hispanics in the US, their sun-safety behaviors are poorer than non-US Hispanics. Occupational exposure to ultraviolet radiation (UVR) is a risk factor for skin cancer, and Hispanic individuals are over-represented in a number of outdoor occupations. Approximately 21% of the 2018 US Hispanic workforce were employed in industries that involved significant amounts of occupational UVR exposure such as construction. Therefore, an increasing effort to raise awareness regarding sun protection and skin self-examination behaviors is needed to address the existing gap of skin cancer research among Hispanics. This research project seeks to develop a mobile-based and user-centered intervention to promote sun protection and skin self-examination among a diverse sample of Hispanics using an iterative approach to capture relevant contextual issues and evaluate the preliminary effects of the intervention. During the K99 phase, I will: 1) collect, analyze, and triangulate data from the Hispanic community and other stakeholders (e.g., health care providers and community leaders) for skin cancer digital intervention development; and 2) through a user- centered approach, develop an innovative WhatsApp intervention to promote skin cancer-related health behaviors among Hispanics to improve participants’ engagement in the intervention. During the R00 phase, I will: 3) evaluate the feasibility and acceptability of this mobile intervention in a pre-, post-test study among Hispanics at risk for skin cancer; and 4) refine the intervention and conduct a pilot randomized controlled trial using this mobile service among Hispanics at risk for skin cancers and assess the preliminary effects of the mobile intervention at post-intervention and 6-month follow-up. The intervention has strong potential for cost- effective, widespread dissemination and targets an understudied group at-risk for future cancer development. The training experiences and mentoring obtained during this K99/R00 project are critical foundations for a successful independent cancer research career.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Screening with low-dose CT (LDCT) scans reduces lung cancer mortality. However, the potential harms associated with screening include false-negative and false-positive results, incidental findings, overdiagnosis, radiation exposure, and complications from invasive diagnostic procedures and treatments. Given the complexity of lung cancer screening (LCS) decisions, the United States Preventive Services Task Force strongly recommends that patients receive counseling about smoking cessation and shared decision-making (SDM) with a health care provider before being referred for LDCT. The SDM discussion about LCS should address the benefits and harms of screening, the importance of adhering to annual lung cancer LDCT screening and recommended diagnostic testing and treatment, and tobacco avoidance. Yet, there is uncertainty about how to most effectively engage patients in SDM for LCS. Both patients and primary care clinicians perceive important barriers to LCS decision making and accessing health service. When screening discussions are conducted, they often fail to meet expectations for SDM. We propose to address these deficiencies by implementing a workflow aware telemedicine SDM intervention that includes decision coaching and patient navigation that is a potentially scalable and efficient approach to meeting national screening recommendations. The study’s long-term goal is to reduce disparities and the burden of lung cancer among heavy smokers by supporting high-quality decision making about LCS and smoking cessation and abstinence. Our short-term goal is to identify an effective intervention that can readily be implemented in real-world primary care settings to support high-quality SDM in racially and ethnically diverse populations. We will conduct an effectiveness-implementation hybrid type I trial guided by the Practical, Robust Implementation and Sustainability Model (PRISM). A cluster randomized trial design including 40 primary care practices, 100 providers and 400 patients will evaluate whether a telemedicine decision coaching and navigation intervention (TELESCOPE) compared to enhanced usual care (EUC) will improve the quality of decision making, increase adherence with screening and diagnostic testing, and generate more referrals for smoking cessation. The specific aims are to: 1) Test the effectiveness of a decision coaching intervention for LCS delivered by nurse navigators vs. EUC on the quality of patient decision making about LCS, subsequent screening and diagnostic testing, and smoking cessation referrals for current smokers; 2) Evaluate the implementation potential of navigator-led decision coaching for LCS; and 3) Determine the resources and costs required to implement the navigator-led decision coaching intervention for LCS. This highly impactful research has the potential to greatly advance the field of SDM implementation and improve quality of care by providing patients with high-quality decision support about LCS, testing feasible strategies for busy PCPs to support SDM for their high-risk patients, and demonstrating for policy makers and payors new models for effective delivery of SDM for LCS.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT With incidence rates more than tripling in the last 45 years, the population of melanoma survivors in the US is estimated at more than a million persons. Survivors are at elevated risk for recurrence and new primary cancers. Most recurrent melanomas are found by survivors themselves, which is why physicians educate survivors about the importance of regular, thorough skin self-exams (SSE) and why professional guidelines for follow-up surveillance recommend regular, thorough (SSE). More than two thirds of melanoma survivors do not perform regular, thorough SSE. To address this significant problem, our experienced team developed a digital intervention, called mySmartSkin (MSS), and tested it in an RCT against usual care in New Jersey. MSS illustrated promising effects on thorough SSE. In this application, we propose to prepare MSS for large-scale dissemination using an innovative Type 1 hybrid effectiveness-implementation trial. A Type 1 hybrid effectiveness-implementation design allows us to engage multilevel stakeholders throughout the research process, evaluate the effectiveness of the enhanced MSS, and identify critical factors for wide-scale implementation. The study’s three aims are guided by implementation frameworks and behavior change theories. In Aim 1, we will enhance MSS using multi-level stakeholder engagement by collaborating with key stakeholders in enhancing MSS through qualitative interviews and usability testing of potential enhancements. Potential enhancements are based on empirically-validated behavior change techniques (BCTs) and findings from our prior study. We will utilize an iterative process that includes key informant interviews with survivors, providers, and relevant professional organizations regarding proposed enhancements, conversion to an enhanced mobile-based intervention delivery platform, usability testing with survivors, and iterative program refinements. Aim 2 compares the effects of enhanced MSS vs. a non-interactive educational webpage on comprehensive SSE in an RCT with survivors recruited through two state cancer registries and social media (N=300). In Aim 3, we identify factors relevant to future scale-up for widespread dissemination and implementation using mixed methods to assess selected implementation outcomes from the RCT and explore perspectives from survivors, care providers, and professional organizations about how to best disseminate and implement MSS on a broad scale. We will estimate program costs and assess cost-effectiveness of MSS. This project addresses a documented gap in care for melanoma survivors by enhancing effects of a promising survivor-facing intervention and proactively identifying barriers and facilitators to future implementation. We innovatively “design for dissemination” by ensuring that enhancements are designed with the target population of potential users. Serving as a model for optimizing promising fully-automated online interventions for cancer survivors for dissemination, this project will provide important information about potentially cost-effective ways to reach survivors as well as about how to adapt such an intervention for dissemination.

