Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Both healthy individuals and those with addictive disorders experience cravings, a strong urge for a particular substance. Yet despite this and the recognized impact craving has on some individuals, such as those with food addiction, leading to overconsumption of highly palatable, high-calorie/high-fat foods, little is known about the neural mechanisms underlying craving and its impact on decision making. Past fMRI studies have identified canonical value and emotion/interoceptive processing regions of the brain that are sensitive to craving. However, these studies rely on cue-reactivity paradigms that do not examine subjective value computations, an essential component of behavioral intent understood to dictate - and potentially bias - decision making under craving. Work in my lab has shown craving scales subjective value (i.e., how much an individual feels an item is worth) in a multiplicative manner along a similarity dimension. Meaning people disproportionately value a craved item and those similar to it more than dissimilar items during craving. However, the precise neural mechanisms supporting this biased increase in subjective value in food addiction remain unknown. To address this, I will induce craving via a multisensory food activity and have subjects complete willingness-to-pay probes during fMRI so I may track how individuals’ subjective value changes pre- and post-craving. Furthermore, I will use the Yale Food Addiction Scale to select for normative (control) and addictive food consumption (food addiction) subjects to compare how craving may differentially exert its effects in food addiction. In Aim 1, to test how craving differentially exerts its effect in food addiction, I will examine how subjective value changes for craved and non- craved foods pre- and post-craving induction with the hypothesis that the food addiction group will exhibit more disproportionate increases in subjective value for both the craved snack and non-craved snacks compared to controls who will display a more targeted effect. Furthermore, to determine what neural bases may be primed in food addiction to produce these disproportionate increases in subjective value, in Aim 2 I will assess whether patterns of neural activity (i.e., neural representations) for the value of the craved and non-craved snacks are less distinct in food addiction compared to controls, serving to drive more generalized overconsumption. The training and research outlined in this F31 application will enhance my predoctoral training by: (1) solidifying my understanding of motivational and decision neuroscience (neuroeconomics) methods and theory and (2) increasing my competency in craving and behavioral addictions. The activities planned are aimed at advancing my theoretical understanding of how motivational states interact with decision making, neuroimaging skills, and clinical knowledge, all of which will be essential to achieving Aims 1 and 2, results from which would provide novel insights into the precise neural mechanisms that underlie craving in food addiction.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY While current treatment approaches can cure most children diagnosed with cancer, chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem with a negative impact on quality of life. Given that more children with cancer now survive into adulthood, identification of biomarkers that can predict and/or mediate susceptibility to cognitive decline, in conjunction to novel therapeutic interventions to treat CICI, are urgently needed. Poly (ADP-ribose) polymerase 1 (PARP1), the main nicotinamide adenine dinucleotide (NAD+) consuming enzyme, is activated by DNA damage and causes cellular NAD+ degradation, contributing to neurodegeneration. Similarly, our preliminary studies demonstrate that various chemotherapeutics including methotrexate, cisplatin and paclitaxel cause neuronal DNA damage, resulting in increased cleavage of PARP1 expression in the adult mouse hippocampus and human excitatory neurons. Remarkably, we further show that PARP1 inhibition through administration of a potent PARP1/2 inhibitor, veliparib effectively prevents cisplatin-induced anxiety-like behavior and neurogenic defects. Taken together, these observations strongly suggest that hyperactivation of PARP1 by chemotherapy causes NAD+ loss to further impair neuronal and cognitive function. Based on these together with the fact that methotrexate, which is routinely used for childhood cancers, also increases cleaved PARP1 expression, potentially mediating neurotoxicity, we hypothesize that methotrexate-induced PARP1 hyperactivation causes cellular NAD+ loss, an effect that can be prevented by inhibition of PARP1 activity, and thus ameliorating CICI. In addition, given that NAD+ loss has proven to be a promising biomarker for the age-related neurodegenerative conditions, we also propose to test the hypothesis that NAD+ and its associated metabolites can be novel biomarkers to predict and/or mediate CICI. To address these hypotheses, Aim 1 will test if veliparib prevents methotrexate- induced cognitive impairment in tumor-free and primary T-cell acute lymphoblastic leukemia (T-ALL) juvenile mouse models. In addition, given the importance of PARP1 signaling in cancer development, we will also evaluate the impact of veliparib on tumor growth and chemotherapy’s anti-neoplastic activity using clinically relevant T-ALL patient-derived xenograft (PDX) mice. Subsequently, using cell-type specific conditional PARP1 KO mice, Aim 2 will test which neural cell type is responsible for CICI. Moreover, we will also elucidate if NF- kB-mediated cyclooxygenase-2 (COX-2) inflammatory signaling is a key downstream PARP1 effector driving CICI. Lastly, Aim 3 will test if PARP1-dependent NAD+ metabolic pathway can be promising biomarkers that can predict and/or mediate susceptibility to cognitive impairment in a cohort of ALL pediatric patients and primary T-ALL juvenile mice. Our proposed translational work will provide critical mechanisms mediating CICI and pave the way for transformative clinical interventions to ameliorate the cognitive disabilities associated with chemotherapy, ultimately improving the quality of life for pediatric ALL and other cancer survivors.

