Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Rapid and sensitive point of care tests that can detect all forms of drug resistance are urgently needed to enable appropriate treatment for TB. Molecular drug susceptibility tests (mDSTs) which use nucleic acid amplification techniques to detect mutations associated with resistance to the primary tuberculosis (TB) drugs isoniazid (INH), and rifampin (RIF), and in a few rare cases fluoroquinolones (FQs) have demonstrated the potential of this susceptibility testing approach. However, current mDSTs are unable to detect the large numbers of mutations which encode for resistance to the critical new anti-tubercular drug, bedaquiline (BDQ), and linezolid (LZD). These new drugs along with FQs and another new drug Pretominid (Pa) comprise the backbone of the most promising TB treatments of the future. Yet, without the availability of companion mDSTs, the world risks losing these new drugs to drug resistance within a few years of deployment. We propose to use innovative new fluidic and assay designs to enable detection of hundreds of different mutations encoding FQ, LZD, and BDQ resistance using the standard Cepheid assay cartridge. This new test would retain all the advantages of current Cepheid TB assays, a robust manufacturing and instrument placement base enabled by the high volume of assays currently produced. This research program will include 4 aims. Aim 1. Develop mis-match tolerant or “sloppy” molecular beacons (SMBs) that identify mutations associated with FQ and LZD resistance that are optimized for ultimate use in the new three-phase highly multiplex system to be developed in this grant. Aim 2. BDQ assay development detecting mutations in atpE and a new SMB tiling approach that queries the entire Mtb Rv0678 gene to identify mutations causal of BDQ resistance. Aim 3 Optimize three-phase cartridge fluidics for highly multiplex mutation detection. Aim 4. Perform an initial laboratory and clinical validation study of the final aim 1-3 assays using stored clinical samples.

NIH Research Projects · FY 2026 · 2024-02

Abstract Systemic lupus erythematosus (lupus) is characterized by polyclonal B cell activation, leading to the production of pathogenic class-switched autoantibodies that promote tissue injury. These B cells undergo somatic mutation and immunoglobulin isotype switching in extrafollicular (EF) sites and germinal centers (GCs) located within secondary lymphoid organs, sites of CD4+ T cell-dependent B cell maturation. Mounting evidence suggests that in lupus, autoantibody-producing B cells such as memory B cells, CD11c+Tbet+ B cells, and plasma cells are generated via both EF and GC reactions. Yet, the contribution of each of these B cell subsets to the generation and activity of autoantibodies in lupus remain unclear. CD11c+Tbet+ B cells (Tbet+ B cells herein) are a distinct B cell subset that differentiate following viral infections as well as autoimmunity in mice and humans. Emerging studies have shown that in murine and human lupus, Tbet+ B cells are critical drivers of pathogenic autoantibodies. In lupus, Tbet+ B cells are capable of differentiating into class-switched autoantibody-secreting cells upon stimulation by cytokines and TLR agonists. The presence of Tbet+ B cells in severe disease has been well elucidated, but their development and contribution as disease progresses in lupus is poorly understood. We found that the kinetics of Tbet+ B cell development and expansion in lupus-prone mice mirror the increase of autoantibodies and worsening disease state. Moreover, we show a temporal loss of the GC-derived Tbet+ B cell population coinciding with their expansion in the blood as disease progresses. We previously demonstrated that Tbet+ B cells arise predominantly independent of GCs during viral infections, and our preliminary data show that Tbet+ B cells appear to be mainly, but not exclusively, from EFs in lupus-prone mice as well. Tbet+ B cell development in requires IFN- a subset of CD4+ T helper cells, T follicular helper (Tfh) cells. These cytokines are secreted by Tfh cells throughout disease promoting pathogenic Tbet+ B cell responses. We found that CD9 expression on Tfh cells identifies the IL-21 and IFN-γ secreting subset, which we found to expanded in mice and human lupus. Our overarching hypothesis is Tbet+ B cells that arise from EF or γ and IL-21 signaling from GCs are transcriptionally and functionally distinct, but in lupus the chronic inflammatory milieu in different tissues leads to their aberrant regulation and differentiation into ASCs that contribute to disease. Accordingly, we will explore temporal changes in genetic regulation that functionally impact pathogenic Tbet+ B cell development from EF or GCs and from tissues such as the kidney in autoimmune disease. We will use unique transgenic lupus mice, combined with cellular techniques and novel genomic approaches to investigate the genetic regulation influencing function of these B cells at different stages of disease. We will also examine the requirement for the CD9-expressing Tfh cells in the generation and differentiation of Tbet+ B cells on both mouse and human lupus. Ultimately, this work will help distinguish the pathway and tissue of origin of pathogenic and nonpathogenic B and T cell subsets, aiding new avenues of therapeutic design to treat autoimmunity.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Per- and polyfluoroalkyl substances (PFAS) are biologically and environmentally persistent anthropogenic chemicals. Over 98% of the U.S. population has detectable levels of PFAS in their blood (serum). People may be exposed to PFAS through contaminated drinking water and food, house dust, or consumer products. Some populations may experience additional PFAS exposures from their jobs or hobbies. PFAS are of public health concern because of their associations with numerous adverse health outcomes including dyslipidemia, an imbalance of blood lipids such as high cholesterol. Dyslipidemia is a primary risk factor for ischemic heart disease (IHD), the leading cause of cardiovascular disease (CVD) in the U.S. and globally. Volunteer firefighters are community members who fill a critical public safety function, particularly in suburban and rural areas. Firefighters can be exposed to PFAS through combustion products, firefighting foams, and firefighter protective clothing. The association between PFAS exposure and dyslipidemia is of major concern in this population because cardiac events are the primary cause of line-of-duty deaths among all firefighters. However, the extent and pathways of volunteer firefighters’ PFAS exposures, and the ways these exposures may affect their blood lipid levels, are unknown. While 65% of the over 1 million U.S. firefighters are volunteers, they are understudied, creating critical knowledge gaps in evidence-based efforts to protect and improve the health of volunteer firefighters and the communities they serve. To address these gaps, we will leverage existing data from the Rutgers Firefighter Cancer Assessment and Prevention Study (CAPS), a cohort of volunteer firefighters from 8 U.S. states. This F31 fellowship builds upon the applicant’s preliminary work with CAPS data using pilot funding. Two specific aims will be used to achieve the objectives of identifying (a) predictors of serum PFAS concentrations including sociodemographic, firefighting, and occupational characteristics, and (b) associations between PFAS and lipid concentrations in volunteer firefighters. Aim 1: Assess the seroprevalence, predictors, and possible exposure sources of PFAS among U.S. volunteer firefighters. We hypothesize that heterogeneous distributions and concentrations of serum PFAS will be associated primarily with community-related exposure sources. Aim 2: Examine associations between serum PFAS and dyslipidemia among U.S. volunteer firefighters. We hypothesize that serum PFOA and PFOS (the most frequently detected and studied PFAS) will be positively associated with total cholesterol and LDL. We will also assess associations between less commonly studied PFAS and seven lipid measures. We will use single-pollutant and mixture models to characterize the effects of multiple simultaneous PFAS exposures. This work will advance our understanding of the health impacts of this environmental exposure in a critical population of community-based first responders.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY/ABSTRACT Despite psychoeducational efforts highlighting consequences of opioid use, relapse remains common for individuals with opioid use disorder (OUD). This clinical observation indicates a need for better understanding how undesirable information about drug use is evaluated and incorporated into patient’s beliefs about personal risk. People hold biased beliefs about their personal risk in various life domains, expecting more good outcomes to happen to them than bad outcomes. This “optimism bias” can be explained by a biased belief updating process that weighs better-than-expected past outcomes more heavily than worse-than-expected past outcomes when forming future expectations. This “optimism bias” could explain mechanisms that drive opioid use despite well- recognized risks for harm. Such biased beliefs in OUD have primarily been studied using self-report measures. Additionally, neuroimaging work on these biases has been restricted to healthy individuals. The psychological and neural determinants of these biases as they relate to drug use in OUD remain unknown. I propose to, for the first time, quantify domain-specific optimism biases in OUD and to re-assess these biases as participants engage with their daily life outside of the lab. Here, I will study the behavioral, neural, and longitudinal mechanisms of biased beliefs in treatment-seeking individuals with OUD and matched healthy controls. Using a neurocomputational framework, during functional magnetic resonance imaging (fMRI), subjects will estimate their likelihood of drug- and nondrug-related negative events occurring to them (e.g., overdose, bone fracture). They will then be shown the true base rate of these negative events and will be given the opportunity to update their estimates. In Aim 1, I will use this approach to test whether opioid users underestimate their likelihood for negative events and whether they would update their beliefs more after receiving better-than expected vs. worse- than-expected information, especially when outcomes are related to their drug use. To test how biased belief updating emerges in the brain, in Aim 2, I will record brain activity during the initial estimation and updating period of the task in Aim 1, which I hypothesize to involve cortico-limbic-striatal circuitry centered on the inferior frontal gyrus and ventral striatum. Following the MRI session, in Aim 3, subjects will be enrolled in a 4-week ecological momentary assessment (EMA) study and complete an abridged version of the optimism bias task to determine the maintenance and durability of domain-specific optimistic beliefs. The proposed Diversity-F31 training and research plan will support the formal training I will receive in my doctoral program by: (1) increasing my knowledge in human addiction neuroscience; (2) increasing proficiency in methods and concepts in cognitive neuroscience and advanced neuroimaging techniques; and (3) developing training in advanced multi-level statistical and computational modeling. By using a rigorous decision neuroscience approach, this research has the potential to inform future efforts to refine and develop more robust psychoeducational interventions for OUD.