NIH Research Projects · FY 2026 · 2022-03

Populations at elevated risk for HIV in the U.S. continue to experience a high and disproportionate burden, particularly younger groups for whom HIV incidence continues to rise despite advances in HIV prevention. Evidence suggests that differences in individual risk behaviors do not fully explain variations in HIV outcomes and underscore the need to move beyond models of individual-level risk factors to identify and intervene upon the broader contextual factors that shape risk environments. However, much of the research to date is limited in scope and focuses on cross-sectional HIV prevalence, which limits the ability to treat contextual factors as dynamic or to investigate the environments within which risk behaviors occur. We propose to enroll a cohort of approximately 5,500 individuals ages 16 and older in the U.S. who are at higher risk for HIV infection. We will use a combined approach to recruitment that is adaptive to known shifts in digital technology. Participants will complete a survey and home-based sampling for lab-based HIV testing at enrollment and annually thereafter for three years and an ecological momentary assessment (EMA) for six weeks after enrollment. Concordant with study enrollment, we will develop novel metrics to quantify contextual factors (state-level regulatory and social environment indicators) that may influence HIV vulnerability (Aim 1a). We will subsequently utilize the newly developed metrics from Aim 1a along with local contextual factors (local-level HIV prevalence and socioeconomic indicators) and baseline and EMA data to test the hypothesis that broader environmental influences contribute to HIV risk—this hypothesis will specifically test both the impact of contextual factors on daily exposures and the interaction of environmental influences with individual behaviors on undiagnosed HIV infection at baseline (Aim 2). These data will also be used to test a longitudinal model of mechanisms through which state and local contextual factors directly and indirectly influence HIV seroconversion and access to emerging HIV prevention technologies (e.g., emerging PrEP modalities) (Aim 3). Study findings will be systematically reviewed and translated into practical recommendations for Ending the HIV Epidemic–related public health strategies and community-level interventions (Aim 1b). Developing and testing a contextual model of HIV risk has strong potential to improve the next generation of HIV prevention interventions aimed at reducing HIV incidence in the U.S.

NIH Research Projects · FY 2026 · 2022-03

PROJECT SUMMARY Paneth cells are crypt-localized secretory intestinal epithelial cells (IECs) that play important functions in regulating gut mucosal immunology, microbial community, and intestinal stem cell homeostasis. Prevalent loss or reduced Paneth cell number and their secretory granules are found in numerous human intestinal diseases, including inflammatory bowel disease, graft-versus-host disease, necrotizing enterocolitis, as well as pathologies triggered by infection or environmental risk factors related with smoking and diets. Lower numbers of Paneth cells often link to severity of disease, lower therapeutic response, and higher mortality due to non-relapse causes, or more rapid disease recurrence after surgery. A correlation between Paneth cell loss and excessive oxidative stress faced by the gut tissue has been speculated in recent studies, but a direct causation has not been established. Specifically, how Paneth cells respond to and manage non-physiological oxidative stress is not understood, but of high importance for mucosal innate defense and gut health. We found high oxidative tolerance in a subset of Paneth cells that possess an enhanced antioxidant network leading to cell-autonomous protection, survival, and support of the overall mucosal innate defense against lethal infection. Conversely, impairment of Paneth cell-specific oxygen species production or management system causes substantial oxidative damage and death to adjacent proliferating epithelial cells, leading to detrimental epithelial dysplasia, barrier defect and inflammation. We hypothesize that an intrinsic redox management program in a subset of Paneth cells promotes high oxidative tolerating capability, survival, and overall protection against oxidative stressors. Harnessing these mechanisms will help restore healthy Paneth cells that will in turn enhance gut innate defense and intestinal health. The proposed two aims will use live enteroid imaging, genetic cell lineage tracing, and multimodality omics analysis to determine the physiological regulation of heterogeneous response to oxidative stress in different Paneth cell populations and use genetically engineered mice to test newly identified antioxidant pathways in Paneth cells. Importantly, results from this project will reveal molecular mechanisms for the widely observed Paneth cell loss and degranulation across human intestinal inflammatory diseases. Thorough determination of redox management in Paneth cells can be leveraged to restore functional Paneth cell populations, which will contribute to IEC renewal, mucosal immunology, and gut health. Feasibility with meaningful outcomes has high probability becaue the group has not only engineered the Paneth cell reporter mice but also developed aged and gnotobiotic colonies of these mice, allowing for mechanistic research into physiological and pathological oxidative stressors.

NIH Research Projects · FY 2025 · 2022-03

Shaping the Indications for Periodontal Adjunctive Antibiotics in dental practice: A PBRN Clinical Trial Periodontitis is a bacterial inflammatory disease that has been reported to affect nearly 40% of Americans aged 30 years or older. If left untreated, periodontitis can lead to tooth loss and patient-perceived morbidity. Historically, antibiotic use has been an integral part of periodontal disease treatment. However, antibiotic stewardship calls for rationalizing their prescription to reduce antibiotic misuse and development of resistant strains. Across medical disciplines, there is a clear direction to identify individuals who in fact may benefit from antibiotic use and to provide guidelines for their use. As of 2018, the American Dental Association has developed evidence-based guidelines limiting circumstances for prophylactic antibiotic use in dental practice; however, no national guidelines exist for antibiotic use in treatment of periodontal infections because of lack of adequately powered trials assessing disease- and person-specific indications. Thus, dentists are left to decide when adjunctive antibiotics are indicated, and which dental patients need them to achieve periodontal health. In the context of periodontitis treatment, a biological rationale exists to support adjunctive antibiotic use against periodontal pathogenic bacteria, but clinical results of their use have presented conflicting results. Currently, very limited documentation of the prescription patterns and utilization of antibiotics as periodontal treatment adjuncts among US practitioners exist. Nonetheless, data from academic studies suggest that adjunctive systemic antibiotics may only be beneficial for certain populations, as the biological response to treatment is highly variable across individuals. This marked variability warrants the identification of person- and/or disease-related characteristics that are linked to maximum benefit from adjunctive antibiotic treatment. Consequently, clear guidelines can then be established for tailored indications for their use with the ultimate goal of minimizing antibiotic misuse in periodontal treatment to avoid development of antibiotic resistance. The objective of this study is to assess the effectiveness of adjunctive Amoxicillin/Metronidazole combination antibiotics to non-surgical periodontal therapy in clinical practices within the National Dental PBRN by conducting the largest randomized clinical trial (RCT) of adjunctive antibiotics. Further, within this PBRN study, current decision-making factors for adjunctive antibiotic prescription will be surveyed to assess the state of affairs in clinical practice. Importantly, leveraging the well-powered RCT dataset, high responders to adjunctive antibiotic treatment will be identified and the predictive validity of decision-making factors currently employed by clinicians will be assessed to develop clear indications for prescription. Collectively, results of adjunctive antibiotic use at present are ambiguous because indications are based on empirical information without evidence-based guidelines, which may lead to antibiotic misuse and lack of efficacy. The present pragmatic well-powered RCT was designed to enable the development of evidence-based guidelines for periodontal adjunctive antibiotic use.