NIH Research Projects · FY 2026 · 2024-06

PROJECT ABSTRACT Tuberculosis (TB) drug resistance is a major threat to global health, with only about a third of the half million drug-resistant TB patients enrolled into treatment, highlighting a critical gap for diagnosing drug resistant TB. To address this challenge, investigators from Princeton, Rutgers, Fudan, and Harvard University have convened clinical, technologic, laboratory and epidemiologic expertise to develop and evaluate a new platform to address critical unmet TB drug susceptibility testing needs. To improve accuracy and comprehensiveness within rapid, simplified workflows for TB drug susceptibility testing, we will leverage a highly-multiplexed CRISPR platform called CARMEN. Our project benefits from optimization of CARMEN over the last 4 years for viral, bacterial, and single nucleotide polymorphism-based variant and drug resistance detection, machine-learning based design strategies, and ongoing advancements in simplified workflows. The project further benefits from a large bank of MDR-TB strains and sputum samples for assay optimization and validation and a team with complementary expertise in molecular TB drug resistance, technology development and validation, and clinical implementation. This proposal will test the hypothesis that a TB DST based on the CARMEN platform will meet or exceed minimal WHO performance and operational targets for high-priority first and second line drugs. Specific aims are to develop a comprehensive CRISPR-based TB drug susceptibility test to achieve accurate genotypic and phenotypic predictions for: (1) resistance to high-priority first-line drugs, (2) resistance to high-priority second line drugs, and 3) to further simplify the manual workflow, speed, and instrumentation to exceed operational criteria for use in peripheral laboratories.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Liver transplantation (LT) is the only definitive cure for end stage liver disease; however, there is a growing gap between organ demand and availability. This has led centers to rely on extended criteria donors (ECD), which include grafts from older donors, fattier livers, or following donation after cardiac death (DCD). These grafts are particularly vulnerable to preservation injury and carry increased risk of post-LT complications. Optimizing organ preservation techniques would improve patient outcomes, increase utilization of ECD grafts, and improve access to life-saving LT. Hypothermic Oxygenated Machine Perfusion (HMP-O2) provides continuous liver flush with oxygenated preservation solution. HMP-O2 shows great promise in early clinical trials in the US and Europe. Recipients exhibit decreased preservation injury and improved early post-LT outcomes. The exact molecular pathways modulated by HMP-O2 remain largely undefined. Our team has pioneered machine perfusion in LT. With a novel portable perfusion pump, the LifePort® Liver Transporter (LLT, Organ Recovery Systems), we are the lead institution in the first US prospective, randomized controlled multi-center trial comparing HMP-O2 vs Static Cold Storage (SCS, conventional storage on ice) in LT (NCT 03484455). Under the continued access phase, with non-randomized enrollment of patients, we have increased utilization of ECD grafts at our center with excellent outcomes. To characterize the molecular targets of early allograft injury, we have paired this with an extensive longitudinal bio-specimen collection protocol. The long-term goals of the present research are to (1) define the protective pathways activated by HMP-O2 compared to SCS and (2) to identify target biomarkers for organ monitoring and for future therapeutic optimization of allograft function. Initial data from our center show HMP-O2 improves post-LT morbidity. Preliminary biochemical, molecular, and tissue injury analyses demonstrate improved tissue structural integrity, decreased inflammatory signaling, and preserved cellular function. We hypothesize that HMP-O2 improves early allograft function and risk of post-operative complications by decreasing inflammatory signaling, moderating cellular metabolic dysregulation, and ultimately, promoting cellular homeostasis. Specific aims are proposed to (1) immune cell activation, inflammatory signaling, and metabolic dysfunction mitigated by HMP-O2, as well correlate proteogenomic markers of preservation injury between tissue and liver perfusate in HMP-O2 define as to (2) compared to SCS to establish thresholds of irreversible injury for ex vivo monitoring. Capitalizing on our extensive biorepository, histologic, biochemical, genetic, and protein markers of injury will be defined in tissue (liver and bile duct), preservation fluid effluent, and bile. We expect to see decreased markers of inflammation, abrogated cell injury, and increased homeostasis during and following HMP-O2 compared to SCS. These studies are critical to identify molecular targets to improve pre-LT organ monitoring, facilitate earlier recognition of graft injury, optimize liver graft utilization, and increase access to life-saving LT.

