Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Continued tobacco use among cancer survivors is linked to an increased risk of lowered effectiveness of cancer treatment, greater cancer-related mortality, developing a secondary primary cancer, worse quality of life, and increased cancer treatment costs ($3.4 billion/year). Despite high quit rates at cancer diagnosis, more than half of survivors who quit resume smoking shortly thereafter. Mindfulness-based interventions (MBIs) hold great promise in enhancing smoking abstinence among cancer survivors given its emphasis on purposefully paying attention to immediate experience, thereby reducing reactivity to smoking triggers. The current proposal addresses significant gaps in the extant smoking cessation literature for cancer survivors, which include: (1) A limited understanding of the role of dynamic relations between cancer-specific (e.g., fatigue, pain, fear of cancer recurrence) and general smoking risk factors (e.g., negative affect) contributing to smoking relapse given the known chronic high stress level among cancer survivors, (2) Lack of real-time cessation interventions using portable mobile devices such as smartphones (i.e., mobile health [mHealth]), (3) Little attention given to cancer- specific cessation barriers for cancer survivors (e.g., shame, guilt) and (4) Barriers to treatment accessibility among existing MBIs due to the time-intensiveness and in-person format. To address these gaps, the objective of this proposal is to develop a mindfulness-based ecological momentary intervention (mindEMI) that delivers MBI content in real-time and in the real world where quitting smoking takes place, and, when an elevated level Dr. Yang’s long-term career goal is to develop and evaluate accessible and scalable mHealth smoking cessation interventions for cancer prevention with expertise in real-time measurement of cognitive-affective constructs. As such, training goals address tobacco use and cancer survivorship, mHealth and clinical trials methodology, quantitative and qualitative methods, clinical delivery of MBIs, and professional development. of cancer-specific smoking relapse risk is indicated through ecological momentary assessment (EMA). There are three specific aims. The K99 phase will take place at the Moffitt Cancer Center. The aims during the K99 phase include: (1) To identify the most psychometrically sound EMA items for measuring negative affect, positive affect, and state mindfulness and (2) to develop a mindEMI targeting cancer-specific smoking vulnerabilities through an iterative multi-step process among cancer survivors who smoke. The R00 phase aims to conduct a 2-arm pilot randomized controlled trial (RCT) among cancer survivors to test the feasibility and acceptability of the mindEMI for smoking cessation. Feasibility of RCT procedures in preparation for a larger subsequent study will also be examined. This proposal is highly innovative because the mindEMI will address a crucial gap in the literature by targeting cancer-specific smoking vulnerabilities and deliver an MBI in real-time when relapse risk is high for cancer survivors. This work will inform a future trial to fully test the efficacy of mindEMI and directly addresses the NCI’s mission to conduct and support cancer research to promote longer and healthier lives.

NIH Research Projects · FY 2026 · 2023-04

Abstract: TB-RICC 3.0 is designed to support the production of the highest quality observational and interventional research on tuberculosis (TB) and TB-HIV. To accomplish this goal, TB-RICC 3.0 will: i) collaborate with RePORT Country-Network Data Centers and Biorepositories to ensure that common data elements (CDE) of the Common Protocol and Specimen Tracking are accessible through the Global Data Template; ii) organize and/or strengthen select sites to participate in diagnostic studies and clinical trials; and iii) support the RePORT Country-Networks to ensure further development of TB diagnostic laboratories, TB-RICC 3.0 specialized laboratories, and biorepositories.

NIH Research Projects · FY 2024 · 2023-04

PROJECT SUMMARY This K01 application is designed to provide Jessica King, PhD, with the mentored training necessary to transition into an independent tobacco regulatory science researcher. Dr. King will be mentored by a team of renowned tobacco control and tobacco regulatory scientists and will complete mentored training, coursework, and professional development in the areas of advanced statistical analyses, policy impact analyses, and health disparities. This additional career development and mentorship will directly contribute to completing the proposed research strategy, which examines the impact of cigar pack quantity on tobacco use behaviors. Cigar use is the third most commonly used tobacco product among adults, and second most commonly used product among youth, with use increasing among low income, minority, and young adult populations. Given the significant health effects attributable to cigar use, this represents a critical health disparity. Low cost is often cited as a reason for increased use among these populations, in part due to low taxes and varying pack quantities. Research on cigarettes has shown minimum pack quantity laws increase price and decrease use. As of 2016, the FDA has regulatory authority over cigars, allowing it to regulate the marketing, manufacturing, and distribution of cigar products, including mandating minimum pack quantities. However, cigar-specific data are needed to inform FDA's regulation. Thus, the goal of the proposed analyses are to advance understanding of the relationship between cigar pack quantity and tobacco use behaviors to inform regulation on minimum cigar pack quantity. Specifically, we aim to (1) assess whether cigar pack quantity is associated with between- and within-person changes in cigar use and whether there are differences by sociodemographic factors, (2-3) identify the impact of local minimum cigar pack quantity laws on cigar and other tobacco use and cigar sales and whether impacts differ across communities of varying demographics, and (4) characterize differences in the implementation and enforcement of minimum cigar pack quantity laws through qualitative interviews with key implementation personnel. In this mixed-methods approach, we will utilize national datasets, including the Population Assessment of Tobacco and Health Study, the Tobacco Use Supplement to the Current Population Survey, the Youth Risk Behavior Surveillance System, and Nielsen retail scanner data. Each aim will explicitly examine the impact among racial and ethnic minorities, low income populations, youth, and young adults, each vulnerable populations. This research will directly address the FDA Center for Tobacco Products Scientific Domains of behavior and impact analysis. The findings from this study may inform future FDA rulemaking on cigar pack quantity.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT Solute carrier (SLC) proteins are membrane transporters that govern the cross-membrane exchanges of glucose, amino acids, inorganic ions, and other small molecule metabolites. Many SLC genes have been shown to be causes of Mendelian diseases in humans, and a number of SLC transporters are important drug targets. However, due to myriad technical difficulties, a large fraction of SLC family members are still orphan transporters without known substrates, which represents both a significant knowledge gap and a huge opportunity for new drug development. In order to systematically study the biochemical functions of the orphan SLC transporters, a computational workflow was developed in our lab, which combines public transcriptomic and metabolomic datasets to uncover the metabolic function of SLC transporters. Using this association analysis, an uncharacterized gene, SLC45A4, was identified to be the single greatest determinant of γ-Aminobutyric acid (GABA) levels in human cancer cells. GABA, which is mostly known as an inhibitory neurotransmitter in the mammalian central nervous system, functions in peripheral tissues to regulate cell proliferation, differentiation, and migration. Given the importance of these functions in both cancer and normal cells, it is essential to understand how SLC45A4 functions in the context of GABA metabolism in non-neuronal cells. Using stable isotope tracing, it was found that SLC45A4 increases cellular GABA levels not by promoting GABA uptake but by facilitating GABA de novo synthesis, suggesting an entirely new mechanism of the regulation of GABA synthesis. Therefore, it is hypothesized that SLC45A4 encodes a subcellular ornithine transporter that supports GABA production. This program will move forward in three directions: Aim 1, determining the biochemical mechanism by which SLC45A4 promotes cellular GABA production; Aim 2, determining the subcellular compartmentalization of SLC45A4 transporter and GABA synthesis; and Aim 3, determining substrate preference and enzymatic properties of SLC45A4. The overall goal is to determine how SLC45A4 regulates de novo GABA synthesis, which contributes to the fundamental knowledge of human biochemistry and may provide new therapeutics targeting GABA metabolism.