NIH Research Projects · FY 2026 · 2022-02

ABSTRACT Uncontrolled inflammation is central to the pathophysiology of asthma and COPD which can develop following chronic exposure to ozone. Evidence suggests that these pathologies are due to an inability to adequately resolve the acute inflammatory response to lung injury. This suggests that promoting the resolution of inflammation will be more beneficial than suppressing persistent unrestrained inflammation. Our studies are focused on macrophages which play a key role in both initiating and resolving inflammatory responses to tissue injury. This activity is mediated by distinct subsets broadly classified as proinflammatory M1 and proresolution M2 macrophages. Effective resolution of inflammation depends on metabolic reprogramming of macrophages from an M1 phenotype to an M2 phenotype, which involves a switch from glycolysis to oxidative phosphorylation as a source of energy. We discovered that this reprogramming is suppressed following chronic ozone exposure. The goal of our studies is to analyze mechanisms underlying suppression of macrophage reprogramming. In recent studies we identified farnesoid-X receptor (FXR), a nuclear receptor important in bile acid metabolism, with anti-inflammatory activity, as important in promoting M1 to M2 macrophage reprogramming in the lung. Following ozone exposure, macrophage FXR activity is downregulated. This is associated with increased activity of proinflammatory M1 macrophages and reduced activity of proresolving M2 macrophages. We also found that microRNAs that regulate the proinflammatory transcription factor NFκB are dysregulated in macrophages after ozone exposure. As a consequence, there is protracted activation of NFκB signaling resulting in increased production of TNFα, IL-1β, and cytotoxic reactive nitrogen species. We hypothesize that these mediators suppress FXR activity which prevents activation of the nuclear receptor NR4A1, a key inducer of macrophage M1 to M2 metabolic reprogramming. To test this hypothesis, we will (1) Determine if persistent inflammation following chronic ozone exposure and the development of lung disease is due to defective development of proresolution M2 macrophages, and assess whether this is caused by protracted activation of NFκB in M1 macrophages; (2) Analyze the role of FXR and its target NR4A1, in the development of proresolution M2 macrophages in the lung following chronic ozone exposure; and (3) Determine if protracted activation of NFκB is due to ozone-induced alterations in microRNAs regulating NFκB. Results of these studies will provide new mechanistic insights into chronic ozone toxicity and may lead to the development of new approaches for thwarting the development of chronic lung disease.

NIH Research Projects · FY 2025 · 2022-02

Although smoking prevalence has decreased, more than 34 million Americans continue to smoke. Disenfranchised groups increasingly comprise the remaining smoking population, and cigarette relighters may be some of the most disenfranchised (e.g., low socioeconomic status). Relighting refers to extinguishing, saving, and later relighting unfinished cigarettes. Research suggests this is a prevalent behavior engaged in by 44-73% of smokers, with 17-21% of smokers reporting they relight ‘usually’ or ‘frequently’, thus impacting millions of Americans. Apparent reasons for relighting include cost, perceived benefits for health and cessation, and smoking bans. This behavior may increase harms to smokers such as lung cancer and chronic bronchitis. For example, relighting could contribute to worse cessation and health outcomes if relighters (who tend to be highly nicotine-dependent) have lower motivation toward total abstinence because they believe they are minimizing the amount they smoke. They may also be inadequately treated and advised by clinicians because they appear to be less dependent or smoke fewer numbers of cigarettes per day (CPD) compared to non-relighters, despite a greater number of smoking sessions per day and exposure to toxicants. This could lead to under-dosing of pharmacotherapy. Given that reasons for relighting include the increasing cost of cigarettes, prevalence of relighting may grow in the future (especially during this economic crisis) and may continue to impact disproportionately those with greater existing tobacco-related disparities. More research is needed to address these challenges by investigating who relights and why, and potential effects of relighting on tobacco dependence, cessation, and health. Understanding relighting is critical because: 1) current assessments (i.e., CPD) may underestimate toxicant exposure and nicotine dependence among relighters and 2) if relighting continues to be largely ignored by providers, a high proportion of smokers may be undertreated. Specific aims of this four-year project are to: 1) Establish criteria and reasons for, as well as prevalence, frequency, and correlates of relighting in a national survey; 2) Evaluate potential toxic effects of relighting using topography and toxicant analyses; 3) Investigate the potential impact of relighting by observing tobacco treatment and outcomes of relighters in a state-wide tobacco treatment program. Preliminary studies need to be replicated and extended to be more rigorous, comprehensive, and on a larger scale to address numerous remaining questions that would lay the groundwork for understanding the individual and public health impact of relighting. This study will provide important information about the extent, frequency, contextual factors, and potential dangers of this understudied behavior. The study has implications for both surveillance and treatment such as new measures to screen for relighting clinically and in population surveys as well as potentially informing clinicians in prescribing appropriate-intensity treatments for relighters. Together, data from the proposed specific aims will provide a clearer picture of the extent and impact of cigarette relighting.

NIH Research Projects · FY 2026 · 2022-02

Project Summary: Tyro3, Axl, and Mertk (abbreviated TAM receptors) are a family of homologous type I Receptor Tyrosine Kinases (RTKs) that have homeostatic functions under physiological conditions to dampen inflammation and maintain tissue tolerance in multi-cellular organisms. The ligands for TAMs are two vitamin K- modified proteins, Growth arrest specific factor 6 (Gas6) and Protein S (Pros1) that bind phosphatidylserine (PS) on apoptotic cells, and in doing so, act as bridging molecules to facilitate the clearance of apoptotic cells (efferocytosis). While PS-mediated efferocytosis, most emblematically via Mertk expressed on macrophages, have important homeostatic functions to prevent chronic inflammation and autoimmunity, the constitutively externalized PS that occurs in the tumor microenvironment (TME) of solid cancers, in combination with the expression of Mertk on infiltrating macrophages, patho-physiologically subvert PS- mediated tolerogenic functions to suppress host anti- tumor immune responses. The central hypothesis in this application is that constitutively dys- regulated PS externalization observed in the TME, in combination with the infiltration of Mertk-expressing macrophages, act as an important immune inhibitory axis to suppress host anti- tumor immunity. This axis is likely to be activated in a wide range of solid cancers for immune escape, but also may represent vulnerability in cancer if effectively targeted by therapeutics. In this application, we outline mechanistic experiments to identify how externalized PS is dysregulated in the TME (aim #1) as well as determine the mechanisms by which Mertk acts as an inhibitory receptor on macrophages to suppress host anti-tumor immunity and tolerance (aim #2). In aim #3, we propose a series of pre-clinical therapeutic mouse studies to test combinations of a first- in-class anti-Mertk neutralizing mAb in combination with anti-PD1 mAb, as well as explore and validate the biology of Mertk as an inhibitory receptor using human models. Collectively, our studies aim to open up new avenues to interrogate a novel type of checkpoint inhibitory network in immuno-oncology.