NIH Research Projects · FY 2025 · 2024-02

Project Summary Age of puberty is one the most reliable predictors of later mental health outcomes in girls, with early menarche greatly increasing the risk of depression in early adulthood. Environmental exposure to endocrine disrupting compounds (EDCs) has been linked with early puberty onset in girls. Despite this, the neurobiological consequences of EDC exposure, and how they might predispose to depression, remain poorly understood. In a series of preliminary studies, we showed that peripubertal exposure to a model EDC, bisphenol-A (BPA), accelerates puberty onset in female rats, and predisposes to behaviors in early adulthood that are reminiscent of anhedonia, a core symptom of clinical depression. These changes were associated with a persistent impairment in the functioning of the orexin neuropeptide system, the activity of which is normally important for translating motivational states into reward behaviors. Specifically, BPA was associated with reduced reactivity of orexin neurons to reward-predictive stimuli, as well as reduced orexin terminals in ventral tegmental area (VTA), a key region through which orexins initiate reward-directed actions. Based on these data, we hypothesize that: at doses that promote early puberty onset, BPA produces a persistent impairment in the functioning of the orexin-VTA circuit. We predict that these changes are causally linked to the anhedonia-like phenotype observed in early adulthood in BPA-exposed rats. Here, we propose three distinct, yet interrelated aims to begin testing our hypothesis. In Aim 1, we will characterize the baseline activity (using electrophysiology) of VTA-projecting orexin neurons in BPA-exposed rats and determine how this is related to the expression of anhedonia-like behavior in early adulthood. In Aim 2, we will use fiber photometry recordings of a novel orexin sensor to measure orexin signaling in VTA in response to reward-predictive stimuli. Finally, in Aim 3, we will use chemogenetics to stimulate the orexin-VTA circuit to test its causal role in the expression of anhedonia-like behavior following BPA. These studies will be the first to determine the effect of EDC exposure on orexin neurons and their circuits, and will determine their mechanistic involvement in depression outcomes in a model of early puberty onset. The proposed project is thus highly relevant to the goal of NIEHS to understand the impact of environmental chemical exposures on psychiatric illness. Moreover, these studies are a critical first step for developing novel strategies to improve mental health outcomes in young women.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Tuberculosis (TB) is a global health crisis. As the second leading cause of death due to infectious disease, it claims roughly 1.5 million lives a year. Although TB can be treated, the curative regimen is complicated and takes several months. Drug-resistant Mycobacterium tuberculosis (Mtb), including totally drug-resistant strains, is steadily increasing in prevalence. Therefore, novel therapeutics with the potential to decrease treatment duration and increase barriers to resistance are essential for disease eradication. Most TB drug discovery programs have taken target-based approaches and largely ignored intrabacterial metabolism. However, several first- and second- line antituberculars penetrate Mtb as prodrugs and are intrabacterially metabolized into their active form. When faced with the markedly lipid-rich, hydrophobic environment of the Mtb cell envelope, prodrugs have the ability to enter the cell and subsequently release more polar, Mtb-active moieties within the bacterium. Most Mtb prodrugs are activated by non-essential enzymes, and, as a consequence, resistance develops quickly. For example, pyrazinamide (PZA), a key first-line antitubercular that enables a shortened TB drug regimen, is activated to pyrazinoic acid (POA) by the non-essential amidase PncA, and the vast majority of PZA resistance is caused by mutations in this activating gene. Notably, several other Mtb amidases have also been shown to metabolize amide antituberculars, thereby activating prodrugs and inactivating active drug compounds. We hypothesize that we can harness Mtb amidases to design and activate amide prodrugs within Mtb that are active in drug-resistant disease and that have increased barriers to resistance. Our proposal aims to 1) study the amide-amidase interactions to identify amide prodrugs that are activated by more than one amidase and 2) link POA to amine metabolites from parent compounds that demonstrate amide hydrolysis within Mtb to generate potential POA-releasing conjugates that are activated by non-PncA amidases. The majority of amidases are non-essential and likely have overlapping functions, enabling the discovery of amide-containing antituberculars that are activated by multiple amidases. Furthermore, the release of POA by amidases other than PncA would retain PZA-like activity in PZA-resistant strains, restoring the activity of a first-line antitubercular critical for shorter TB regimens. This approach will introduce a novel framework for TB prodrug discovery that can be applied to other classes of small molecules and their activating enzymes. In all, the proposed project and training plan will greatly further my development as a researcher and independent scientific thinker by introducing me to new scientific concepts and techniques and providing ample opportunity for me the integrate my research and clinical experiences. Together, Rutgers New Jersey Medical School, the Public Health Research Institute, and the Global TB Institute create a highly collaborative and highly translational environment that uniquely benefit my training as an infectious disease physician-scientist.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT The overall goal of this project is to identify the role of the gut microbiome in the etiology of benign breast disease (BBD), and thereby shed light on its pathogenesis in relation to breast cancer. Approximately one out of every five women in the United States has been diagnosed with BBD, a well-established risk indicator for breast cancer. BBD share the hormonal-related risk factors with breast cancer. However, the underlying mechanisms linking hormone factors and breast disease are not clear. Emerging evidence suggests that the gut microbiome may be significantly involved in breast disease through the influence on systemic estrogen homeostasis. This evidence supports the hypothesis that the gut microbiome is a key player in breast disease, and it may mediate the associations between hormonal risk factors and BBD. However, no study has systematically studied the role of the gut microbiome and its metabolome on BBD. Dr. Wang proposes to be the first to test this important hypothesis. She will leverage the sub-studies embedded in the well-characterized Nurses’ Health Study II, to test the three specific aims. In Aim 1 (K99), she will identify potential differences in gut microbial composition and functional variation by various hormonal factors among ~1800 participants. In Aim 2 (R00), she will characterize the associations between gut microbiome composition and the high-risk, proliferative subtype of BBD in a nested case-control study (N=300) with breast biopsy sample collection. In Aim 3 (R00), she will incorporate the functional readout of gut microbiome, the fecal metabolomics, to estimate the associations between microbial metabolomic signatures and BBD in the same nested case-control study. Innovative shotgun metagenomic sequencing and semi-targeted metabolomics will be used to discover microbial strains and their metabolites. By integrating metagenomics and metabolomics, she will comprehensively investigate taxonomic composition and functional potential of gut microbial communities that are directly involved in BBD, as well as the potential mediating role of the gut microbiome underlying the hormonal factors-BBD associations. Results from the proposed study may pave the way for novel personalized BBD and breast cancer prevention for high- risk women defined by their hormonal profiles, with the potential modulation of gut microbiome. Dr. Wang’s research aims are supported by a well-rounded training plan tailored to her two training goals: 1) Obtain training and apply advanced bioinformatic analytics to large microbiome metagenomic and metabolomics datasets; and 2) Develop advanced knowledge on hormonal determinants on BBD epidemiology, etiology, pathology, and pathogenesis as it relates to breast cancer. The training environment at Brigham and Women’s Hospital fosters productivity and collaboration with world class biomedical scientists, and she have assembled a multidisciplinary mentoring team that includes leading experts in BBD, human microbiome, bioinformatics, hormonal factors, breast pathology, and breast cancer epidemiology. This K99/R00 award will help her gain the knowledge and experience necessary to effectively pursue her career as an independent breast cancer investigator.