NIH Research Projects · FY 2025 · 2023-04

ABSTRACT Oncology clinical trials are increasingly complex in their design, management, and oversight, and clinical trials continue as the cornerstone to transform cancer care for patients. These multifaceted trials require significant partnership from the institution and investigators to provide support and effort as well as multifaceted teams to conduct and execute these trials seamlessly and effectively. Furthermore, the dissemination of clinical trial findings in a timely and efficient manner requires the continued support from the clinical trials teams, biostatisticians, and co-investigators in terms of time and effort. Dr. Jabbour is a seasoned research specialist, physician scientist, and clinician scientist having a proven track record of diligence and innovation as well as purpose to design, carry out, and complete clinical trials. Her long-standing commitment to clinical trials is paramount as she is a leader at the Rutgers Cancer Institute of New Jersey in mentoring and supporting other clinical trialists, having overseen the Human Research Oversight Committee (HROC/DSMB) and currently overseeing the Scientific Review Board, and she plays integral role in the oversight of clinical trials through a variety of committees both at Rutgers Cancer Institute and nationally. At the national level, Dr. Jabbour is the contact PI for the Rutgers Cancer Institute ETCTN/CTEP grant funding, is a long-standing Co-Chair for the NCI Radiation Research Program Gastrointestinal Interest Group, and is actively involved in a variety of NCI Cooperative Group Committees and Protocols including the ECOG-ACRIN and NRG Oncology Cooperative Groups. Dr. Jabbour is a continued leader and pioneer as a clinician scientist and actively studies the use of novel agents in combination with radiation in ground-breaking clinical trials. Dr. Jabbour will continue her exemplary efforts and work under the auspices of this R50 Mechanism and will continue to revolutionize the care for oncology patients through her state-of-the-art concepts and collaborations through the NCI national cooperative groups.

NIH Research Projects · FY 2026 · 2023-03

Summary 3q29 deletion syndrome is caused by a typically de novo 1.6 Mb deletion of 21 genes. The syndrome is associated with an astonishing 40-fold increased risk for schizophrenia, as well as cognitive disability, a high rate of autism and social disability, executive function deficits and pronounced prevalence of attention deficit hyperactivity disorder (ADHD), clinically significant graphomotor weakness, and manifestation of anxiety disorders. The factors that contribute to this phenotypic heterogeneity are not understood. We propose to evaluate 200 individuals with the 3q29 deletion, to better define phenotypic manifestations and identify risk modifiers for key phenotypes. In particular, we seek to understand how polygenic background and sex of the proband may modify risk for psychosis, cognitive disability, social functioning, and other phenotypes. To facilitate our evaluation and attenuate ascertainment bias, we have developed a remote phenotyping battery, which does not require travel to a testing site. This remote battery removes barriers to participation for our study subjects and dramatically reduces costs, improving the efficiency of our study. Using this validated phenotyping protocol, we will characterize 200 new study subjects with the 3q29 deletion, and identify the full phenotypic spectrum, sex-dependent phenotypic risks and significant comorbid relationships. We will also phenotype biological parents to contextualize the burden of illness in 3q29 deletion syndrome relative to departure from mid-parental phenotype, and clarify the range of phenotypic heterogeneity in 3q29 deletion syndrome. We will collect DNA from our study subjects, to directly test the contribution of polygenic risk to selected phenotypes. Finally, in a collaboration with the NIMH-sponsored Genes 2 Mental Health Network, we will compare the phenotypic spectrum and risk modifiers of 3q29 deletion syndrome with >2,000 samples from other genomic disorders associated with neurodevelopmental and neuropsychiatric disorders, including 22q11.2 deletion and duplication, 16p11 deletion and duplication, 1q21 deletion, and others. At the end of this project, we will have a comprehensive survey of 3q29 deletion associated phenotypes, an understanding of how sex and polygenic background may increase or attenuate phenotypic risks in 3q29 deletion syndrome, and an appreciation for how the 3q29 deletion compares to the broader landscape of rare genetic disorders associated with developmental brain disorders. All genotype and phenotype data from this study will be shared in publicly-available databases, including dbGaP and NDAR.

NIH Research Projects · FY 2026 · 2023-03

Genetic testing (GT) for hereditary cancer and related health services do not reach all segments of the population equitably. Racial disparities in genomic care are profound, persistent, and growing. Less than 30% of high-risk cancer patients are referred for germline GT, with appreciably lower referral and testing rates among racial minorities, especially among Blacks. GT of cancer survivors can directly inform treatment following progression or treatment resistance and can facilitate primary and secondary prevention of cancers in their unaffected relatives. Demand for GC (genetic counseling) and GT continues to increase with expanding GT indications and decreasing sequencing costs yet supply of genetic counselors remains limited. The conventional approach of referral to pretest genetic counseling is a common barrier to receiving GT. Further, evidence suggests that traditional comprehensive, pre-test GC does not meet the needs of many survivors, especially underserved minorities. Thus, new models of genome-based care are needed that are responsive to community needs, improve access, do not overburden scarce genetic counseling resources, and do not widen existing disparities. Some health care systems and commercial GT laboratories use digital interventions, including videos and relational agents (RAs), instead of traditional pre-test GC sessions, without providing specifics about community engagement development, acceptability, or efficacy in oncology settings through a rigorous methodologic strategy as we propose. Given the life-saving benefits of GT, understanding how to effectively educate, empower and test high-risk patients in a culturally acceptable way can move the field forward and reduce persistent racial disparities. This study will address this translational gap. In response to community identified needs and enthusiastic support from cancer patients, relatives and community advocates while also building on our pilot work, we will enroll 428 Black cancer patients meeting national guidelines for GT into a 2-arm randomized controlled trial. This approach may be of particular benefit to hundreds of thousands Black patients and their relatives because they are often unaware of their risks, less likely to have a provider discuss their risk and refer them for GT at the time of diagnosis and are not equably garnering the potentially lifesaving benefits of personalized prevention, screening, and treatment. The specific aims are to: 1) Compare the efficacy of a culturally tailored RA vs. Enhanced Usual Care (EUC) on engagement in genetic education and GT uptake; 2) Evaluate the impact of the RA vs. EUC on informed decision-making and psychosocial outcomes; and 3) Explore potential mechanisms by assessing mediators and moderations of effectiveness. Data from this trial can be used to guide clinical practice and policy decisions for advancing cancer health equity and improving access to genetic education and GT. If successful, this approach could be applied to other cancers and chronic conditions.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is the second most common leukemia in adults and typically has a dismal prognosis and high mortality, which is exemplified by a 28% five-year overall survival rate. Venetoclax, a selective inhibitor of the anti-apoptotic protein BCL-2, has received FDA approval for the treatment of AML. Despite promising early responses of AML patients to venetoclax, drug resistance ensues after prolonged treatment and highlights the urgency for a deep understanding of the underlying mechanisms. Recently, I discovered that mitochondria in AML cells undergo a morphological change upon venetoclax resistance. Using a genome-wide CRISPRi screen in human AML, I identified genes involved in mitochondrial structure as synthetic lethal vulnerabilities for venetoclax in AML. Mitochondria of venetoclax-resistant AML cells actively modify their architecture and function to prevent apoptosis. Supporting this, OPA1, the master regulator of mitochondrial cristae structure, and CLPB, a mitochondrial chaperonin, were strikingly upregulated in venetoclax-resistant AML cells relative to the sensitive cells. CLPB directly interacts with OPA1 to maintain the physiological mitochondrial morphology. Promisingly, genetic CLPB or OPA1 ablation enhances venetoclax-induced apoptosis of AML cells, by promoting cristae remodeling and mitochondrial stress. This proposal aims to leverage these observations by 1) delineating the mechanistic details by which mitochondrial dynamics and homeostasis lead to acquisition of drug resistance in AML, using super-resolution microscopy, electron tomography, and biochemical techniques, and 2) assessing the therapeutic potential of perturbing mitochondrial structure to augment venetoclax action in preclinical AML mouse models. This research stands to have significant clinical impact, because it can serve as a basis for developing new combinational targeted therapies for patients with AML. In addition, this proposal outlines my career development plan for obtaining the requisite training to transition into a successful independent investigator. This includes 1) guidance from my esteemed mentor Dr. Iannis Aifantis, expert in blood malignancies and mouse models; 2) scientific training by an expert advisory panel, consisting of Drs. Raoul Tibes, Hans-Willem Snoeck, Kivanc Birsoy and Evripidis Gavathiotis, all in top institutes of NYC; 3) hands-on training using state-of-art equipment, including super-resolution microscopy with Dr. Eli Rothenberg; 4) collaboration with experts in microscopy and bioinformatics; and 5) career development courses sponsored by NYU. The laboratory of Dr. Aifantis and NYU Department of Pathology will provide the resources critical to my training and research, ensuring my success. This extensive professional growth program will guide me during the mentored phase excelling as an independent academic scientist. Collectively, the proposed research and career development plans are expected to generate data with significant impact on circumventing targeted-therapy resistance in AML and setting the basis of my future research as an independent researcher.