NIH Research Projects · FY 2026 · 2022-02

Abstract: Although often overlooked as a significant health problem, pulmonary infections with fungal pathogens present a clinical problem of growing concern. Aspergillus fumigatus (Af) and Cryptococcus neoformans (Cn) are two clinically important fungal pathogens that affect immunosuppressed patients worldwide. Both infections are difficult to treat and are associated with high mortality rates. A better understanding of immune mechanisms of host defense against fungi hold the promise of providing the basis for the future development of novel, immune based interventions to improve patient outcomes. Pulmonary macrophages are critical, front-line mediators of host protection against fungi and other pulmonary pathogens. Despite the well-defined role of lung macrophages as crucial initiators of immunity to diverse sets of pathogens, our understanding of how previous infection history shapes subsequent macrophage responses to fungal infection in the lung remain poorly defined. Moreover, an emerging body of literature has now revealed that macrophage populations in the lung are more heterogeneous than originally appreciated and can undergo innate training; an enhanced response to diverse secondary challenges. It is now also understood that alveolar macrophages present in the lung can originate from embryonic precursors (tissue-derived alveolar macrophages-TD-AMs) or from blood monocytes (monocyte-derived alveolar macrophages-Mo-AMs). Whether TD-AM and Mo-AM are equally capable of undergoing innate training is currently unclear. It is also unknown whether innate training is a conserved response to any infectious stimuli or regulated by specific pathways. In preliminary studies, we uncovered that priming with an immunogenic strain of Cn (HK-fbp1) could confer heterologous protection against infection with Af even in the context of drug-induced immunosuppression and in a T cell-independent manner. Preliminary data gathered, suggest that neutrophils and STAT1-dependent signals are important regulators of antifungal monocytes and their differentiation into monocyte-derived cells. Based on our aggregate observations, the central hypothesis of this project is that: CCR2+mo are critical mediators of antifungal immunity and can be instructed by HK-fbp1 into trained mo-AM via the coordinated actions of neutrophils and an interferon (IFN) cascade. We will address two related but independent aims: Aim 1: Investigate the impact of HK-fbp1 immunization to pulmonary innate cell priming and training to promote antifungal immunity; Aim 2: Decipher the contributions of neutrophils in the regulation of antifungal trained immunity.

NIH Research Projects · FY 2026 · 2022-02

ABSTRACT The development of acute kidney (AKI) injury in hospitalized patients may be catastrophic. In general, the in- hospital mortality rate for patients with AKI has been estimated between 20% to 25%. AKI prolongs hospitalization, increases costs, and requires the utilization of additional resources. Drugs are implicated in roughly one-quarter of hospitalized patients who develop AKI, and roughly half of the cases are related to antibiotics. While broad spectrum antibiotics are essential to treat infections, they carry risk. Clinicians can alter modifiable risk factors, but many patients are inherently at an increased risk of AKI. The exact molecular mechanisms of antibiotic induced AKI are unclear, but emerging data supports oxidative stress and mitochondrial dysfunction. Melatonin, a hormonal dietary supplement, has antioxidant properties via the nuclear factor erythroid 2–related factor 2 (NRF2) pathway and can also restore mitochondrial bioenergetics. As such, melatonin is an attractive option for kidney protection. This proposal will test the hypothesis that melatonin reduces the risk of antibiotic-associated AKI through activation of the NRF2 transcriptional pathway and balancing of mitochondrial function and bioenergetics. To test this hypothesis, we propose a translational strategy to investigate mechanism and efficacy in parallel. First, in our in vitro studies, we will expose human renal proximal tubule (RPT) cells to nephrotoxic antibiotics in the presence /absence of melatonin. RPT cells will include control cells as well as those with disrupted NRF2 and KEAP1 function. Analyses will include 1) targeted biomarkers of mitochondrial/cellular health and 2) transcriptomics to identify complementary and alternative reno-protective pathways. Next, we will enroll 300 hospitalized patients prescribed vancomycin and piperacillin-tazobactam and randomize them 1:1 to melatonin 5 mg or matched placebo. Whole blood will be analyzed for gene expression (NRF2/KEAP1) and plasma to evaluate antibiotic and melatonin biodistribution. Further, traditional and novel biomarkers of kidney injury and mitochondrial stress will be assessed. The studies described in the two aims will provide evidence to support the use of melatonin and provide evidence of the mechanism.

NIH Research Projects · FY 2026 · 2022-02

Project Summary Leukemia inhibitory factor (LIF) is a multi-functional cytokine. Our previous studies reveal that LIF is a direct target gene of tumor suppressor p53 and mediates the function of p53 in maternal reproduction, and at the same time, LIF forms a negative feedback loop with p53 to inhibit p53 function in tumor suppression. LIF has a complex role in tumorigenesis; LIF has been reported to suppress or promote tumorigenesis in different types of cancers. Emerging evidence, including ours, has shown that LIF is frequently overexpressed in colorectal cancer (CRC). Further, LIF overexpression is often associated with poor prognosis in CRC patients. These observations strongly suggest a critical role of LIF in promoting colorectal tumorigenesis. Currently, the precise role and mechanism of LIF in colorectal tumorigenesis are poorly defined. Colorectal tumor-initiating stem-like cells (TICs) play a critical role in CRC initiation, progression and resistance to therapy. Eliminating TICs has been actively tested as a therapeutic strategy for CRC. Our recent study shows that LIF is present in the intestinal stem cells (ISC) niche and is essential to maintain ISC number and functions. Oncogenic activation in ISCs plays a critical role in the initiation of CRC. Our preliminary studies further suggest that LIF drives lipid metabolic reprogramming of colorectal TICs as an important mechanism whereby LIF promotes colorectal TIC number and functions. These findings prompt us to hypothesize that LIF is essential for colorectal TIC number and functions, which in turn promotes colorectal tumorigenesis. We further hypothesize that targeting LIF and LIF-driven metabolic reprogramming can suppress colorectal TICs and inhibit colorectal tumorigenesis. In this proposed study, we will determine the role of LIF in colorectal tumorigenesis and colorectal TIC number and functions by using different mouse models (Aim 1). We will determine whether increasing colorectal TIC number and functions through LIF-driven lipid metabolic reprograming is a critical mechanism whereby LIF promotes colorectal tumorigenesis. We will investigate whether LIF regulates the levels and activities of critical transcription factors involved in lipid metabolism in colorectal TICs, including p53, to drive lipid metabolic reprogramming (Aim 2A). We will further test whether the LIF-driven metabolic reprogramming can be targeted for CRC therapy (Aim 2B). The goal of this study is to elucidate the role and mechanism of LIF in CRC, and assess whether targeting LIF-driven lipid metabolic reprogramming is an effective strategy to eliminate TICs and treat CRC with LIF overexpression. If accomplished successfully, this study will establish the critical role of LIF in CRC, reveal its underlying mechanisms, and provide the rationale and base for the development of new therapeutic targets and strategies for CRC with LIF overexpression.