NIH Research Projects · FY 2025 · 2024-01

Project Summary/Abstract Breast cancer affects many women in their lifetime. A major challenge remains how to reduce breast cancer risk as well as to understand what causes breast cancer. Two-thirds of breast cancer diagnosed in patients belong to estrogen receptor (ER)-positive breast cancer. Many chemicals, with similar structure to estrogen, have been suggested to mimic the biological functions of estrogen, potentially contributing to the initiation or progression of breast cancer. Environmental estrogenic endocrine disruptor contaminants, such as bisphenols, phthalates and zeranols, have been known to have estrogenic activity in cell culture and animal models. However, the impact of endocrine disruptors on breast cancer development in humans remains unclear. We hypothesize that endocrine disruptors, by increasing breast cancer stem cells and altering tumor metabolism, promote the development of breast cancer. The objectives of this project are to determine impact of endocrine disruptors in breast cancer development and to understand mechanisms of endocrine disruptors in alteration of cancer stem cells and metabolome leading to accelerating ER-positive breast cancer. We propose two Specific Aims as follows. In Aim 1, using the estrogen sensitive ACI strain, we will investigate the impact of endocrine disruptors on the mammary gland proliferation in vivo. We will test three representative classes of common environmental endocrine disruptors, bisphenols, phthalates and zeranols for this Aim. In Aim 2, we will determine endocrine disruptors-induced alteration of breast cancer stem cells and cell metabolism in the ER-positive breast cancer model. MCF-7 mammosphere culture and MCF-7 xenografted tumor models will be utilized to investigate the role of endocrine disruptors in enhancing cancer stem cells and altering tumor metabolism in vitro and in vivo. We will test three representative classes of endocrine disruptors, bisphenols, phthalates and zeranols in vitro. Selected endocrine disruptors will be further evaluated for in vivo tumor studies. Endocrine disruptors have long been suggested for its potential role in promoting cancer development and progression. This project seeks to understand the mechanism of endocrine disruptors in the mammary tumorigenesis by focusing on cancer stem cells and metabolism shift. Environmental factors and lifestyle have led to significant changes in breast cancer risks. Our study with endocrine disruptors could provide the valuable link between environmental exposures and human health.