NIH Research Projects · FY 2026 · 2024-06

ABSTRACT With increasing legalization of medicinal cannabis, there is an urgent need to identify patients at-risk for cannabis use disorder (CUD), which can occur as an unintended adverse effect of using medicinal cannabis. A national survey indicated that 11% who used medicinal cannabis met criteria for a past year DSM-IV CUD. However, DSM-based CUD diagnosis has limitations when applied to medicinal cannabis (MC). Specifically, many MC patients might report tolerance and withdrawal due to frequent MC use, but not show a pathological pattern of cannabis use (e.g., impaired control over use). To improve identification of MC patients who show a pathological pattern of use, we extend DSM-5’s model for diagnosing substance use disorder for prescription medication to MC (CUD-MC). CUD-MC addresses limitations by putting the focus on symptoms indicating a pathological pattern of cannabis use, and recognizing that tolerance and withdrawal might occur as expected neuroadaptations from cannabis used in a medicinal dosing regimen. However, tolerance can be a significant clinical problem because it decreases a medication's effects, resulting in dose escalation and, for some people, impaired control over use, whereas withdrawal can drive continuing, heavy cannabis use (e.g., use to avoid or relieve withdrawal) that may be associated with cannabis-related problems. This project investigates the roles of tolerance and withdrawal in the likelihood of a pathological pattern of cannabis use (CUD-MC), and identifies risk factors for cannabis misuse in MC patients to help prevent the iatrogenic effect of CUD-MC resulting from MC use. To generate new insights into the roles of tolerance to specific cannabis effects (e.g., relief of pain, anxiety) and withdrawal in likelihood of CUD-MC over 2-year follow-up, this project uses the innovative combination of Ecological Momentary Assessment (EMA) with longer-term follow-up to examine the likelihood of CUD-MC, focusing on two key criteria, tolerance and withdrawal, in MC patients. This project will recruit patients (N=400, age >18; 50% female; 25% new patients), e.g., from MC dispensaries. In this repeated measures study, participants complete a baseline visit, followed by 14-day EMA. Follow-ups at 6-month intervals through 18-months trigger 14-day EMA data collection. Follow-ups occur on-line at 6- and 18-months; and in-person at 12- and 24-months to collect biomarkers such as quantitative THC and CBD metabolite level and lung function measures (spirometry). Project aims are to (1) examine how DSM-5 tolerance is associated with THC dose, specific cannabis effects (e.g., relief of pain, anxiety) and CUD-MC; (2) determine how pattern of MC use (in EMA and at longer intervals) is associated with DSM-5 withdrawal and CUD-MC over 2-years; and (3) identify risk factors for CUD-MC; and examine cannabis-related health outcomes (e.g., lung functioning), including change in use of other medications, over 2-years. Identifying risk factors for CUD-MC aligns with NIDA's Cannabis Policy Research Agenda and Strategic Plan. Project results will help inform MC practice guidelines and the development of personalized interventions to minimize cannabis-related harms.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY. The prevalence of parasitic helminth infections is estimated at two billion individuals infected worldwide. Many helminths migrate through the lung as part of their developmental cycles and as a result promote substantial lung damage and tissue fibrosis. Our studies and those of others have shown that alveolar macrophages (AMs) with an alternatively activated or M2 phenotype are critical regulators of these responses. Alveolar macrophages are the most abundant immune cell in the parenchyma of the lung and play diverse metabolic and immunoregulatory roles that are needed to maintain lung function. Despite their importance, the molecular mechanisms that regulate AM activation and their M2 responses remain to be fully defined. Gaining a better understanding of the factors that regulate AM activation could reveal novel therapeutic targets to treat diverse forms of lung inflammation including fibrosis. Our new studies have shown that the enzyme carbonic anhydrase 4 (Car4) is a lineage-identifying feature of AMs. Carbonic anhydrases are a family of enzymes that are traditionally known for their ability to regulate pH and CO2 homeostasis. However, our published studies have recently identified that Car enzymes also play important roles in regulating immune cell activation and antihelminth immunity. Therefore, we sought to investigate whether Car4 regulates the phenotypes and functions of AMs. To test this, we generated a novel Car4-floxed mouse to selectively delete Car4 in AMs. Importantly, mice with Car4-deficient AMs (Car4-AM-/- mice) exhibited spontaneous induction of M2 and profibrotic pathways and presented with features of altered lipid metabolism and increased hypoxia-inducible factor (HIF) signaling. To further investigate the role of Car4 in regulating the M2 activation of AMs we infected Car4-AM-/- mice with Nippostrongylus brasiliensis (Nb), a parasitic infection that promotes robust M2 responses and lung pathology. Importantly, Car4-AM-/- mice infected with Nb exhibited dramatically elevated M2 responses, increased lung fibrosis and suffered from significantly reduced oxygen levels. Collectively, these data provoke the hypothesis that Car4 regulates the metabolism of AMs in a manner that restricts M2 activation and tissue fibrosis. This hypothesis will be tested in the three Aims. Aim 1 will focus on the importance of HIF-associated pathways in regulating the bioenergetic state of AMs and their M2/profibrotic phenotype. Aim 2 will investigate the role Car4 plays in regulating M2 activation and pulmonary fibrosis in the context of helminth-induce inflammation. Aim 3, will investigate whether Car4 also instructs the activation of newly seeded monocyte-derived alveolar macrophages that populate the lung post-Nb infection and acquire an M2 phenotype. Gaining better insight into these pathways may lead to the development of new therapeutic strategies to treat lung disease and tissue fibrosis.