NIH Research Projects · FY 2026 · 2023-02

Project Summary Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and reduced insulin secretion. Cellular repressor of E1A-stimulated genes 1 (CREG1), a small glycoprotein involved in membrane trafficking in the endocytic and secretory pathways, may be involved in the pathogenesis of T2DM, as suggested by the insulin resistance, glucose intolerance, elevated glycemia and hypoinsulinemia in whole-body Creg1 knockout mice. Gain- and loss-of-function studies using cultured hepatocytes and liver-specific Creg1 knockout mice demonstrate that CREG1 autonomously regulates cellular insulin signaling, insulin sensitivity, and the expression of insulin receptor on the plasma membrane. In pancreatic ?-cell-specific Creg1 knockout islets, increased proinsulin and diminished insulin levels lead to impaired insulin secretion. Furthermore, CREG1 expression is nutritionally regulated and is progressively downregulated by high-fat diet consumption. This project will test (1) whether loss of CREG1 inhibits insulin receptor recycling and consequently impairs insulin signaling and insulin action, (2) to what degree CREG1 downregulation contributes to insulin resistance in metabolic disease, and (3) whether Creg1 ablation impedes insulin granule trafficking and enhances insulin degradation. In the first Aim, we will delineate the role of CREG1 in the regulation of insulin receptor trafficking and its contribution to hepatic insulin action and cellular insulin signaling. We will restore CREG1 expression in high fat diet fed mice via adeno- associated virus-mediated CREG1 gene delivery and test if this improves insulin sensitivity and insulin signaling. In the second Aim, we will elucidate how loss of CREG1 leads to reduced ?-cell insulin content with a focus on proinsulin processing and insulin degradation. Pulse-chase labeling and live cell imaging, electron microscopy, and biochemical analysis combined with complex physiological study protocols will be used in the proposed studies. Our long-term goals are to elucidate how CREG1 regulates hepatic insulin action and ?-cell insulin secretion, and to target CREG1 to treat T2DM.

NIH Research Projects · FY 2026 · 2023-02

Abstract Chronic itch is a debilitating condition and represents a clinical challenge. Increase evidence has demonstrated that neuronal and astrocytic signaling pathways in the spinal cord play a crucial role in chronic itch. Although several molecules have been identified as key itch mediators/modulators, molecular mechanisms underlying chronic itch remain incompletely understood. Our research has been focused on role of store-operated calcium channels (SOCs) in pain and itch. We have shown that the primary SOC family members STIM1 and STIM2 (endoplasmic reticulum Ca2+ sensors) are expressed in dorsal horn neurons and astrocytes, but their functional significance in the spinal cord is still elusive. We recently generated vesicular glutamate transporters 2 (Vglut2, an excitatory neuron marker) conditional STIM1 and STIM2 knockout (KO) mice. Our pilot data showed that deletion of STIM1 in Vglut2+ neurons attenuated nociception, but did not affect pruritogen-induced scratches. In contrast, ablation of STIM2 in Vglut2+ neurons (v-STIM2 KO) markedly attenuated pruritogen-induced scratches, but had no effect on nociception. These exciting pilot work suggests that STIM1 and STIM2 play distinct roles in pain and itch. Our pilot data also show that inhibition of STIMs by intrathecal, not intradermal injection, decreased histamine (His)- and chloroquine (CQ)-induced itch behavior. Moreover, inhibition or deletion of excitatory neuronal STIM2 attenuated FITC- and DNFB-induced chronic itch, suggesting that neuronal STIM2 play a role in both acute and chronic itch. Importantly, STIM2 expression was increased in the dorsal horn from diphenylcyclopropenone (DCP)- and 1-fluoro-2, 4-dinitrobenzene (DNFB)-induced mouse models of chronic itch. GRPR plays a critical role in itch transmission. Our pilot data showed that deletion of STIM2 in Vglut2 or Lbx1 (specifically expressed in spinal and hindbrain neurons)-expressing neurons drastically attenuated GRP-induced Ca2+ responses and itch behavior. It is known that signal transducer and activator of transcription 3 (STAT3) and its downstream lipocalin-2 (LCN2) are key modulators of chronic itch. We found that activation of TLR4 upregulated STIM2 expression via STAT3 signaling. Based on these findings, we hypothesize that spinal STIM2 plays a crucial role in chronic itch through a combination of neuronal and astrocytic signaling pathways. In Aim 1, we will determine whether ablation or knockdown of spinal STIM2 attenuates chronic itch. In Aim 2, we will examine the expression and function of STIM2 under chronic itch conditions. In Aim 3, we will investigate the mechanisms underlying spinal STIM2 involvement in chronic itch. The proposed work will establish a novel role of STIM2 in itch sensation and will provide new insights into the mechanisms of GRPR in itch transmission. Successful completion of this research will not only identify STIM2 as a key modulator in chronic itch, but also decipher the cellular and molecular mechanisms underlying chronic itch.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY. Mucosal surveillance of the intestinal barrier by tissue-resident lymphocytes is critical for preventing the invasion of enteric pathogens and a necessary component of protective immunity. A single layer of epithelial cells lines the intestinal tract and provides a physical barrier between microbes, dietary antigens, toxins and the rest of the tissue. Therefore, the reactivation of lymphocytes at the intestinal barrier must be tightly regulated, as too robust of a response could result in destruction of the epithelium leading to microbial translocation and eventual autoimmunity, as observed in inflammatory bowel disease and celiac disease. Tissue-resident intraepithelial lymphocytes (IELs) in the intestine provide a first line of defense against invading microorganisms and the intestinal IEL compartment is composed of what has been termed induced and natural IELs. Induced IELs are CD8ab+ TCRab+ tissue resident memory (Trm IELs) cells that are recruited to the epithelial compartment following antigen exposure. In contrast, natural IELs are not MHC-restricted and include CD8aa+ IELs expressing TCRgd (gd IELs). gd and Trm IELs represent the majority of the lymphocytes in the intestinal epithelium and could serve both protective and pathogenic roles, yet mechanisms regulating their activation during infection in vivo remain largely unexplored. CD103 (aEb7 integrin) is expressed by the majority of gd and Trm IELs located in the intestine and at other barrier sites. CD103 binds to epithelial E-cadherin and plays an important role in the recruitment and maintenance of tissue lymphocytes. However, the contribution of CD103 to IEL functionality within the intestine during infection has not been addressed. Successful completion of the proposed aims will provide fundamental insight into the molecular mechanisms by which CD103 ligation to E-cadherin promotes (1) the motility and activation of Trm and (2) gd IELs and the role of CD103 in promoting protective responses to enteric infection. These studies will uncover novel mechanisms by which direct interaction between IELs and epithelial cells contribute to host immunity and further define the molecular cues regulating sentinel lymphocyte populations in mucosal homeostasis and infection.