NIH Research Projects · FY 2025 · 2024-01

Abstract T cells play a central role in the anti-cancer immune response. Engineering and administrating tumor-specific T cells have successfully treated some types of cancer. Compared to chimeric antigen receptor (CAR)-T cell therapies, T cell receptor (TCR)-T cells engage tumor cells through engineered TCRs that bind peptides presented by human leukocyte antigen (HLA). These peptides can be derived from tumor antigens in any cellular compartment, making TCR-T an attractive approach to developing novel engineered T cell therapies. Identifying suitable tumor-specific TCR is the most critical step for developing TCR-T therapies. However, only a small number of TCRs that recognize shared tumor antigens have been identified, which is the major bottleneck for developing novel TCR-T therapies. Here, we have identified two tumor-infiltrating lymphocytes (TILs) from the sample patient that can be dramatically activated by three independent ccRCC cell lines, indicating that these TILs contain T cells recognizing a shared tumor antigen. We further found that ccRCC- TCR1 was dominant in these TILs and was shared by all activated T cells. This ccRCC-TCR1 is HLA-B0702 restricted, which is carried by ~26% of Americans. In vitro killing assays showed that these TILs are highly cytotoxic to the ccRCC cell lines in an MHC-I-dependent manner. These data collectively suggested a high- affinity TCR that potentially recognizes a widely shared ccRCC tumor antigen. We propose two aims to develop TCR-T therapy with ccRCC-TCR1 to treat kidney cancer: 1) determine antigen specificity of ccRCC- TCR1; 2) determine in vivo antitumor activity of ccRCC-TCR1 T cells. By identifying the antigen of ccRCC- TCR1 and evaluating its antitumor activity in vivo, this translational project will pave the way for future clinical applications. At the completion of the project, the expected outcomes are to have tumor-shared antigens identified and move forward to conduct additional pre-clinical studies and prepare to initiate a clinical trial for ccRCC-TCR1 T therapy.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that occurs primarily in children but can also occur in adults. Despite recent advances in treatments, 20-50% of patients do show primary resistance or relapse after treatment and ultimately die from their disease, highlighting the need to discover novel targeted therapeutic approaches. The detection of highly prevalent NOTCH1 activating mutations in T-ALL, seen in ~60% of patients, led to the discovery of NOTCH1 signaling inhibitors such as gamma-secretase inhibitors (GSIs), that block a critical proteolytical cleavage step required for NOTCH1 maturation and activation. GSIs are currently being explored in clinical trials for relapsed/refractory cases, however, the responses observed as a single agent treatment have been generally limited, such that the identification of novel targets and combination therapies capable of delivering strong and synergistic antileukemic responses in patients is one of the most urgent goals in the T-ALL field. Our lab has previously demonstrated the therapeutic benefit of targeting metabolic routes in T-ALL. In this context, my preliminary results strongly suggest that targeting the glycolytic enzyme pyruvate kinase (PKM) has strong antileukemic effects on its own, and significantly synergizes with GSI treatment in vivo. Still, the role of PKM in T- ALL remains largely unknown. Notably, PKM has two different isoforms, PKM1 and PKM2, and we have already generated conditional knockout leukemias for each specific isoform, as well as for both of them concomitantly, which will allow us to exquisitely analyze the effects of pyruvate kinase in leukemia progression and response to therapy in vivo. Thus, the aim of this project is to mechanistically dissect the function of PKM in T-ALL by using a combination of gene expression, metabolomic profiling, epigenetic profiling and experimental therapeutics in vivo, taking advantage of our unique genetic tools. Our results will shed light on the mechanisms by which NOTCH1 controls cancer cell metabolism and will reveal PKM as a putative novel target for the treatment of T-ALL.

NIH Research Projects · FY 2026 · 2024-01

Project Summary/Abstract The purpose of this research is to assess the use and effects of a new generation of misleading descriptors and imagery in combustible tobacco marketing. While regulatory efforts to date have made strides in restricting the use of especially misleading terms in tobacco marketing (e.g., “mild”, “natural”), industry marketing has evolved to utilize newer descriptors and imagery that are known to be associated with these restricted terms; yet, research studying this evolution is quite limited. As the tobacco industry continues to mislead consumers with attempts to skirt regulatory actions via implied reduced risk claims (e.g., “organic”, “tobacco and water”), it is crucial to track their misleading marketing tactics and monitor effects on vulnerable youth and young adults (YYAs), especially as this suggestive marketing for traditional tobacco products now exists alongside other products actually authorized for designation as modified risk (i.e., Modified Risk Tobacco Products, or MRTPs). Through a preliminary literature and marketing content review under Aim 1, this research will characterize newer descriptors and imagery utilized in misleading marketing for combustible tobacco products (because these products pose the greatest harms), focusing specifically on cigarettes and cigarillos. Aim 1 focus groups with YYAs will assess attention, product appeal, and risk perceptions for products advertised/packaged with these descriptors and imagery, as well as other products by the same brands and MRTPs. Results will inform a discrete choice experiment (DCE) (Aim 2) that manipulates a series of target descriptors and images as well as modified risk claims on cigarette and cigarillo packs, in order to isolate independent and joint effects of the target features on product appeal and preferences. Under Aim 3, an eye-tracking study will examine young people’s attention to ads and packs using salient descriptors and images (per focus group and DCE results), and in combination with the prior activities, will provide preliminary data to inform research avenues for future regulatory efforts. This K01 will support the pursuit of my long-term career goal of becoming an independent tobacco control researcher at the intersection of tobacco policy, health communication, and tobacco misbeliefs; it will develop my content expertise (i.e., trends in/effects of cigarette and cigarillo marketing) and cultivate new methodological skillsets (i.e., focus groups, DCE, eye-tracking). The proposed research will allow me to work towards research independence and an R01 grant to further study misleading tobacco marketing, with a new focus on additional products and an emphasis on regulatory remedy.