NIH Research Projects · FY 2024 · 2024-06

PROPOSAL SUMMARY There is an increasing need to develop novel strategies within vital pulp treatment (VPT) to address limitations in existing therapies and to help overcome tooth injury due to caries, restorative procedures or trauma. Currently, there remain significant gaps in our knowledge regarding the molecular and cellular mechanisms that regulate tertiary dentinogenesis and wound healing of pulp tissues after injury. This knowledge plays a critical role in preserving pulp tissues after damage caused by caries and traumatic injury. Our long-term goal is to design new biologically-based strategies aimed at modulating pulpal inflammation in cases of advanced pulpitis, as well as to create novel regenerative techniques to therapeutically target biological processes to stimulate repair of dental pulp. The objective for this application is to elucidate how MMP13 specifically regulates the dental pulp’s reparative processes as well as the immunological response in acute pulpitis. The overarching hypothesis is that MMP13 stimulates tertiary dentin formation and regulates progression of the pulpal inflammatory response in the damaged dentin- pulp complex. Guided by strong published and preliminary data, this hypothesis will be tested by pursuing the following three specific aims: Aim 1: Determine the influence of MMP13 on reactionary and reparative tertiary dentin formation, Aim 2: To determine the molecular and cellular mechanism by which MMP13 regulates the immunological response in pulpitis, and Aim 3: Translate MMP13’s role in tertiary dentin formation and pulpitis to human tissues. Conditional (odontoblast or myeloid cells specific) MMP13 knockout mice will be used to achieve the first two aims and the third aim will employ ex vivo human tissue models. Importantly, initial characterization of our models indicates that MMP13 involved in tertiary dentin formation as well as inflammatory response after tooth injury in vivo. Translationally, our data will lead to the identification and understanding of important mediators, so that novel targeted therapeutic solutions can be designed within Cariology and Regenerative Endodontics. This will lessen the burden of existing therapies aimed to treat damaged pulp affected by caries and traumatic injury.