NIH Research Projects · FY 2025 · 2023-02

Abstract Over the next decade, more than 70% of people living with HIV will be older than 50, of whom the majority are men who have sex with men living with HIV (MLWH) The increasing burden of the non-communicable diseases (NCDs) hypertension, diabetes, and dyslipidemia has already begun to present key challenges to effective HIV care among aging PLWH. Because these NCDs often present together as comorbid conditions, interact with each other adversely, and are influenced by varying systemic and environmental factors, they may comprise a synergistic epidemic. In the U.S., there is variation in disease prevalence across demographic and geographic populations related to prevalence and/or control of NCDs and HIV. Behavioral and psychological stressors may contribute to observed differences in health outcomes through direct and indirect mechanisms. Directly, negative experiences in healthcare settings may contribute to healthcare avoidance, decreasing success rates along HIV and NCD continua of care domains of retention, treatment, adherence, and disease control. Indirectly, negative experiences in healthcare settings may contribute to co-occurring challenges such as emotional strain, depression, and substance use, thereby contributing to HIV and NCD incidence, prevalence, and poorer disease control. Very few if any studies have prospectively assessed the contribution of these factors in NCD incidence, prevalence, and control among MLWH; and few if any studies have rigorously assessed how behavioral and psychological stressors may influence the relationship between demographic factors and NCD and HIV outcomes. Collecting data over a four-year period, we will utilize the MACS/WIHS Combined Cohort Study, the longest-running cohort study of MLWH the U.S., to assess the following specific aims among MLWH and without HIV: 1) assess variation in behavioral and psychological stressors across demographic and geographic populations in the context of HIV; 2) assess variation in NCD incidence and prevalence across demographic and geographic populations in the context of HIV; and 3) assess how behavioral and psychological variables may act as risk and protective factors for geographic and demographic variance in NCD outcomes. Our key scientific premise is that behavioral and psychological stressors mediate differing health outcomes in NCD incidence, prevalence, and control by geography and demographics among men in the context of HIV. The proposed work will extend research on the HIV continuum of care to the NCD continuum of care. This study will provide critical data for informing the development of integrated interventions designed to improve care coordination and treatment adherence across geographically and demographically defined populations.

NIH Research Projects · FY 2026 · 2023-02

Multimorbidity, defined as the co-occurrence of two or more medical conditions, impacts two-thirds of older individuals over 65 – corresponding to 36 million U.S. adults, and is a major driver of healthcare spending, polypharmacy, and mortality. However, the routine exclusion of older and more multimorbid patients from clinical trials has resulted in the paucity of data regarding the risks and benefits of medications in this population, or an understanding of how multimorbidity alters treatment effects. To address this unmet need, this proposal will evaluate the role of multimorbidity in modulating medication effects and identify the optimal approach that best quantifies its impact on medication outcomes. Our central hypothesis is that (a) by attenuating drug-related benefits and amplifying drug-related harms, multimorbidity should be a key consideration when making treatment decisions, and that (b) approaches that incorporate the cumulative burden of illness – especially the multi- morbidity weighted index [MWI] – can better characterize these alterations in medication effects (preliminary analysis). The proposal will use Medicare fee-for-service data from >23 million patients and replicate findings in two large external databases. We will focus on cardiometabolic therapies as: older adults have the highest burden of these conditions, and since 2010, more than 20 new cardiometabolic therapies have been approved, highlighting the immense need to study these medications. We will identify patients with: (a) type 2 diabetes initiating sodium glucose co-transporter 2 inhibitors vs established antidiabetic therapies; (b) atrial fibrillation initiating direct oral anticoagulants vs warfarin; and (c) atherosclerotic cardiovascular disease [CVD] initiating newer antiplatelet drugs (e.g. ticagrelor) vs clopidogrel. Aim 1 will evaluate how clinical (e.g. cognitive impairment) and non-clinical (e.g. social deprivation) factors interact with multimorbidity to influence medication prescribing of cardiometabolic therapies in the real world. Aim 2 will elucidate the role of multimorbidity in modulating the risks and benefits for newer compared to established cardiometabolic medications by estimating the adjusted rates of disease specific benefits (i.e. reduction in CVD events), harms (e.g. major bleeding) and universal outcome measures (e.g. home-time, loss of functional independence) by levels of multimorbidity. We will also validate multimorbidity measures (e.g. MWI, Elixhauser index) and frameworks (e.g. disease dyads) against medication outcomes. The impact of this proposal is significant as it will establish a rigorous and readily scalable framework to study the effects of multimorbidity on drug outcomes in older adults. It will also represent the first effort to systematically evaluate and validate multimorbidity indices and approaches against medication outcomes, beginning a new and exciting line of research that has potential to expand to other populations (e.g. middle-aged adults) and clinical areas. Given the paucity of data from clinical trials, study findings will serve as the primary source of information for patients, caregivers, and clinicians to make individualized evidence-based decisions.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ABSTRACT Advanced heart diseases lead to a reduced blood supply from the heart and consequently fatigue and deficits in performing physical activity. In the proposed research, we will assess the lack of physiological reserve in older adults with advanced heart disease, focusing on motor and cardiac function, to develop a novel, objective, quick, and accurate frailty score. We designed this approach to enhance candidate selection of older adults going through invasive therapies for advanced heart diseases. Although our approach is generic, to reduce between- subject variability we focus on transcatheter aortic valve replacement (TAVR) for older adult with aortic stenosis. Therapeutic options continue to grow for TAVR; however, it can be difficult to identify candidates with frailty level that prohibit them from tolerating the stress from aggressive therapy and those with potential reversible frailty. It is thus critically important to introduce meaningful routine objective frailty assessment into clinical care of cardiac patients. Frailty assessment is, however, not common in cardiology because current assessment tools are burdensome for older adults with advanced heart disease and impractical to implement in busy clinical environments. More importantly, no disease-specific tool is available to identify heart disease-related frailty. In continuation of our research program in the field of sensor-based frailty assessment, within our multidisciplinary team of engineers, cardiologists, and geriatricians, we propose the multimodal upper-extremity function (UEF) test for identifying frailty among older adults with advanced heart disease. UEF incorporates a synchronized system of motion sensors and electrocardiography (ECG) to measure motor performance and heart rate (HR) during a rapid 20-second elbow flexion task. Using our previously established UEF motion tracking component, we can precisely measure the level of deficits in motor performance (slowness, weakness, inflexibility, and fatigue), which are not detectable using eyeball assessment. Using the ECG setup, minimizing the motion artifact using this localized task, we accurately track HR response to the physical demand, as well as recovery behavior after the task. HR behavior during the task and recovery (HR dynamics) provide a measure of cardiac reserve associated with frailty in heart disease. We will further quantify dysregulation between HR response and motor demand as a novel measure of resilience. Based on our preliminary data, we expect a weaker and delayed HR response to physical activity as well as an impaired motor function due to frailty. The proposed research will be a four-year study at the University of Arizona Cardiovascular program. In the first arm, we will establish a new HR score and merge it with our previously validated UEF motor score to develop a multimodal frailty score among older adults with advanced heart disease (n=120). In the second arm, in a longitudinally setting we will validate the UEF multimodal frailty score for predicting TAVR complications for advanced heart disease (n=75). Accomplishing these aims, we will promote HR dynamic assessment for risk stratification of older adults with advanced heart disease, with huge potentials for other comorbid conditions.