NIH Research Projects · FY 2025 · 2024-01

ABSTRACT Health systems struggle to consistently deliver care that is safe, effective, timely, efficient, equitable, and patient- centered. Pragmatically leveraging science to provide quality health care efficiently and equitably can profoundly impact population health. Undertaking the deliberate work of establishing a premier Learning Health System (LHS), we will build platforms and integrate Cores to enable investigators to perform cutting-edge Patient Centered Outcomes Research (PCOR), Comparative Effectiveness Research (CER), and Dissemination and Implementation Science (D&I) to improve healthcare delivery, health, and health equity. These foundational resources and services will also provide a nurturing environment to train the next generation of LHS Scientists. To expand and reimagine LHS across NJ, we propose creating an innovative, impactful LHS Scientist Training and Research Center in New Jersey (LHS STAR NJ) with distinct goals that: 1) trains the next generation of LHS Scientists; 2) accelerate improvements in the quality, safety, outcomes, equity, efficiency, coordination, and patient-centeredness of care delivered by a diverse alliance of health system and organizational partners (LHS partners); 3) models the value of LHS Science in driving continuous learning and improvement into real-world practice; and 4) improves the health and health equity of NJ. To accomplish these goals, we will develop the structure, resources and services, and cultivate LHS and community partnerships to support LHS training and science; create formal didactic and experiential education, training, mentorship and career development activities in LHS science for a diverse group of embedded investigators, clinicians, and health system personnel tailored to their professional interests to create the next generation of LHS Scientists in academia, industry, and government; support LHS Scientists’ and other researchers conduct of rigorous, impactful PCOR and CER in our LHS partners to improve the processes, outcomes, and equity of care among diverse patients, populations, and settings; and promote the communication and pragmatic use of our findings in LHS partners and to researchers, health systems, and other stakeholders regionally and nationally. As a natural laboratory, LHS STAR NJ combines the expertise of established LHS investigators and mentors with the assets of a Big 10 health sciences university with 7 health professions schools, 6 different health systems, the state’s largest insurer and home care agency, and 2 government agencies. To increase our cohort of LHS Scientists, we will provide disparate training pathways to expand and diversify our LHS workforce. In all endeavors, we will leverage approaches that embrace diversity, inclusion, equity, and accessibility (DEIA) in trainees, mentors, and study populations. LHS STAR NJ will also support scientist- and health system-generated LHS projects within which we can embed Scientists overseen by a jointly governed committee of academic-health system representatives. Our LHS projects will address the lifespan, diverse healthcare settings, populations, disease states, and AHRQ/PCORI priority areas with the goal to improve health and healthy equity in New Jersey.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Full transcriptome defines clinically relevant “subtypes” of disease and the basal-like subtype of PDAC is associated with advanced stage, metastasis, resistance to treatment, and poor patient survival. The mechanism by which the tumor microenvironment drives PDAC subtype differentiation remains uncharacterized. Understanding the cancer- extrinsic factors in the tumor microenvironment that promotes the basal-like state could uncover cancer vulnerabilities and lead to the development of new therapeutic approaches. We found that inactivation of the histone demethylase gene Kdm8 reprograms PDAC cells into a highly metastatic state. Morphologically, Kdm8 inactivation reduces the expression of genes defining the classical PDAC subtype and drives a profound loss of differentiation in a genetically engineered PDAC mouse model. Importantly, the enzymatic function of Kdm8 requires molecular oxygen and hypoxia diminished the phenotypic changes induced by Kdm8 inactivation. We noted a global upregulation of histone 3 lysine 27 (H3K27) trimethylation upon the inactivation of Kdm8, supporting the involvement of its demethylase function in regulating the chromatin and cell state. In human PDAC, KDM8-regulated gene signatures are an exceptionally good predictor of the disease subtype. Our preliminary results suggest that hypoxia within the tumor microenvironment restricts the demethylase function of Kdm8, thereby suppressing the classical PDAC subtype while promoting a basal-like state and metastasis through epigenetic reprogramming. We hypothesize that a hypoxia-KDM8-chromatin axis plays a critical role in PDAC subtype determination and metastatic ability. In the proposed study, we aim to determine the mechanism by which Kdm8 controls PDAC subtypes and metastatic progression and the mechanism by which hypoxia suppresses Kdm8 function to promote chromatin reprogramming and PDAC metastasis. Overall, our study will fill the major gap in our understanding of how hypoxia within the PDAC tumor microenvironment promotes the basal-like molecular subtype and metastasis. Our mechanistic study will uncover fundamental insights into the role of KDM8 in subtype determination and may discover novel vulnerabilities of the basal-like PDAC state. The long-term objective is to gain a better understanding of the key cell-extrinsic factors in the tumor microenvironment that promote the aggressive or basal-like PDAC subtypes.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Peri-implantitis, an inflammatory disease resulting in destruction of peri-implant soft tissue and bone, remains a major obstacle to dental implant survival due to a lack of effective treatment strategies for this disease. Until recently, oral bacteria were considered a primary factor triggering peri-implantitis as observed for periodontal diseases. However, peri-implant disease research has shifted focus to understanding oral immune mechanisms which sense external cues in the oral cavity and maintain homeostasis with the oral microbiome. One well- established mechanism of oral immune surveillance is Toll-like receptor (TLR) sensing of lipopolysaccharide (LPS), an endotoxin and component of gram-negative bacteria, ubiquitous in the oral cavity. The regulation of the LPS/TLR4 axis, known as endotoxin tolerance, is an important mechanism in maintaining oral homeostasis. TLR4 activation triggers signaling cascades involved with multiple cellular functions including immune cell recruitment, reaction oxygen species (ROS) generation to neutralize invading microbes, and proinflammatory cytokine secretion. The LPS/TLR4 axis is tightly controlled by multiple negative regulators at several stages of TLR4 signaling cascades which mitigate uncontrolled inflammation resulting in host tissue destruction. During peri-implant inflammatory disease progression, excess ROS levels, i.e., oxidative stress, occurs, which disrupts cellular processes including regulation of LPS/TLR4 signaling. Suppression of TLR4 negative regulators is hypothesized to drive TLR4 overexpression in peri-implantitis, thereby increasing sensitivity to LPS. Titanium (Ti) particle dissolution from a dental implant surface can accumulate in adjacent peri-implant tissue, and increasing concentrations of Ti particles are associated with peri-implantitis. However, the role of Ti particles in mediating peri-implant disease remains to be elucidated. In this proposed study, the impact of implant-derived Ti particles (iTiPs) on excess ROS production and subsequent dysregulation of the LPS/TLR4 axis is explored. In Aim 1, transcriptome analysis of human peri-implantitis-affected tissue containing Ti particles is performed via RNA sequencing, while focused gene translation study for TLR4 signaling, ROS production, their regulators, and proinflammation cytokines is assessed via immunohistochemistry. In Aim 2, ex vivo Ti particles in human peri- implant tissue are characterized to generate morphologically similar iTiPs, which are then assessed for induction of ROS production in monocyte-derived immune cells in vitro. In Aim 3, the ability of iTiPs-induced ROS to dysregulate LPS/TLR4 signaling, ROS generation, and proinflammatory status is evaluated via gene expression studies and imaging flow cytometry in vitro and a murine oral mucosal model in vivo. This fellowship will help the applicant pursue a career as an independent investigator in the field of biomaterials, immunology, and oral microbiome studies with a focus on LPS/TLR4 signaling to identify potential therapeutic targets for peri-implant inflammatory disease treatment. Successful completion of this project will fill a crucial knowledge gap by elucidating the role of iTiPs and its interaction with oxidative stress and TLR4 signaling in driving peri-implantitis.

NIH Research Projects · FY 2025 · 2023-12

ABSTRACT The human body is composed of at least 400 different cell types, each distinguishable by distinct cellular markers. Cancer cells also express distinct cellular markers, differentiating them from their precursor cell-type prior to malignant transformation. Accordingly, the broad goal of oncology is targeted, tumor-specific therapies designed to maximize therapeutic efficacy while avoiding undesired off-target effects. This is recognized as a major obstacle for the application of current gene editing technologies. Proposed here is a strategy for tumor-specific gene editing involving combined use of the chimeric adeno-associated virus / phage (AAVP) vector together with the clustered regularly-interspaced short palindromic repeat (CRISPR) / CRISPR-associated protein (Cas) gene editing system – collectively referred to as AAVP-CRISPR. The tissue-specific targeting aspect is carried out by the phage capsid of AAVP, which can be modified to display a targeting peptide for ligand-directed delivery of a desired transgene. AAVP, first introduced in 2006, is a well-characterized gene delivery tool that has been explored in numerous tumor models. Here we plan to introduce two separate CRISPR/Cas systems with previously demonstrated gene editing efficacy into the AAVP vector. The first construct will contain the conventional CRISPR/Cas9 system, while the second construct will contain the more recently discovered hypercompact CRISPR/CasΦ system, referred to as AAVP-CRISPR/Cas9 and AAVP-CRISPR/CasΦ, respectively. The two constructs will be engineered to display RGD4C, a well-known, clinically viable tumor- targeting peptide, and carry various gene editing guide RNA (gRNA) combinations. Gene editing using the two constructs will first be performed in an in vitro setting, to confirm activity of the elements of each CRISPR/Cas system, including receptor binding, cell internalization, Cas gene expression, and gene editing activity. Several gRNA configurations will be tested in vitro and AAVP-CRISPR constructs containing the leading gRNA candidates will be evaluated for tumor targeting, Cas expression, and gene editing activity in vivo. Successful completion of the proposed studies will provide insight into the efficacy of AAVP-CRISPR for tumor-specific gene editing and contribute to the development of much needed novel therapeutic strategies for cancer.