NIH Research Projects · FY 2026 · 2024-06

One in four older persons living with HIV/AIDS (PLWHA) report at least one suicide attempt in their lifetime, and the risk of death by suicide is 100 times higher in PLWHA than in the general population. In the United States, there are approximately 1.2 million PLWHA, and 35% are adults aged 55 and over. Older PLWHA experience unique combinations of stressors including externalized and internalized stigma from advanced age and disease status. Despite the increased risk and unique risk factors older PLWHA have for suicide mortality, there have been no interventions developed specifically for this population to address suicide risk. Dialectical Behavioral Therapy (DBT) shows significant impact at reducing suicidal behaviors by improving one’s self- efficacy to manage negative emotions. To our knowledge, DBT has never been evaluated with PLWHA for suicide prevention, representing a critical gap in the science. Innovative solutions to mental health care, such as AI-powered chatbots, have also not been studied extensively in older PLWHA. The objective of this R34 Intervention Development and Pilot grant proposal is to adapt DBT Skills and Coaching for suicide prevention in older PLWHA to be delivered via brief videos and Angel. Angel is an artificial intelligence (AI)-powered conversational agent developed by CareAngel, a company that leverages cutting edge AI and natural language processing technology. We plan to adapt existing evidence-based DBT skills videos and add coaching support from Angel in a 6-week intervention with older PLWHA. This proposal has the following specific aims: Phase 1: Adaptation: Aim 1) To adapt DBT Skills and Coaching for PLWHA seeking care in infectious disease practices to be delivered via Angel. Phase 2: Pilot feasibility and preliminary efficacy RCT with n=50 PLWHA: Aim 2) To establish the feasibility, acceptability, and usability of the adapted DBT Skills and Coaching intervention through key metrics of use, survey item responses, and qualitative interviews surrounding barriers and facilitators to use with patients enrolled in the intervention. Aim 3) To explore the preliminary efficacy, relative to usual care control, of DBT skills videos and Angel-delivered DBT Coaching on the target mechanism, self- efficacy to manage negative emotions, as well as exploratory clinical outcomes including suicide outcomes, mood, and medical treatment adherence. This proposed work is of high scientific and public health significance for numerous reasons: 1.) older PLWHA have elevated suicide risk. 2.) there is a paucity of suicide prevention intervention research for PLWHA. 3.) while Dialectical Behavioral Therapy has been studied in over 30 randomized controlled trials with demonstrated efficacy to improve psychological outcomes in diverse populations, to our knowledge, this intervention has never been piloted with older PLWHA. 4.) Innovative solutions to mental health care, such as AI-powered chatbots + videos, have not been studied in older PLWHA, thus this proposal represents an exciting opportunity to fill critical gaps in the literature on potentially scalable, implementable, and effective approaches to suicide prevention in PLWHA.