NIH Research Projects · FY 2025 · 2023-01

Project Summary/Abstract The overarching goal of this proposal is to develop the skills required to achieve my career goal of becoming an independent investigator with a research focus on the role of blood coagulation factors in cell signaling during tissue injury and inflammation. Accordingly, I have developed a Research Plan that will build a strong foundation for conducting research across disciplines in hepatology, toxicology, and thrombosis and hemostasis. Strong clinical and experimental evidence suggests that the blood coagulation cascade plays a pathologic role in the progression of hepatic fibrosis, i.e., “scarring” of the chronically injured liver. One hypothesis linking coagulation activity to hepatic fibrosis proposes that the coagulation protease thrombin drives hepatic stellate cells (HSCs) to a collagen-expressing myofibroblast phenotype by activating its primary receptor, protease-activated receptor- 1 (PAR-1). However, the precise mechanisms linking PAR-1 activation to the HSC pro-fibrotic phenotype are unknown. My central hypothesis is that thrombin activation of PAR-1 drives HSCs to a pro-fibrotic phenotype by amplifying the signaling functions of tissue factor (TF), the transmembrane receptor for coagulation factor VIIa (FVIIa). To test this hypothesis, I propose three Specific Aims. First, I will determine the mechanisms whereby PAR-1 activation drives a pro-fibrotic phenotype in hepatic stellate cells. I hypothesize that PAR-1 activation amplifies the HSC pro-fibrotic phenotype through induction of TF:FVIIa signaling. The role of TF:FVIIa signaling in PAR-1-mediated HSC activation will be determined using a combination of in vitro approaches including exogenous FVIIa treatment and HSCs lacking TF or PAR-2 (i.e., the receptor mediating TF:FVIIa signaling). The role of HSC TF in experimental hepatic fibrosis will be determined using novel mice with HSC-specific TF deficiency. Next, I will determine the role of thrombin:PAR-1 signaling in experimental hepatic fibrosis. The precise role of thrombin-mediated PAR-1 activation in hepatic fibrosis has never been investigated in vivo because PAR-1 can be cleaved by multiple proteases. I hypothesize that activation of PAR-1 by thrombin drives experimental hepatic fibrosis. To test this hypothesis, I will use a combination of strategies including mice expressing ~10% of normal prothrombin levels and novel mutant mice expressing PAR-1 that is selectively insensitive to cleavage at specific residues by thrombin or by other agonist proteases. Finally, I will identify the mechanisms driving coagulation activation in the injured liver. I hypothesize that coagulation activation in experimental CCl4-induced chronic liver injury is driven by the intrinsic coagulation pathway. I will use complementary genetic and pharmacologic approaches to determine the precise role of the extrinsic and intrinsic pathways of coagulation cascade activation in hepatic fibrosis driven by experimental chronic liver injury. The proposed studies will allow me to carve out a unique research niche investigating the cell signaling functions of blood coagulation factors, and would ultimately drive development of novel therapeutics which target local coagulation-mediated cell signaling events to reduce hepatic fibrosis with minimal impact on normal hemostasis.