NIH Research Projects · FY 2026 · 2023-12

Project Summary Non-polio enteroviruses (NPEVs) are etiological agents for several human diseases including respiratory infections, hand-foot-and-mouth disease (HFMD), aseptic meningitis, encephalitis, neonatal sepsis, myocarditis, conjunctivitis, and acute flaccid paralysis. Among the more than 100 serotypes of NPEVs, some of the most significant pathogens are enterovirus D68 (EV-D68), enterovirus A71 (EV-A71) and coxsackievirus B3 (CV-B3). According to CDC, these NPEVs combined have caused 10 to 15 million infections and tens of thousands of hospitalizations in the U.S. Clearly, NPEVs are a public concern for both U.S. and the world. No vaccines are available in the U.S. for the NPEVs such as EV-D68, EV-A71, and CV-B3. Three inactivated EV-A71 vaccines are available in China. However, there are not broadly protective, and the efficacy is limited to certain strains. There is no FDA-approved antiviral for any of these NPEVs. Thus, there is a pressing need to develop orally bioavailable pan-enterovirus antivirals. This proposal focuses on targeting the enterovirus nonstructural 2C protein for the development of orally bioavailable broad-spectrum NPEV antivirals. Specifically, in Aim 1, we will optimize the antiviral activity and pharmacokinetic properties of three series of 2C inhibitors. In Aim 2, we will determine the high-resolution X- ray crystal structures of EV-A71, EV-D68, and CV-B3 2C proteins with structurally disparate 2C inhibitors. In Aim 3, we will evaluate the in vivo antiviral efficacy of 2C inhibitors in EV-D68 and EV-A71 infection mouse models. Successful implementation of this proposal will provide orally bioavailable broad-spectrum NPEV drug candidates for further development.

NIH Research Projects · FY 2025 · 2023-11

Project Summary The lung is a major target of infections and allergies. Dendritic cells (DCs) in the lung function as sensors of the immune system that detect and process pathogens and allergens to activate T cell-dependent adaptive immunity. In addition, pathogens and allergens often stimulate airway sensory neurons either directly or indirectly, leading to primary defense response such as coughing and sneezing. Recent studies highlighted the role of neurons in immune responses, but the interaction between these two sensor modules, DCs and sensory neurons, in inflammation in the lung is incompletely understood. Infection with helminth parasites is a major health burden worldwide. Some helminth species such as roundworms and hookworms in humans and Nippostrongylus brasiliensis (Nb), a commonly used model agent to study hookworm infection in mice, traffic to the lung during their life cycle and cause potent type 2 inflammation. The larvae of these parasites stay in the lung only transiently before they get coughed up and swallowed to migrate to the intestine, where they eventually mature and lay eggs. Thus, the cough-triggering sensory neurons seem to play an important role in their life cycle, but their role in the regulation of inflammation remains unclear. We previously identified CD301b/Mgl2 as a marker for the migratory type 2 conventional DCs in peripheral organs including the lung, and showed that CD301b+ DCs are required for the differentiation of Th2 cells. We recently found that CD301b+ DCs are required for Nb-induced lung inflammation as well as for timely clearance of the parasite. Interestingly, our data also suggest that CD301b+ DCs and sensory neurons suppress each other to regulate lung inflammation during Nb infection. Based on these data, we hypothesize that Nb parasites are sensed by CD301b+ DCs and sensory neurons, which then mutually regulate each other to orchestrate type 2 inflammation in the lung. By using Nb infection as a model, the long-term goal of this project is to understand how sensory neurons modulate type 2 inflammation in the lung. Since the lung is a major site not only for helminth infection but also for other type 2 inflammation disorders such as allergy, asthma and fibrosis, understanding the mechanism for the regulation of type 2 inflammation is of clinical relevance.

NIH Research Projects · FY 2025 · 2023-11

Abstract The high mortality and morbidity of tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), calls for development of novel adjunct host-directed therapies (HDTs) to improve treatment outcome and restrict the emergence of multi-drug-resistant Mtb strains. Knowledge of immunometabolism offers new opportunities for controlling this deadly disease. We and others have characterized immunometabolic changes in multiple animal models of TB and found that metabolic remodeling to the HIF-1-mediated Warburg effect is a general response of host immune cells to Mtb infection. Through detailed analysis of immunometabolic dynamics of the macrophage response to Mtb infection, we discovered that M1-like polarization at initial stages of infection is accompanied by upregulation of ARG2, a type II arginase located in mitochondria. Given the critical roles that mitochondria play in mediating the signaling and metabolic pathways during macrophage activation, the upregulation of mitochondrial ARG2 suggests a little-studied role of this enzyme in M1-like polarization. Indeed, macrophages from Arg2 KO mice showed a diminished proinflammatory response and dysregulated mitochondrial dynamics. The identification of arginine metabolism-associated pathways, as well as upregulation of a related set of genes that include Arg2, using metabolomics and transcriptomics studies of Mtb-infected mouse lungs, also indicate that ARG2-mediated arginine and/or ornithine metabolism is an important regulator of host immunity to control Mtb infection in vivo. Based on these observations, we hypothesize that mitochondrial ARG2 activity contributes to M1-like polarization by regulating mitochondria dynamics and functions, including generation of signaling molecules, activation of signaling networks, and changes in mitochondrial metabolism to meet the biosynthetic and bioenergetic demands of activating macrophages. We will test the hypothesis 1) by delineating ex vivo effects of ARG2-mediated arginine metabolism on mitochondrial biology and macrophage polarization, using multiple approaches/assays that include stable isotope tracing metabolomics; and 2) by characterizing the role of ARG2-mediated arginine/ornithine metabolism in regulating the expression of innate and adaptive immunity during Mtb infection in vivo. We will also test an adjunct HDT through arginine or ornithine supplementation to improve infection outcome. We expect to aid the development of urgently needed adjunct HDTs with dietary supplementation of arginine/ornithine that should help clear the pathogen at an early stage of infection, prevent reactivation from a latent infection, and/or shorten the duration of antibiotic therapy.