NIH Research Projects · FY 2024 · 2024-06

Project Summary/Abstract Racial/ethnic minority and low-income women are most vulnerable to poor oral health during pregnancy. These vulnerable women are less likely than White and higher-income women to utilize dental care during pregnancy. However, pregnancy is often the only time when these women can access dental care through the Medicaid program. National evidence-based guidelines advocate for dental care during pregnancy to improve oral health. However, prenatal oral health programs designed to increase dental utilization among vulnerable pregnant women have had disappointing results. The major obstacle to identifying upstream barriers to downstream dental care utilization during pregnancy is the lack of longitudinal data on factors that predict dental care utilization and oral health in vulnerable women. This study is informed by the Theory of Constrained Choice (Bird & Rieker, 1999), which posits that women’s opportunities to create a healthy lifestyle are constrained due to social and gender-related processes that interact with biological processes (e.g., pregnancy). This study will leverage an ongoing interprofessional collaboration between the New York University College of Dentistry and the Bellevue Hospital Obstetrics and Gynecology Service. We will collect survey data on socio-behavioral and psychosocial factors common in these vulnerable women during the first trimester of pregnancy. We will conduct clinical oral examinations to evaluate tooth loss, dental caries, gingivitis and periodontitis and will refer all women for dental care. We will re-survey and re-examine these women during the third trimester of pregnancy and will use Medicaid claims to evaluate dental care utilization. We will use cross-sectional and longitudinal structural equation modeling to identify socio-behavioral and psychosocial predictors of dental care utilization and oral health during pregnancy. This project explicitly addresses RFA-OD-19-029’s call to examine sex and gender influences on oral health and oral disease and expand research on female-specific conditions and diseases, including reproductive stages and maternal and gynecologic health. This research will elucidate which factors must be addressed when designing interventions to improve dental care utilization and oral health outcomes among pregnant women at elevated risk for oral disease. This study is the first step in addressing our long-term goal to improve the oral health of vulnerable women by intervening during pregnancy.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY Black adolescents and young adults (AYA) face profound and increasing suicide rates. Evidence suggests that differences in individual risk factors (e.g., mood disorders, substance use) do not account for these trends. Longitudinal research is needed to highlight whether mental healthcare access and availability may be driving increases in Black AYA suicide risk, including suicidal thoughts and behaviors (STBs), and to translate these findings into public health interventions for U.S. American AYA. We propose to build from an existing infrastructure supporting our U.S. national U-award study, to enroll a cohort of 1,000 Black AYA from ages 16 to 24 in the U.S. and Puerto Rico. We will use a combined approach to recruitment (e.g., digital recruitment techniques, community partner networks) that is adaptive to known shifts in digital technology and capitalizes on community-, school-, and internet-based networks maintained by our collaborators. Participants will complete a web-based survey at enrollment and annually thereafter for two years that assesses STBs, established microsystemic suicide precursors (interpersonal risk factors [thwarted belongingness, perceived burdensomeness], local suicide prevention resources [access to psychotherapy, health services]), STB correlates (e.g., stress, anxiety, substance use), and key sociodemographic (e.g., age) and contextual variables. Concordant with study enrollment, our multidisciplinary team of researchers, care providers, and public health experts will develop novel metrics to quantify mental healthcare access and availability for Black adolescents and young adults (Aim 1). We will subsequently utilize these metrics and the longitudinal follow-up data to test whether there are direct associations from mental healthcare access and availability for Black adolescents and young adults to later STBs (Aim 2). We will also use these data to test indirect associations from mental healthcare access and availability for Black adolescents and young adults to STBs through increased interpersonal suicide risk factors (thwarted belongingness, perceived burdensomeness; Aim 3a) and decreased access to local suicide prevention resources (psychotherapy; AYA health services Aim 3b). The proposed study will provide evidence to develop and disseminate recommendations to reduce suicide among all U.S. American AYA by identifying risk and prevention factors among one of the groups at highest risk for suicide: Black AYA.

NIH Research Projects · FY 2024 · 2024-05

Project Summary Neuroscience has been revolutionized by the widespread adoption of two experimental methods: optogenetics, where light is used to control neural activity, and calcium imaging, where light is used to monitor neural activity. ‘Sculpted Light in The Brain’ refers to the optical process of changing the shape of light to be more useful for both imaging and stimulation purposes and is a fundamental theme of this conference. With the advent of these approaches conventional electrical recording and stimulation tools are being progressively complemented and sometimes replaced by these light-based approaches. However, progress is still needed for these optical techniques to reach the speed, specificity, and range necessary to understand neural activity. This meeting is timely since this new generation of advanced light-based biological tools is fundamentally transforming how neuroscientists interrogate the nervous system, relying on the fusion of computational and optical methods with neuroscience. The repeated success of the SLB meetings highlights the timely nature of this topic and the extreme interest in the topic. Sculpted Light in the Brain (2017) was originally designed as a brief (1 day) local conference at University of California at Berkeley. However, due to overwhelming interest as well as the engagement and commitment of the organizers, the meeting was rapidly expanded to a reoccurring international meeting series, having meetings in London (2019), Boston (2022), and now Paris (2024). Feedback was overwhelmingly positive, and the conference was highlighted in Neurophotonics (Shanker et al 2017), spawned a dedicated research grant just for meeting attendees (The Kavli SLB Innovation Grant (2022)), has been spoken of as a model of conference childcare support, and sparked enduring scientific collaborations. The program for the 2024 Sculpted Light in the Brain meeting was designed by an interdisciplinary, international committee guided by suggestions from the field. The meeting organizers include four returning members from the 2022 and 2019 organization teams, as well as 3 new members. Four of the seven meeting organizers are women, and two are based internationally. They are aided by the continued support of the SLB Board (the original six organizers) and an advisory group of senior scientists. This meeting will generate future collaboration opportunities by gathering established scientists and the next generation of researchers from the fields of optics, computer science, and neuroscience in a discussion focused on developing future light-based technologies that will enable real time communication with the living brain. This forward-looking unique new conference satisfies an urgent need in the scientific community that is currently completely unmet, since there are no other standalone meetings directly dedicated to this rapidly growing scientific area.