NIH Research Projects · FY 2026 · 2023-01

Melanoma, while composing only 1% of all skin cancers, causes the majority of skin cancer related deaths. In the United States alone, over 100,000 new patients have been diagnosed with melanoma in 2021. While plastic surgeons are frequently responsible for the oncologic reconstruction and removal of melanoma, few surgeons in this field have the basic science training needed to understand the underlying molecular defects of this condition or the dynamics of the mammalian epidermal microenvironment, in which they specialize. Such knowledge is crucial for a holistic approach to the field of plastic surgery because the dysregulation of intercellular communication between cells in this skin microenvironment, such as melanocytes, fibroblasts, and keratinocytes, leads to various aesthetic and life altering defects such as those seen in vitiligo, keloid formation and melanoma. We believe that a better understanding of developmental melanoblast migration can provide a framework for future patient interventions and provide much needed context for future surgeons. This belief is supported by recent studies in human melanoma, which show that the transcriptomic genetic profile of melanoma cells closely mimic developmental melanoblasts. Second, it is well established that one of the hallmarks of malignant melanoma is the loss of E-cadherin and upregulation of N-cadherin, but how adhesive interactions between melanocytes and their surrounding keratinocytes via E-cadherin regulate melanocyte behavior and homeostasis is not well understood. I hypothesize that melanocytes form specialized adhesions with keratinocytes that serve to maintain the epidermal barrier while simultaneously promoting melanocyte migration, colonization, and retention within the epidermis. I plan to test this hypothesis, by using the Cre-Lox system under the control of a K14 epithelial promoter to selectively label melanocytes and knockout E-cadherin in the keratinocyte microenvironment of the epidermis. I will then characterize the impact of disrupted melanocyte-epithelial adhesions on melanocyte migration, protrusivity and colonization (Aim 1), identify the composition and localization of melanocyte-epidermal adhesions and actin regulators (Aim 2) and determine the impact of disrupted melanocyte-epithelial AJs on melanoma progression in a melanoma mouse model (Aim 3). This proposed project will be the first of its kind to characterize the impact of the surrounding keratinocyte microenvironment on melanoblast migration and function; thus, seeing the epidermis as a complex microenvironment with varying cell types, a biological reality that is often overlooked in medical training. This proposed project and the training plan herein is designed to cultivate the necessary training to provide an increase in translational research to the field of plastic surgery. This collaboration between Princeton University and Robert Wood Johnson University Hospital Department of Plastic Surgery provides the clinical, basic science training, mentorship, and resources necessary to accomplish this goal. It is our hope that this work will be used to benefit patients with a history of melanoma worldwide.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ABSTRACT Evidence suggests that the prevalence of certain developmental disorders, specifically autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), has increased sharply in recent decades. Recent studies have shown a moderate heritability for neurodevelopmental delays (NDDs), suggesting a nongenetic component contributing to its etiology. The estimated annual cost of environmentally mediated NDDs in US children is $18.3 billion. Epidemiologic studies examined prenatal and early childhood exposure to air pollutants and NDDs, with non-conclusive evidence on the effects of different pollutants, interactions, sensitive windows of exposure and chemical components of PM2.5. In addition, the role of socioeconomic status (SES) in these associations is complex. Our overarching goal is to comprehensively investigate the independent and joint prenatal and early childhood exposure to PM2.5, NO2 and O3, PM2.5 chemical components and interactions with temperature on NDDs as well as effect modification by SES. The specific aims of this application are: 1) Quantify the association prenatal and early childhood exposure to PM2.5, NO2, O3, temperature and NDDs, 2) Examine the association between prenatal and early childhood exposure to PM2.5 chemical speciation and NDDs, and 3) Examine pathways and synergistic effects, among environmental exposures and SES on NDDs. We have established a birth cohort of more than 4 million pregnancies from two population-based databases—the Medicaid Analytic eXtract and IBM MarketScan—that include rich information on location and individual-level characteristics. By 8 years of age, 23.9% of publicly insured children and 11.0% of privately insured children received a diagnosis of 1 or more NDDs. For all pollutants, PM2.5 chemical components and temperature, we have validated highly resolved daily predictions for the entire continental US. The unique composition of these two cohorts, allows us to determine the extent to which SES modifies these associations. For our analyses, we will adjust for a wide range of individual-level characteristics and spatiotemporal covariates. We will estimate hazard ratios and their 95% confidence intervals using cox regression, distributed-linear/non-linear lag models, and we will examine effect modification by infant sex. We will use advanced statistical methods to estimate the effects of mixtures. Our prior work and data support both the hypothesis for and the feasibility of the proposed study. The proposed research is innovative because it will be the first study to: 1) investigate associations between air pollutants, temperature and NDDs on a national scale; 2) use state-of-the-art spatiotemporal models to assess individual exposures to PM2.5, NO2, O3 and temperature; 3) employ innovative resources of clinical data by leveraging two large pregnancy cohorts. The proposed research is of great significance because it will guide decisions and pollutant regulations to protect the health of pregnant women and children, inform heat wave warning systems, potentially reducing rates of NDDs and subsequent social, financial, and public health burden.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY / ABSTRACT The microbiome is the community of bacteria, fungi, and viruses that live in and on a host. Over the past few decades, advances in sequencing technology have allowed us to better understand the composition of the mammalian microbiome and the ways it affects host development. Recent evidence shows that Caesarean- section delivery, though a medical necessity for some births, may disrupt the vertical transfer of microbiota from mother to child. This can cause different microbial communities during critical periods of development. The brain may be particularly sensitive to microbiome changes because neurogenesis in many brain regions and myelination continue through childhood. This may be one explanation for the increased prevalence of neurodevelopmental disorders like autism spectrum disorder and attention deficit hyperactivity disorder that are associated with Caesarean delivery. Nevertheless, it remains unknown whether microbial communities, and specifically those caused by differential birth mode, can cause neuroanatomical changes. To advance our understanding of Caesarean delivery’s effect on neurodevelopment, we will use a mouse model of Caesarean delivery that will allow us to separately quantify the effect of birth mode on both the offsprings’ microbial communities (Aim 1) and neurodevelopment (Aim 2). We hypothesize that perturbation of the infant microbiome by Caesarean delivery will disrupt the normal pattern of neurodevelopment in pre-weaning mice (≤ postnatal day 21). To test this hypothesis, in Aim 1 we will study microbial communities through next generation sequencing, community structure analysis, and predicted bacterial gene content . Additionally, the direct and local effects of the microbial community will be quantified by mRNA transcriptomic analysis of gastrointestinal tissues. In Aim 2, we will study brain development through histology and transcriptomics of the cerebellum and hippocampus. Both regions exhibit neurodevelopment in the early postnatal period and are implicated in the pathogenesis of neurodevelopmental diseases. Gene expression will be quantified in each brain region through mRNA transcriptomics. The results of this proposed study may inform targeted microbiome-based interventions that restore microbial composition and function and facilitate proper neurogenesis. This research will be completed between two labs at Rutgers university that have expertise in microbiome analysis and neurodevelopment. The fellow will receive training to achieve his goal of becoming an independent physician-scientist. This will entail field-specific training in microbial ecology and neuroscience, as well as the generalizable skills necessary to become an independent investigator, including: experimental design, scientific writing and communication, and presentation skills.

NIH Research Projects · FY 2026 · 2022-12

ABSTRACT Asian Americans are the fastest growing demographic group in the US, with Chinese now representing the third most common language spoken after English and Spanish. Diagnosis-based studies have shown reduced dementia risks among older Chinese adults in the US and China, but assessment-based studies have suggested significant under-diagnosis by 50% or more. A major problem in diagnosis is the lack of reliable tools to diagnose mild cognitive impairment (MCI) or dementia (including Alzheimer’s disease [AD]) among Chinese adults in the US: about half of Chinese neuropsychological tests were created through content- only translation without adjustment for cultural, linguistic, or neurological factors, while the remaining only have translated instructions. Because language-independent neuropsychological tests are limited in scope and resolution, detection of MCI/AD in older US Chinese adults is often delayed for early intervention, clinical trial enrollment, and initiation of disease-modifying therapies. Building on the unparalleled bilingual neurocognitive expertise at Rutgers and Stanford, we have developed new Mandarin-based neuropsychological tests accounting for cognition-related differences between Mandarin and English to mirror the National Alzheimer’s Coordinating Center assessments. These include: articulation-normalized forward digit span; articulation- and lexeme-adjusted Craft Story 21; lexeme- and frequency-adjusted word list recall; Mandarin-specific word generation tasks guided by character, phoneme/pinyin, and homonym (one character sound corresponding to multiple characters); and exposure-based Trail Making Test B. We leveraged our existing community relationships to demonstrate the feasibility and reliability of using these tools in older Mandarin speakers, and we will further expand their reliability and relationship to performance using English instruments by bilingual older adults (Aim 1); determine construct and diagnostic validity analysis accounting for imaging and plasma biomarkers of neurodegeneration (Aim 2); and determine if bilingualism mediates the effects of neurodegeneration (Aim 3). We will additionally transfer these tests onto a digital platform which can then be used by centers without Mandarin-speaking clinicians, and explore the feasibility of longitudinal neuropsychological, blood, and MRI analysis in a subset of the older Chinese adults. Through this effort, we will provide the first linguistically, culturally, and neuroanatomically appropriate cognitive tests for Mandarin speakers to enhance clinical detection of MCI/AD, enable equitable enrollment into clinical trials, reduce language-associated health disparities, and determine if bilingualism is neuroprotective among Mandarin speakers.