NIH Research Projects · FY 2025 · 2022-01

PROJECT SUMMARY The aortic arch artery and its branches are blood vessels that route the oxygenated blood from the heart to the systemic circulation. Defects in the development of the aortic arch artery lead to lethal forms of congenital heart disease (CHD) due to interruption(s) in the systemic circulation, for example, the interrupted aortic arch type B (IAA-B). These defects often occur in conjunction with 22q11 deletion syndrome, the most common congenital chromosomal abnormality syndrome in humans. Therefore, understanding genes and mechanisms regulating the development of the aortic arch artery will provide valuable insights into CHD etiology and potential treatments. Aortic arch artery and its branches form following the remodeling of the symmetrical pharyngeal arch arteries (PAAs) into the asymmetrical vascular tree. We demonstrated that the PAA endothelium is mainly derived from progenitors in the second heart field (SHF). Furthermore, we found that genetic mutations resulting in the deficiency in the SHF-derived endothelium cause IAA-B. This grant application describes two new mouse models in which an unexpected source of endothelial progenitors repairs the deficiency in the SHF- derived endothelial cells (ECs) and rescues aortic arch artery formation. Our discovery of an alternative endothelial source that repairs PAA defects has opened the possibility to determine mechanisms regulating this compensatory repair process. We also discovered that the compensatory endothelium is not recruited in the Tbx1+/- mouse model of 22q11 deletion syndrome, resulting in IAA-B and neonatal lethality in ~65% of Tbx1+/- mice. In this grant application, we propose to determine the source of compensating ECs, mechanisms regulating the recruitment of compensatory endothelium, and how Tbx1 regulates this process. To accomplish these goals, we propose the following Specific Aims: 1 To test the hypothesis that the compensating endothelium is derived from a vein, and 2 To determine signals regulating the recruitment of the compensatory ECs to rescue arch artery formation. In this proposal, we will use novel mouse strains, genetic engineering, quantitative 3D confocal imaging, in situ hybridization, and RNAseq to uncover candidate genes regulating the compensatory response. Upon completing the proposed work, we will uncover innate mechanisms of compensation and robustness, whereby a newborn's viability is ensured through alternative mechanisms. Harnessing these mechanisms would provide new opportunities for treatments of CHD in the future.

NIH Research Projects · FY 2025 · 2022-01

Project Summary The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. There is no vaccine or antiviral available for SARS-CoV-2. In this grant, we propose to develop dual inhibitors targeting viral main protease and cathepsin L as SARS-CoV-2 antivirals. Using the FRET-based enzymatic assay, we recently identified several inhibitors including boceprevir, GC-376, and calpain inhibitors II and XII, that have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. Significantly, all four compounds inhibit infectious SARS-CoV-2 replication in cell culture with EC50 values ranging from 0.5 to 3.4 µM. Overall, the compounds identified provide promising starting points for the further development of SARS-CoV-2 therapeutics. Our discovery of calpain inhibitor II as a potent inhibitor against SARS-CoV-2 is innovative as it suggests it might be feasible to develop SARS-CoV-2 antivirals by simultaneously targeting both viral Mpro and host cathepsin L, both of which are essential for viral replication. Compared to recently reported Mpro inhibitors, the hits identified from our study represent the most potent and selective drug candidates with a novel mechanism of action, therefore warranting further development. Given our encouraging preliminary data, we propose to optimize dual inhibitors as SARS-CoV-2 antivirals. The objective of this proposal is to develop dual inhibitors as potent SARS-CoV-2 antivirals with high potency, selectivity, favorable pharmacokinetic properties, as well as broad-spectrum antiviral activity against closely related coronaviruses such as SARS and Middle East respiratory syndrome (MERS) coronaviruses. Our goals of this grant are to identify additional dual inhibitors through both high-throughput screening and structure-based lead optimization of our recently identified dual inhibitors. By targeting the SARS-CoV-2 Mpro, the expected outcomes of the proposed research are broad-acting coronavirus antivirals with a confirmed mechanism of action, a high selectivity index, and favorable in vitro pharmacokinetic properties that are ready for in vivo antiviral efficacy testing in relevant animal models. Overall, this grant is based on strong preliminary data and our expertise in developing antivirals targeting cysteine proteases.

NIH Research Projects · FY 2025 · 2022-01

Project Summary Human Cytomegalovirus (HCMV) is a herpesvirus whose seroprevalence and disease burden remain high worldwide. While disease is often mild in immunocompetent individuals, it is often severe for immunocompromised individuals, and congenital infection remains a leading cause of birth defects. There is currently no vaccine or permanent effective anti-viral therapy against HCMV. The host enzyme telomerase, which maintains telomeres to protect the integrity of DNA, is key for cell survival and has been implicated in several diseases including cancer. Telomerase has been implicated as an important agent in the life cycles and potential oncogenic activity of several herpesviruses, and recently has been shown to be hyperactive in response to active HCMV infection. Furthermore, telomerase inhibition has been associated with a significant reduction of viral infectivity in laboratory and clinical strains of HCMV. However, the significance of telomerase in the HCMV viral life cycle, and the potential therapeutic implications of this relationship, remain unexplored. We hypothesize host telomerase is important for the HCMV viral life cycle. We will first establish telomerase activity upregulation upon HCMV infection, and reduced HCMV replication following telomerase inhibition, in multiple strains and cell lines using several approaches to telomerase repression. Assays of telomerase activity in the presence of pharmaceutical telomerase inhibitors BIBR1532 and MST-312 will establish a reduction of viral infectivity following telomerase inhibition in both laboratory and clinical strains. Subsequent assays using inducible genetic inhibitors, specifically siRNA and inducible shRNA constructs against hTERT, will test whether reduction of viral replication is a result of telomerase inhibition and not off-target effects. To define the mechanism of action by which HCMV upregulates telomerase activity, we will assess telomerase activity following ectopic expression and shRNA-mediated knockdown of key viral genes, and implicated gene products will be subjected to binding assays in infected and telomerase-inhibited infected conditions to assess association with DNA via ChiP and QTIP assays, and with other proteins via IP and mass spectrometry. ChiP assays in infected and telomerase-inhibited infected conditions will also be performed on host proteins previously shown to influence telomerase activity. To define the function of telomerase in the viral life cycle, we will conduct differentially-timed inhibition of telomerase and assess the viral gene class(es) the activity of which is constrained by the absence of telomerase. Overall, these experiments will establish the potential clinical relevance of telomerase in HCMV infection and define both the mechanism of action by which HCMV upregulates telomerase activity and the function of telomerase in the viral life cycle. Increased understanding of these relationships may provide insight into other herpesviruses, inform clinical HCMV management, and lead to new anti-viral therapies.