NIH Research Projects · FY 2026 · 2023-11

ABSTRACT Early detection of tuberculosis (TB) disease to prevent transmission and disability is hampered by the lack of precise biomarkers to diagnose and predict TB progression. The objective of this study is to develop computational imaging tools to characterize and diagnose individuals without TB symptoms who will progress to sputum culture-positive or symptomatic TB disease. In Aim 1, we will combine computed tomography (CT) scans from existing and prospective TB household contact studies to derive a high-resolution radiomic signature to predict and characterize early disease pathology. In Aim 2, we will evaluate methods to enhance performance of field-deployable chest-X-ray computer aided detection (CAD) systems to diagnose early TB using transfer learning, image-to-image training, and integration of clinical and epidemiologic variables. Our goal is to develop a fundamental toolbox for research, diagnosis, and targeted preventive treatment of early TB to prevent transmission and accelerate TB control.

NIH Research Projects · FY 2026 · 2023-11

ABSTRACT Rapid and sensitive point of care tests that can detect all forms of drug resistance in tuberculosis (TB) are urgently needed to address the rise of drug resistance. We propose to develop a novel mutation detection system that uses recently developed nanoreactor bead chemistry and the Blink Diagnostic’s testing platform to identify both the presence of Mycobacterium tuberculosis (Mtb) and all of the clinically important mutations associated with isoniazid (INH), rifampin (RIF), ethambutol (EMB), pyrazinamide (PZA), fluoroquinolone (FQ), linezolid (L), bedaquiline (B), and pretomanid/delamanid (Pa/De) resistance. The new system will include integrated sample processing and rapid thermal cycling technologies to produce results within 30 minutes at the point of care. Mutations will be detected using digital and real-time PCR in novel addressable nanoreactor beads followed by melting temperature analysis enabling robust detection of hundreds of different resistance mutations with the sensitivity of current molecular diagnostics and the quantitation and hetero-resistance detection capacity of digital PCR. This proposal will build upon an established partnership between Blink scientists and engineers who previously developed highly successfully instruments and assays at Alere (currently Abbott Rapid Diagnostics), and the academic team responsible for the suite of Xpert TB assays previously developed in collaboration with Cepheid to perform the following specific aims: 1. Develop mis-match tolerant or “sloppy” molecular beacons (SMBs) that identify mutations associated with INH, RIF, EMB and FQ resistance that are optimized to nanobead format and fully functional on the Blink platform. 2. Finalize a SMB assay that queries the entire Mtb pncA gene to identify mutations causal of PZA resistance specifically adapted for nanobead format in the BLINK system. 3. Finalize development of cartridge based mechanical nucleic acid extraction process from sputum and other matrixes for Mtb. 4. Expand the nanobead assay to test for all clinically relevant mutations causing with resistance to Pa, B and L using the principals and chemistries developed in aims 1 – 2. 5. Perform initial laboratory and clinical validation studies of the final aim 1-4 assays using stored clinical samples.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT The objective of the proposed research is to develop a transfer learning framework to refine existing DNA methylation (DNAm) clocks and provide uncertainty quantification along with age prediction. A growing body of evidence has shown that the DNAm levels at specific age-related CpG sites represent stable and reproducible biomarkers of age. While numerous epigenetic clocks have been constructed to predict chronological age, age acceleration, or age-related diseases, they may lack generality or adaptability as they are mostly developed and validated from a certain subpopulation. There exists little research that explores how to transfer knowledge learned from the existing epigenetic clocks trained with adults when new data are collected from a different subpopulation such as the children and adolescent cohorts. This project will develop an innovative transfer learning approach to update existing epigenetic clocks without re-accessing individual-level data in the original training data. In addition, most existing epigenetic clocks provide only point predictions without uncertainty quantification. However, reasonable accuracy on a fixed validation set is not enough, and this project will also extend the conformal inference framework to construct prediction intervals with a guaranteed confidence level. Such a predictive paradigm with uncertainty quantification is important because it communicates better with the science community by providing a set of plausible predicted outcomes that covers the ground truth with a certain probability. Furthermore, this proposed work will allow for an integration of sequential updating and adaptive calibration procedures that construct prediction intervals with the availability of rich new DNAm datasets collected from diverse populations. The completion of this proposal will greatly improve the generalizability, reliability, and adaptability of existing epigenetic clocks to a new target population such as the children and adolescent cohort.

NIH Research Projects · FY 2025 · 2023-09

Abstract Even though all somatic cells trace their developmental lineages traced back to a single fertilized egg, during the course of development and aging, various mutagenic exposures, DNA replication errors, and imperfect DNA repair lead to accumulation of somatic mutations – resulting in genetic variations among somatic cells in a tissue. While somatic mutations have primarily been investigated in the contexts of phenotypic conditions such as pigmentation patterns, diseases such as cancer, autoimmunity etc, or disease precursors such as field cancerization and clonal hematopoiesis, emerging evidence suggests that somatic mutations in apparently healthy tissues might be more common than previously anticipated, and that clonal makeups of somatic tissues continue to evolve throughout the lifetime. Nonetheless, our understanding of the patterns of ‘normal’ somatic variations in pathologically normal tissues remains limited –in terms of the types of tissues affected, classes of genomic alterations, and their etiologies – in part, due to technological barriers. In particular, many types of genomic alterations in mosaic somatic tissues remain poorly characterized. Recent technological developments have enabled examining complex patterns of genomic alterations and their significance in tissue contexts at unprecedented resolution and high accuracy. Here, utilizing emerging genomic technologies and computational genomics resources, and focusing on organs that have different types of exposure and regeneration abilities, we will ask two related questions: What are the prevalence and patterns of somatic genomic alterations in pathologically normal tissues? To what extent such genomic alterations contribute towards transcriptomic and phenotypic variations at the cellular and tissue-level? This research contributes towards understanding the landscape of somatic variations in pathologically normal tissues in human. Regularity of healthy tissues is taken for granted, which under-appreciates the genetic and non-genetic variations within. Our efforts have potentials to challenge the dogma, that have relevance for development, aging, and many disease types including cancer, immune and neurological disorders. Importantly, it will provide us with a baseline to compare the alterations observed in disease and pre-disease conditions, which would have implications for early detection, disease prevention, and minimizing over-diagnosis. We will also develop computational genomic resources contributing towards reproducible research and community-level resource sharing for advancing our understanding of somatic variations in human tissues.