NIH Research Projects · FY 2025 · 2022-11

Project Summary The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation and disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases risk of sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in new data from our NIEHS-funded R21, α-synuclein (α-syn) preformed fibrils (PFFs). The epigenome is a potential mediator of this relationship between developmental exposures, increased neuronal vulnerability, and adult disease. In line with this idea, we recently identified sex-specific differential methylation patterns in response to developmental dieldrin exposure. We hypothesize that dieldrin-induced epigenetic modifications during development cause changes in gene expression and phenotype that persist into adulthood, altering the sensitivity to parkinsonian insults and contributing to the development of PD. To test this hypothesis, we will determine cell-type specific DNA modifications and expression profiles of previously identified candidate genes in the dieldrin model (Aim 1); analyze the function of synaptic terminals in our novel dieldrin/PFF two-hit model (Aim 2); and determine if dieldrin or altered expression of candidate genes affects susceptibility to α-syn PFFs in a dopaminergic neuron cell culture model (Aim 3). The long-term goal of these experiments is to determine whether dieldrin-associated differentially methylated genes play a functional role in the biological response to parkinsonian toxicity. Completion of these aims will further the mission of NIEHS to increase our understanding of how the environment affects people in order to promote healthier lives, with a specific project goal of connecting exposures with functional changes in gene expression, neuronal phenotype, and PD susceptibility. The experiments proposed here will help to establish a biological mechanism linking developmental exposure to late life disease. This project will also expand our repertoire of tools for interrogating the function of epigenetic changes by establishing an in vitro experimental paradigm to connect specific epigenetic mechanisms with parkinsonian toxicity. With our in vivo model that combines developmental exposure with adult PFF injections, we will have a set of experimental systems in place that will allow us to test a wide variety of exposures, as well as combinations of exposures, both in vivo and in vitro. Together, this suite of tools will enable us to explore the mechanisms by which PD- related exposures alter neuronal vulnerability in PD, furthering the goal of NIEHS to understand how combined exposures affect disease pathogenesis and individual susceptibility.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are complex genetic disorders of the gastrointestinal tract, and a major health burden to patients and society. Multicenter collaborative studies from 6 Genetics Research Centers (GRCs), organized with a Data Coordinating Center (DCC) to form the NIDDK IBD Genetics Consortium (IBDGC) has contributed to tremendous progress in dissecting IBD genetic etiology with identification of over 200 IBD loci by genome wide association studies (GWAS). Our GRC has contributed to all IBDGC studies and has taken roles in IBDGC leadership positions. Our particular GRC focus is uncovering and characterizing the genetic etiology of IBD, and variations in phenotypic expressivity and disease course, in the African-American population. We will continue to recruit and carefully phenotype African-American patients with IBD to maximize power for genetic and phenotype investigations. We will also recruit patients for parallel IBDGC focused studies in the Hispanic/LatinX population. We will expand and refine IBD loci contributing to the genetic risk of IBD in African-Americans by further GWAS, with sex-stratified, and fine-mapping approaches, and evaluate genotype-phenotype associations. We will perform a multiple immune disease association meta-analyses aggregating genome- wide data to maximize power to identify common immune mediated disease loci while also characterizing pleiotropy among the traits evaluated. We will provide critical resources in immune cells isolated from West- Africans and African-Americans and generate gene expression and epigenetic data for colocalization to better define disease causing variants and their effect on gene expression that result in the genetic risks of IBD in the African-American population. Lastly we will continue to participate in all IBDGC activities to maximize the impact of IBD genetics research by this cooperative funding mechanism.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Polysubstance use is common among people with an opioid use disorder (OUD), and, and although approximately 80% of people with OUD smoke cigarettes, tobacco use is rarely addressed in OUD treatment. Smoking cessation interventions that are effective in the general population have been minimally effective among people with an OUD. Yet, smoking cessation is related to reduced drug relapse in this population. Pain and distress, which affect most people receiving methadone treatment (MT) for OUD, are thought to contribute to continued opioid, tobacco, and other drug use. However, typically, MT programs and smoking cessation interventions fail to address the physical pain, emotion dysregulation, and reward processing deficits that co- occur with substance use. Novel behavioral interventions are needed to address these factors and to support opioid, tobacco, and other drug abstinence, simultaneously, in this population, to save and improve lives. Mindfulness-Oriented Recovery Enhancement (MORE) is a novel behavioral intervention that shows promise for addressing opioid, tobacco, and other substance use, separately, and has never been evaluated to address polysubstance use, simultaneously. MORE integrates training in mindfulness, reappraisal, and savoring skills into an 8-week group therapy designed to remediate hedonic dysregulation in brain reward systems underpinning substance use disorders. Also, motivation and self-efficacy for tobacco and other drug use abstinence often differs from motivation and self-efficacy for opioid use abstinence among people in MT; therefore, we will examine the impact of motivational-interviewing (MI) relative to treatment as usual (i.e., “No MI”), prior to MORE or a support group (SG) control intervention, on treatment engagement and outcomes. We will conduct a 2 X 2 randomized trial of MORE vs. a SG, with or without MI, to address opioid, tobacco, and other drug use, simultaneously, among people in MT who smoke cigarettes. All participants will receive combination nicotine replacement therapy (C-NRT). Expedited implementation and dissemination of effective interventions is needed. However, uptake of novel interventions may be slow in MT because time and resources are often limited. To best address potential implementation issues and to optimize future MI and MORE implementation and dissemination, in this study, we will utilize a Type 2, Hybrid Implementation-Effectiveness study design to evaluate an implementation strategy and to assess barriers and facilitators to integrating MI and MORE for polysubstance use into MT. We will: 1) determine MORE’s effectiveness for decreasing tobacco, opioid, and other drug use, simultaneously, among people in MT who smoke (N=420), 2) Determine the effectiveness of an MI session, relative to treatment as usual, for increasing treatment engagement and motivation for decreasing opioid, tobacco, and other drug use, and 3) examine barriers and facilitators to implementing MI and MORE for polysubstance use and evaluate strategies for optimizing training, fidelity, and clinic uptake.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The United States is experiencing an opioid use and overdose crisis. To address this crisis, programs that provide medication for opioid use disorder (MOUD) are being expanded and enhanced. MOUD is the most effective intervention for an OUD, and methadone treatment (MT) is the most commonly prescribed MOUD; however, approximately half of people who begin MT discontinue within a year, and half of people retained in MT use opioids within six months. Physical pain, emotion dysregulation, and reward processing deficits, affecting most people on MT, could be contributing to their ongoing opioid use. Novel behavioral interventions that address physical pain, emotion dysregulation, reward processing deficits and opioid use among people on MOUD are needed. Mindfulness-Oriented Recovery Enhancement (MORE) integrates training in mindfulness, reappraisal, and savoring skills into an 8-week group therapy designed to remediate hedonic dysregulation in brain reward systems underpinning OUD. Across multiple trials, MORE has demonstrated efficacy for reducing opioid use, craving, emotional distress, and pain in other healthcare settings. Our R21 pilot randomized controlled trial of MORE was the first to demonstrate MORE’s feasibility and acceptability as delivered in MT clinics, with indications of preliminary efficacy for decreasing drug use, craving, depression, anxiety, and pain for people with OUD. Further, expedited implementation and dissemination of effective interventions is needed. However, uptake of novel interventions may be slow in MT because time and resources are often limited. Therefore, to best address potential implementation issues and to optimize future MORE implementation and dissemination, in this study, we will utilize a Type 2, Hybrid Implementation-Effectiveness study design. We will not only evaluate MORE’s effectiveness but also assess barriers and facilitators to integrating MORE into MT and evaluate the impact of a sustainable train-the-trainer model on provider burden, intervention fidelity and engagement, and patient outcomes. We will randomize MT clinicians to receive training in 1) a higher intensity MORE implementation strategy consisting of a train-the- trainer model with training in the full MORE treatment manual plus supervision and feedback or 2) a minimal intensity implementation strategy consisting of a simple, scripted mindfulness practice (SMP) extracted from the MORE treatment manual with minimal training, no supervision, and minimal feedback. Specifically, we aim to: 1) using a RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework, examine barriers and facilitators to implementation of MORE and SMP in MT and evaluate strategies for optimizing training, fidelity, and engagement, 2) optimize existing MORE and SMP training and implementation toolkits, including adaptable resources that can accelerate the translation of evidence into practice, and 3) evaluate effectiveness and treatment fidelity of a higher intensity MORE implementation strategy versus a lower intensity SMP implementation strategy as an adjunct to MT (N=420).