NIH Research Projects · FY 2025 · 2021-12

Summary Approximately one person dies from heart disease every 30 seconds in the United States. About 1.5 million Americans die from myocardial infarction each year. Clinically, genetic disorders (e.g. hereditary hemochromatosis) and repeated blood transfusions (as required for sickle cell anemia and beta thalassemia) are known to cause Fe accumulation in the heart with iron overload cardiomyopathy being a major cause of death. It has been recently reported that dilated cardiomyopathy occurs in up to 95% of patients with Duchenne muscular dystrophy and that iron levels are elevated in mouse models. Furthermore, iron levels are known to be elevated in the heart after ischemia followed by reperfusion. Nevertheless, the underlying mechanism(s) involved in Fe associated cardiotoxicity remain unclear. Calcium and iron are both known to play vital cellular roles in the heart. Cells exhibit a remarkable dependence on keen regulation of calcium and iron concentrations. Cellular dysregulation of either ion can result in systolic and diastolic dysfunction and ultimately cardiomyopathy. Loss or disruption of normal homeostasis of cellular calcium and/or cellular iron concentrations can not only cause direct myocardial cardiotoxicity, but can also result in loss of myocardial excitability and abnormal excitation contraction coupling. We propose that a cross talk between calcium and iron combined results in a highly cardiotoxic cellular environment. We posit that the presence of iron can result in cell death via an underappreciated pathway, i.e. ferroptosis in the heart resulting in cardiomyopathy as well as ischemia reperfusion injury. Furthermore, we propose a similar link between myocardial stunning seen after brief periods of ischemia reperfusion to be in part due to the same cross talk resulting in a partially reversible reduction in myocardial systolic function. Linking the transport of calcium and iron signaling is the mitochondria Ca uniporter (mCU) and the activation of transient receptor potential canonical channels. We show that iron can regulate TRPC ion channel function. Our preliminary data have shown that TRPC channels are directly activated by iron. Importantly, activation of TRPCs has been implicated in calcium paradox injury and post- myocardial infarction remodeling. We aim to demonstrate that neither calcium nor iron are simply passive participants in cellular processes, but when forces are joined result in systolic and diastolic failure of the heart, cardiotoxcity, and together are predictive of a reduced lifespan in humans. We will demonstrate that it is cellular diastolic calcium and mitochondrial calcium that defines cell death and myocardial function with iron loading. We hypothesize that mCU accounts for mitochondrial iron overload and that an interaction (or crosstalk) between elevated diastolic calcium and increased mitochondrial iron results in a highly volatile and cardiotoxic environment that causes cardiac cell death via ferroptosis resulting in cardiomyopathy and ischemia reperfusion injury. The field of ferroptosis is nascent in many regards when it comes to the heart. The key drivers and pathways of ferroptosis in the heart differ depending on biological context. In summary, there is a wealth of foreseeable opportunities to elucidate both the trigger(s) and pathways activated that can result in ferroptosis and its role in various forms of cardiac cardiomyopathy and ischemia-reperfusion injury. Our preliminary studies have demonstrated ferroptosis in iron induced cardiomyopathy and Duchenne Muscular Dystrophy cardiomyopathy. We will use woodchucks that have been shown by us to be protected from ischemia reperfusion injury as a tool to identify novel anti-ferroptosis pathways that can be targeted for treatment and/or preventative therapies. We will pursue the following aims. Aim 1: Determine the role of mCU and TRPCs in Fe induced cardiac dysfunction at the level of the isolated myocyte and in vivo. Sub-aim 1-1: We will demonstrate in vitro and in vivo whether mCU mediated Fe uptake and Ca dysregulation are associated with Fe induced cardiac toxicity. We will confirm mito Fe loading is mediated by mCU. The effects of Fe treatment on mito function, oxidative stress and the role of mCU will be defined. Sub-aim 1-2: We will demonstrate Fe induced activation of TRPCs and the relationship to cardiac dysfunction in vitro (acute) and in vivo (Fe-CM). Sub-aim 1-3: Data derived from Sub-aims 1-1 and 1-2 will be used to populate a computer model of E-C-M coupling and simulations run with incorporation of Fe effects. Aim 2: To determine pathways involved in ferroptosis in Fe-CM, DMD-CM, and Woodchucks during I/R injury. Sub-aim 2-1: We will determine whether mito Fe uptake via mCU plays a role in ferroptosis with Fe loading and test other known inducers of ferroptosis. We will determine the role of ROS and TRPC in vitro and in vivo with Fe loading and I/R. Sub-aim 2-2: In DMD-CM hearts, we will determine remodeling of ferroptosis-related genes and proteins, evaluate biomarkers, and test the susceptibility to ferroptosis inducers in vitro. We will test various ferroptosis pathways and attempt to mitigate DMD-CM by inhibiting ferroptosis in vivo. Sub-aim 2-3: We will obtain novel insights into protective mechanism(s) in woodchucks during I/R (in vitro and in vivo).

NIH Research Projects · FY 2026 · 2021-12

Project Summary/Abstract By 8th grade, one in five Black youth and one in four Latinx youth has tried some form of alcohol, nicotine, or cannabis - well after substance use related cognitions (e.g., perceived harm), which impact risk for use - have started to form. Prevention efforts must be grounded in knowledge of how modifiable risk and protective factors that are present prior to early adolescence may vary within (e.g., by gender) and between racial/ethnic groups in their influences on precursors to and early substance use behaviors. Focusing on understudied cultural factors that are especially salient for Black and Latinx youth, such as racial/ethnic discrimination and environmental factors that are highly prevalent in Black and Latinx communities, such as religious involvement, the proposed etiological study will integrate methodological approaches that can address both their unique and collective influences on substance use related cognitions and use from pre- to mid-adolescence. This secondary data analysis project is based on the Adolescent Brain Cognitive Development Study (total N=11,878), an ongoing multi-site, population-based longitudinal study of adolescent development. Drawing on data collected at ages 9- 16 from the 10,360 participants (47.8% female) that were identified by their parents as Black (17.2%), Latinx (23.2%), or White (59.6%), we will address three core aims. First, we will use person-centered analyses (mixture modeling) to identify latent profiles (subgroups) of risk and protection based on cultural and environmental factors (e.g., acculturation, parental support) and substance use related cognitions (perceived harm, expectancies, intentions to use) that predate and evolve as a function of substance use. Second, to gain a more nuanced perspective on the early course of substance use, we will apply mixture modeling, survival analysis, and a novel modeling approach integrating the two, to identify possible distinctions between and among Black, Latinx, and White youth in timing of progression through early stages (experimentation, initiation, and - as the cohort ages - regular use), circumstances of use (e.g., how obtained), as well as type/method of use (e.g., beer vs. hard liquor, cannabis vaping vs. edibles). Third, building on this foundation, we will identify cultural and environmental influences that modify the course of substance use in Black and Latinx youth, focusing on common prevention targets, such as ethnic identity and parental monitoring. In addition to extending the models (e.g., incorporating moderators) derived for Aims 1 and 2, we will apply propensity score matching, integrating geocoded neighborhood data, to parse out the unique influence of risk factors, such as trauma, from the conditions that elevate risk for experiencing them. Identifying similarities and distinctions across and considering differences within (e.g., by gender) racial/ethnic groups in the impact of cultural and environmental influences on precursors to and early stages of substance use will contribute to refining etiological models of substance involvement in Black and Latinx youth that can inform prevention and ultimately reduce substance use related health disparities.