NIH Research Projects · FY 2024 · 2023-09

Project Summary The objective of the proposed research is to understand physiological functions of the mammalian target of rapamycin (mTOR) signaling pathway in the brain circadian (~24 h) clock, the hypothalamic suprachiasmatic nucleus (SCN). To be synchronized with the external and internal environment, gene expression in the SCN clock is regulated by an intracellular signaling network. A major gap exists in our understanding of the key signaling events that couple extracellular and intracellular signals to regulate protein synthesis (mRNA translation). mTOR is a master regulator of mRNA translation. It forms two functionally distinct branches, mTORC (mTOR complex) 1 and mTORC2. Based on our published work and unpublished preliminary data, our overall hypothesis is that mTORC1 controls mRNA translation and SCN cell synchrony, whereas mTORC2 controls circadian cytoskeleton reorganization, both of which are critical for the SCN clock function. To test the hypothesis, activities of specific mTOR components will be manipulated by genetic and pharmacological approaches. The circadian clock functions will be assessed at the molecular, cellular and animal behavioral levels using a multidisciplinary approach. Aim 1 will define the functions of the mTORC1 translation effectors S6Ks in the SCN. We hypothesize that S6Ks regulate the photic clock resetting by regulating mRNA translation. Aim 2 will assess a role for mTORC1 in mediating photoperiodic regulation of SCN cell synchrony. We hypothesize that mTORC1 mediates the regulation of SCN synchrony by photoperiods. Aim 3 will identify a role for mTORC2 in the circadian clock. We hypothesize that mTORC2 regulates SCN properties by controlling circadian cytoskeleton reorganization. The proposed work is innovative because it utilizes our latest mouse genetic models to address conceptually novel questions regarding the role of mTOR in the brain clock. The contributions of the proposed work are expected to be significant, because it will elucidate fundamental mechanisms whereby mTOR regulates the function of the circadian clock. Aberrant mTOR activities in the brain are identified in neurological and psychiatric diseases, which are often accompanied by disrupted daily rhythms in patients. FDA-approved mTOR inhibitors can cause sleep problems. The proposed research will generate new knowledge that is essential for a mechanistic understanding of the clinical issues regarding mTOR and clock/sleep disruptions.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract In 2019, nearly 14 of every 100 U.S. adults aged 18 years or older (14.0%) currently smoked cigarettes. Current strategies of tobacco use risk communication include using quantitative information to explain the likelihood that a consequenceof using aproduct will occur (to prevent initiation/encourage cessation) or to explain the reduction of risk when switching products or quitting. Although increasing numeracy (the ability to comprehend numerical information) can increase healthy behaviors, there is a critical barrier in research regarding how numeracy is related to risk understanding and decision-making around tobacco use. There is also a gap regarding how this relationship differs by demographic factors. My overall project goal is to examine the interrelationships among numeracy, risk perception, tobacco product use, cessation, and product switching. These findings will provide evidence for tailored risk communications for individuals with differing numeracy levels. In the F99 phase, we will analyze cross-sectional and longitudinal data to determine whether or not there are associations among numeracy, risk comprehension, and tobacco use behaviors, and if these associations differ by demographic factors. We will use these findings to determine who should be targeted with public health campaigns and how risk should be communicated. In the K00 phase, we aim to find, defend, implement, evaluate, and modify public health campaign strategies to disseminate risk information. Risk communication will be tailored for subpopulations with differing numeracy levels. Numeracy, risk perception, and tobacco-related behaviors are expected to be associated, providing evidence for tailored risk communication for subpopulations with differing numeracy. By identifying which segments of the population have low numeracy (F99 phase), these specific subgroups can be targeted with tailored educational campaigns that communicate risk in a numeracy-level appropriate manner (K00 phase). This project will use both objective and subjective numeracy measures, different types of risk perceptionmeasures, and will look at familiar (e.g., lung cancer) and less familiar (e.g., bladder cancer) tobacco-related health risks. We will analyze data from nationally representative data sets (The Population Assessment of Tobacco and Health (PATH), the Health information National Trends Survey (HINTS), and the Program for the International Assessment of Adult Competencies (PIAAC)) which contain demographic, tobacco use, risk perception, and numeracy measures. The proposed studies will explore numeracy and risk perception of tobacco-related diseases and will add to current literature in this area by focusing on its relationship with specific tobacco-related health behaviors: use, cessation, and product switching. This research will advance the field of cancer prevention by exploring how tobacco product risk can best be communicated to groups that need it. These communications will encourage healthy behaviors and decrease tobacco-related disease outcomes (such as cancer). The findings will help to inform who should be targeted with public health campaigns, how risk should be communicated, and whether these campaigns are efficient.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Maternal-fetal resource allocation is governed by complex maternal physiological adaptations; however, conditions such as obesity and Gestational Diabetes Mellitus (GDM) are associated with a suboptimal adaptive response to pregnancy resulting in under- or overnutrition in utero. In utero overnutrition (i.e., fetal over- nourishment by excess exposure to maternal fuels) is a concern given the earlier onset of obesity and cardiometabolic disease in youth. Moreover, higher glycemia and adiposity, even below thresholds of clinical GDM and obesity, have detrimental effects on offspring health. Such metabolic heterogeneity is noteworthy as it influences target tissues involved in fetal development, such as the placenta. Characterizing metabolic variability in pregnant women and assessing associations with offspring metabolic health will reveal nuances in maternal phenotypes that contribute to metabolic disease risk in offspring. However, the associations of maternal metabolic heterogeneity with maternal fuels (e.g., glucose, insulin, lipids) and modifiable behaviors are unclear. Moreover, it is unknown if placental signaling, which is implicated in fetal programming, reflects metabolic heterogeneity assessed via circulating biomarkers during pregnancy. Dr. Ellen Francis’ proposal addresses these knowledge gaps by integrating low- and high-dimensional observational data and applying advanced statistical techniques to test the hypothesis that distinct maternal metabolic subgroups correspond to differences in placental signaling pathways, and that the maternal subgroups and placental pathways are involved in programming of offspring metabolic risk. This proposal will use existing samples of fasting maternal blood during pregnancy (N=1410), placental villus tissue, and collect new metabolomics in offspring at 4-8 years of age. Through didactic instruction and mentored training, Dr. Francis will obtain training in the analysis of ‘omics data within a lifecourse epidemiological framework to characterize metabolic variability in pregnancy and generate metabolic subgroups related to adiposity and maternal fuels. She will advance her understanding of placental and developmental biology (fetal programing) by receiving extensive hands-on-training (inclusion in lab and bench training, and conference and seminar attendance) from mentors with expertise in placental and perinatal biology. In the independent phase, she will use training gained in the mentored phase to assess if maternal metabolic subgroups are reflected in placental nutrient sensing pathways, generate metabolomics data in offspring and create offspring metabolic profiles. She will then assess whether maternal metabolic subgroups are associated with offspring metabolic profiles in childhood, and the extent to which these associations are mediated by placental nutrient sensing pathways. Findings from these complementary studies will improve our understanding of metabolic pathways involved in fetal development, contribute to knowledge of how maternal metabolic variability influences metabolic risk in offspring, and could reveal key cellular and behavioral targets for prevention strategies, while assisting Dr. Francis’ to establish a career as an independent investigator.