NIH Research Projects · FY 2026 · 2022-09

Drug safety and effectiveness in adults does not assure safety and effectiveness of the same drugs in children. In the United States, >40% of systemic drugs ordered for children are off-label (used outside of an FDA- approved age, indication, etc.). Furthermore, rates of off-label use in children are rising, particularly for treatment indications unapproved at any age. Use, overuse, and combined use (polypharmacy) of off-label medicines for unsupported indications may put millions of children at risk each year for serious drug-related harms that outweigh uncertain benefits of treatment. This team’s long-term goal is to improve the judicious, evidence-based use of medicines that will inform clinical decision-making and make children healthier and safer. The specific objective of this project is to characterize the risks for serious drug-related harms in children from some of the drugs used most commonly despite insufficient evidence of efficacy and safety: psychotropic drugs. The central hypothesis is that use of certain psychotropic drugs in children is associated with increased risks of serious harms. Psychotropic drugs are used as applied examples for many reasons: 1) high and rising prevalence of unsupported off-label use in children; 2) insufficient evidence of efficacy in children; 3) potential for serious or fatal harms; 4) potentially greater harms in children than in adults; 5) critical therapeutic needs; 6) available therapeutic alternatives (e.g., safer drugs, non-pharmacologic interventions); and 7) measurable outcomes. Based on these criteria, gaps in the literature, and preliminary data, this proposal focuses on selected serious harms (namely, suicide, arrhythmias, and severe skin reactions) possibly associated with antidepressants (e.g., venlafaxine) and antiepileptic drugs/mood stabilizers (AEDs) (e.g., lamotrigine). Specifically, this proposal aims to evaluate the extent to which: 1) certain antidepressants and AEDs increase or decrease the risk of death by suicide in children (Aim 1); 2) certain antidepressants and AEDs increase or decrease the risk of ventricular arrhythmias, cardiac arrest, or sudden death in children (Aim 2); and 3) certain antiepileptic drugs/mood stabilizers or drug combinations increase or decrease the risk of severe skin reactions in children (Aim 3). The project team will study distinct pediatric populations within two national claims and electronic health records databases to accomplish these aims. This research will produce generalizable, actionable, clinically relevant evidence now lacking on relative and absolute risks of serious harms from drugs and drug combinations increasingly used off-label and with insufficient evidence in children. These rare outcomes cannot be feasibly studied with clinical trials due to the need for prohibitively large sample sizes. Comparisons across age groups, diagnoses, drug doses, and concomitant drugs will not only quantify risks in key subgroups but will also shed light on underlying biology and mechanisms. This project also begins an important new line of work that will inform improvements the overall quality of evidence for drugs that children commonly use despite insufficient evidence of efficacy and safety.

NIH Research Projects · FY 2026 · 2022-09

Summary Toxic aggregation of proteins is a pathogenic mechanism in neurodegenerative disease (ND). Proteins such as TDP-43 in frontotemporal dementia (FTD) or Alzheimer’s disease (AD) misfold into aggregates, which both disrupts endogenous protein functions and confers toxic new functions that lead to neuronal cell death. There are no cures for AD or FTD, but current research suggests aggregate clearance is a promising therapeutic strategy. Aggregates of TDP-43 are influenced by the proteostasis network consisting of chaperones and degradation machinery, though which factors can mediate aggregate clearance and how they do so is not known. Prior work using small molecule ligands called PROTACs to induce proximity of target proteins to components of the ubiquitin-proteasome system has proven a promising approach for clearing aberrant protein species. Analogously, this proposal aims to systematically screen the large, uninterrogated portion of the proteostasis network for its ability to clear aggregates of TDP-43 by ligand-induced proximity. In addition to proteins that may function as degraders or disaggregases, RNAs will also be screened for aggregate clearance activity. This work will reveal new quality control factors and mechanisms involved in aggregate clearance and will provide a platform for translational development of multispecific drugs for ND. This work will be accomplished in three Aims, providing me with critical training for transition into independent research. In Aim 1, I will develop an experimental workflow to image aggregate-prone TDP-43 expressed in a multiplexed tag cell library. I will write computational pipelines to characterize mechanisms of aggregate clearance and integrate them with automated in-situ sequencing to reveal the identity of the putative effector in each cell. This aim will optimize reagents and develop analysis methods for induced proximity screens, training me in models of ND and pooled image analysis. In Aim 2, I will focus on screening proteostasis network components by scalable induced proximity and validate factors mediating aggregate clearance in neurons and in vitro, gaining training in cell biology and biochemical techniques to characterize degraders and disaggregases. This work will uncover recruitable factors inducing aggregate clearance. In Aim 3, as an independent investigator, I will develop pooled tagging of transcripts and use the resulting multiplexed cell libraries to screen for RNAs with induced proximity-based aggregate clearance activity. The outcome of this work will systematically characterize the proteostatic potential of RNAs in modulating aggregation and greatly expand the space of recruitable effectors with potential therapeutic benefit. The expert mentoring team I have assembled, as well as the excellent training environment at CHOP and Penn, will greatly facilitate my research and training during the mentored phase of this proposal and provide me with the skills necessary to begin independent research systematically characterizing proteostasis mechanisms involved in ND-associated protein aggregation.