NIH Research Projects · FY 2025 · 2021-12

Abstract Our goal is to investigate the impact of diet and pressure overload on the histone code, and how this influences changes in gene expression in the healthy and hypertrophied/failing hearts and, in turn, how it impacts progression of the disease. Deciphering the histone code and how diet can modify it, provides us an educated means to exploit it to our advantage, especially during pathological conditions. Acetylation and methylation of histone lysine (K) residues were the first histone modifications discovered and are, therefore, the most widely studied and understood. However, to-date, there are 11 confirmed modifiers of histone lysine residues, including the acyl groups butyryl (Bu), crotonyl (Cr), and b-hydroxybutyrate (bHB) 1, whose source, genomic distribution, and functional relevance, remain largely unknown in the heart, and are the focus of our study. Our recent findings uniquely show that dietary fat is a major regulator of histone butyrylation, including H3K9-butyryl (H3K9Bu). Using genome-wide chromatin immunoprecipitation-sequencing (ChIP-Seq), we show that H3K9Bu is abundant at all transcriptionally active promoters. Both a high-fat diet and stress accelerated the conversion of butyryl-CoA to crotonyl-CoA via acyl-CoA dehydrogenase short chain (ACADS), resulting in a substantial reduction in global promoter-H3K9Bu. A deletion of ACADS both in the mouse heart and in human cells reversed this effect and increased promoter and gene-body H3K9Bu. Paradoxically, though, a fat-free diet had the highest levels of H3K9Bu. Deletion of fatty acid synthetase (FASN), abolished H3K9Bu in cells maintained in a glucose-rich, fatty acid-free, but not in a fatty acid-rich, medium, proving that fatty acid synthesis from carbohydrates substitutes for dietary fat as a source butyryl-CoA. In contrast to H3K9Bu, there were minimal dietary-induced changes in H3K9-acetyl (H3K9ac) levels. Importantly, RNA-sequencing (RNA-Seq) revealed that diet-induced changes in H3K9Bu abundance in the mouse heart was associated with differential changes in gene expression, but only when stressed by pressure overload. Moreover, promoter-H3K9Bu levels inversely correlated with the extent of changes in gene expression levels, as evidenced by the more robust changes seen in the hearts of mice on a, short-term, high-fat vs a fat-free diet, as well as, after deletion of the ACADS. Interestingly, H3K9Bu abundance inversely correlated with H3K9-crotonyl (H3K9Cr) and Cdk9. In sum, our data uniquely show that H3K9Bu is enriched at active promoters, is negatively regulated by high-fat and stress in an ACADS-dependent fashion, and its abundance inversely correlates with stress-induced changes in gene expression. We are proposing that histone H3K9Bu, H3K9Cr, and H3K9-b-hydroxybutyryl (H3K9bHB), are products of the b-oxidation intermediates, butyryl-CoA, crotonyl-CoA, and b-hydroxybutyryl-CoA, or the ketone body, b-hydroxybutyrate, which serve as substrates for histones modifications. These marks are labile and differentially influence pressure overload-induced gene expression, but not baseline expression. Specifically, as H3K9Bu decreases it is replaced by H3K9Cr during a high-fat diet. This exchange exaggerates gene expression and worsens the outcome of cardiac failure. Conversely, H3K9bHB that increases during a ketogenic diet has the opposite effect, as it is reported to have beneficial effects on health and aging. This differential influence of the histone marks on gene expression is mediated by regulating the recruitment of Cdk9 to gene promoters. We hypothesize that 1) A high-fat diet (60 Kcal% fat, 20 Kcal% carb), or pressure overload, accelerates the conversion of nuclear butyryl- CoA to crotonyl-CoA in an ACADS-dependent manner, thus, reducing H3K9Bu and increasing H3K9Cr, which is responsible for exaggerating stress-induced gene expression and worsening the outcome of heart failure (HF). In contrast, a ketogenic diet (84 Kcal% fat, 0% carb) will produce high levels of b-hydroxybutyryl that will increase H3K9bHB, which curbs changes in stress-induced gene expression in a b-hydroxybutyrate dehydrogenase (BDH1)-dependent fashion, improving the outcome of HF. Supplementing a diet with b-hydroxybutyrate will also increase H3K9bHB, with similar beneficial effects. 2) Therefore, knockdown of ACADS reduces the conversion of butyryl-CoA to crotonyl-CoA, increasing H3K9Bu and improving the outcome of heart failure during a high-fat diet. Conversely, deletion or inhibition of BDH1 reduces H3K9bHB and worsens conditions. 3) H3K9Cr enhances the dynamics of cyclin-dependent kinase 9 (Cdk9) recruitment to promoters during stress, whereas, H3K9Bu and H3K9bHB temper it, thus, reducing the extent of changes in gene expression and improving disease outcome. The specific aims are: 1) Examine the effects of high-fat, ketogenic, and b-hydroxybutyrate-enriched diets on the genome-wide distribution and changes in H3K9Bu, H3K9Cr and H3K9bHB, changes in gene expression, and their impact on the progression of cardiac hypertrophy and failure. 2) Investigate the roles of ACADS and BDH1 in regulating the levels of H3K9Bu, H3K9Cr, and H3K9bHb, and the progression of cardiac hypertrophy and failure. 3) Investigate the role of Cdk9 in mediating the differential transcriptional regulation directed by promoter-H3K9Cr vs. H3K9Bu or H3K9bHB during cardiac hypertrophy and failure.

NIH Research Projects · FY 2025 · 2021-11

Project Summary/Abstract Asthma remains a serious public health threat with unmet therapeutic needs. The development of successful therapies relies a more in-depth understanding of the immune subsets and pathways involved. MAIT cells are innate-like T cells that recognize microbial riboflavin metabolites presented by MR1 and can function through both TCR dependent and independent pathways. Interestingly, previous studies indicated an inverse association between MAIT cells and human asthma. The precise role of MAIT cells in asthma development and exacerbation, however, remains unknown. Our recently published work and additionally preliminary data indicate a striking anti-inflammatory role for MAIT cells in allergic airway inflammation. We hypothesize that a deficiency of MAIT cells in asthma patients contributes to exacerbated airway inflammatory responses to allergens, and that increasing MAIT cell numbers may help alleviate allergen-induced airway inflammation and hyperresponsiveness. Using fresh lung samples from deceased organ donors, we will examine the abundance and molecular properties of lung-resident MAIT cells in severe asthma patients and control individuals without lung diseases. We will use MAIT cell deficient mice and adoptive transfer strategies to interrogate the specific roles of MAIT cells in allergic airway inflammation. Finally, we will test whether boosting the number of MAIT cells by an engineered probiotic strain can help alleviate ongoing airway inflammation induced by common allergens.

NIH Research Projects · FY 2024 · 2021-09

PROJECT SUMMARY/ABSTRACT Education is a critical social determinant of health (SDOH). Low-income, Latino dual language learners face large gaps in school readiness, which perpetuate inequities in academic achievement and subsequent health. Primary care is an ideal setting to promote school readiness for at-risk children given its frequent near universal contact with children and the opportunity to build on established relationships with their families. In fact, school readiness is a Bright Futures priority topic at the 4 and 5-year well child visits. However, the current structure of well child visits, which seeks to address a growing list of topics during 10-15 minute appointments, is limited in its ability to achieve this goal. To date, primary care innovations to address SDOH have largely missed an opportunity to promote 360-degree child health by simultaneously addressing academic and physical readiness for school. To address this gap, we developed an online family wellness program that uses anticipatory guidance on health topics intrinsically important to school readiness (e.g., nutrition, physical activity) to introduce basic language and literacy skills to low-income, Latino dual language learners, a fast- growing and particularly high-risk group, and their families (AHRQ priority populations). The online family wellness program was developed through a cross-sector partnership between educators and pediatric professionals and consists of parent-child workshops led by bilingual educators and reminder text messages. The program occurs during the transition into Kindergarten, a critical developmental stage, and uses promising approaches such as group structure, strategic use of technology, and partnerships with non- medical professionals. The yearlong program tightly integrates Bright Futures anticipatory guidance with the Kindergarten curriculum. During pilot testing, our team found that the family wellness program was feasible, well attended, and highly acceptable. We now propose testing the effect of the family wellness program on child and parenting outcomes using a rigorous mixed methods and community-engaged approach. In aim 1, we will conduct a developmental evaluation to refine the family wellness program and optimize the likelihood of successful implementation. In aim 2, we will conduct a randomized controlled trial testing the effects of the family wellness program on child language, literacy, and social-emotional outcomes as well parent health routines, learning activities, and self-efficacy. In aim 3, we will conduct a mixed methods process evaluation, which will provide insight into reach and implementation as well as user experience. The current proposal will yield insight into how primary care innovations can address education, which responds directly to AHRQ's interest in primary care innovations that address SDOH (NOT-HS-19-011). If effective, the online format will allow us to work with local, state, and national partners to disseminate the program rapidly to promote high- quality healthcare for vulnerable populations.

NIH Research Projects · FY 2025 · 2021-09

Project Abstract Candidate: Elissa Kozlov’s career goal is to be an independent investigator dedicated to improving the mental health outcomes of older adults with serious illness and their families, while establishing herself as a leader in the field of geriatric mental health care and palliative care. She is a licensed clinical psychologist with expertise in geriatrics and palliative care, and she has authored 25 peer-reviewed (15 first-authored) manuscripts. Research: Up to 70% of adults with serious illness have symptoms of anxiety. Undiagnosed and undertreated anxiety contributes to higher risk of pain, depression, fatigue, dyspnea, and polypharmacy. Patients with high symptom burden and anxiety heavily impact family caregivers, which nearly 8 million older adults in the U.S. rely on for assistance. Decades of research reveal the negative effects of caregiving on caregivers, (e.g., high levels of stress, depression, and anxiety). Furthermore, there is a mutuality of distress in the caregiver/patient dyad — when patients suffer psychologically, the caregiver suffers too. Unfortunately, older adults and their caregivers have limited access to mental health resources because of shortages of mental health providers as well as logistical issues including time constraints, transportation, and scheduling. The objective of this study is to evaluate the feasibility, acceptability, and preliminary efficacy of Mindfulness Coach, an mHealth Mindfulness Therapy intervention developed by the Veterans Affairs, to reduce anxiety in older adults with serious illness and their family caregivers. An efficacious and scalable behavioral intervention that mitigates symptoms of patient and caregiver anxiety has the potential to reduce distress and enhance coping in the patient–caregiver dyad without contributing to polypharmacy or burdensome appointments. Research is urgently needed to evaluate the feasibility, acceptability, and preliminary efficacy of dyadic mHealth mindfulness therapy in older adults with serious illness and their caregivers. Career Development: Dr. Kozlov has assembled an interdisciplinary team of mentors (Primary: Drs. Dong & Reid, Mentorship Committee [Israel, Duberstein, and Hoover]) with expertise in geriatrics, mental health, dissemination and implementation sciences, caregiving, and mHealth. Her career development plan integrates coursework, seminars, and mentorship in the following areas: (1) Skills in mHealth interventions, data analysis and clinical trials, 2) Dyadic interventions and analyses in geriatrics and palliative care, 3) Dissemination and Implementation sciences (D&I), and 4) Leadership and grantsmanship. With support from the Rutgers University Institute for Health, Health Policy and Aging Research, The School of Public Health and RWJ Barnabas Healthcare System, Dr. Kozlov is positioned to lead geriatric mental health initiatives that are supported by rigorous, programmatic research. The proposed research, training, and mentorship plan will provide Dr. Kozlov with the data, skills and experience needed to become a leader in implementing and delivering innovative mental health care to older adults with serious illness and their caregivers.

NIH Research Projects · FY 2025 · 2021-09

Overall – Abstract In response to RFA-MD-21-007, we propose the Rutgers-NYU Center for Asian Health Promotion and Excellence (CAHPE) to advance interdisciplinary research on comorbid cardiometabolic disease and mental health of Asian adults. There are currently significant disparities in relationship to Heart and Mind, with lower thresholds for BMI for Asians and disproportionate disparities related to cardiometabolic disease and mental health. Such an important focus in research, population and investigators will inform both practice and policy at community, regional and national levels. Asians are the fastest growing yet most understudied US minority group at 23 million people and growing 26% from 2010-2019. Yet, < 1% of NIH research funding in the last 10 years were focused on US Asian populations. Moreover, this population experiences the “Asian Paradox”: while on average, US Asians, are the highest-income earners and the most highly educated, more Asians, especially older adults, live below the poverty line, are less likely to participate in biomedical research, and suffer disproportional health disparities compared to white Americans. These health inequities are further complicated by the heterogeneity of these immigrant populations, especially with respect to culture, religion, language, sexual identity, and trauma exposure, many of which challenge our assumptions about the “model minority” stereotype. Building on two decades of rigorous aging research in minority populations and track records of successful academic achievements, we have leveraged strong existing transdisciplinary partnerships across multiple academic and community institutions to build a center designed to foster the next generation of researchers in a nurturing environment that is conducive to success and promotes highly relevant and rigorous translational research on cardiometabolic and mental health outcomes among US Asians. With strong institutional support of $3 million in matching funds, our Center will have five inter-connected aims: 1) Provide leadership, organizational communication, and evaluation systems designed to achieve the overarching goals of supporting high quality and enduring inter-disciplinary research on cardiometabolic and mental health outcomes among Asian adults; 2) Guide solicitation and selection of 6 pilot studies per year; 3) Implement the three interdisciplinary, translational, and synergistic R01-like projects with specific focus on: Nutritional, Positive Affect, and Dementia Caregiving Interventions to multi-prong target Asian population at high risk; 4) Enhance, track, and evaluate existing infrastructure to support and synchronize the pilot and center projects; and 5) Disseminate these findings to the local, regional, and national levels in order to inform the design of future prevention/intervention research commodities. The overall aims of this application reflect the synergistic work of the Administrative Core (AC), Investigator Development Core (IDC), Community Engagement Core (CEC), and research projects.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY The overall goal of this Application is to improve our understanding of the genetic and molecular control of adrenal gland homeostasis by studying how osteocalcin originating from maternal skeleton, affects adrenal growth and steroidogenesis of the offspring during development and after birth. Specifically we intend to 1] Establish that maternal Ocn is necessary for proper adrenal gland development and function. We will also 2] Establish genetically and in vivo that osteocalcin favors adrenal gland growth and steroidogenesis by signalling directly in the adrenal cortices through its receptor Gpr158. A third purpose of this application is to determine with precision the temporal course of osteocalcin’s effect on the adrenal gland development/function and investigate how maternal osteocalcin affects this process in the offspring. We will use mouse genetic, molecular and biochemical assays to investigate the molecular bases of the cross-talk between bone and the adrenal gland through osteocalcin in the regulation of adrenal steroid production. Together, this application will significantly advance our understanding of adrenal development and physiology in bony vertebrates by describing a novel regulation of adrenal gland development and steroidogenesis, which originates from the mother and is biologically relevant since its absence can be lethal.