NIH Research Projects · FY 2025 · 2024-05

PROJECT ABSTRACT Tobacco use disorder is the most common substance use disorder. Cigarette smoking is highly concentrated among individuals with low socioeconomic status (SES); however, they often lack access to smoking cessation services. Thus, smoking cessation in low SES adults remains a critical public health concern that warrants further study and attention. Smokers attempting to quit are at the highest risk for lapse within the first weeks of their quit attempt, and an initial lapse is highly likely to lead to full relapse. It is essential to identify and understand behavioral factors that may increase or decrease the likelihood of successful smoking cessation among low SES adults during a quit attempt (pre- and post-quit). Recently, sleep dysregulation, such as insufficient sleep duration, has been considered as a potential intervention target to improve smoking behavior (e.g., number of cigarettes smoked per day) and smoking cessation outcomes (e.g., abstinence). On the other hand, studies have found the lower SES is associated with higher rates of poor sleep. Thus, SES must be accounted for when assessing sleep dysregulation and smoking behavior and cessation outcomes. Although previous studies have examined the relationship between sleep dysregulation and smoking behavior and/or cessation outcomes, they have several methodological limitations, including the use of retrospective survey methods, not using the integrated sleep health dimensions (usually only sleep duration or quality), use of cross- sectional surveys, laboratory-based data collection, omitting low SES smokers, and focusing on a single pathway rather than dynamic associations. Therefore, this proposal will use a Real-Time Data Capture approach among low SES smokers who are attempting to quit. This approach will involve a granular examination of the bidirectional and temporal association of daily sleep dysregulation and smoking cession processes (pre- and post-quit) using smartphone-based ecological momentary assessment (EMA) and wearable sensors among low SES smokers. Specifically, we aim: 1) During the pre-quit period, to examine the within-person and between-person effects of sleep dysregulation on smoking behavior and cessation and 2) During the post-quit period, to identify bidirectional and temporal associations of daily smoking abstinence and sleep dysregulation via EMA and wrist-worn sensors during the first four weeks of a smoking cessation attempt. The proposed research and training plan will take place at Rutgers Cancer Institute of New Jersey. Training will focus on increasing knowledge of the understanding and measuring of sleep dimensions, health disparities in smoking cessation studies, and application of advanced mHealth technologies (including EMA and actigraphy data analyses techniques). It is expected that completion of these aims will yield the necessary preliminary data for developing and implementing Just-in-Time-Adaptive Interventions (JITAI) that aim to improve sleep health during smoking cessation.

NIH Research Projects · FY 2026 · 2024-05

PROJECT ABSTRACT Tobacco use disorder is the most common substance use disorder. Cigarette smoking is highly concentrated among individuals with low socioeconomic status (SES); however, they often lack access to smoking cessation services. Thus, smoking cessation in low SES adults remains a critical public health concern that warrants further study and attention. Smokers attempting to quit are at the highest risk for lapse within the first weeks of their quit attempt, and an initial lapse is highly likely to lead to full relapse. It is essential to identify and understand behavioral factors that may increase or decrease the likelihood of successful smoking cessation among low SES adults during a quit attempt (pre- and post-quit). Recently, sleep dysregulation, such as insufficient sleep duration, has been considered as a potential intervention target to improve smoking behavior (e.g., number of cigarettes smoked per day) and smoking cessation outcomes (e.g., abstinence). On the other hand, studies have found the lower SES is associated with higher rates of poor sleep. Thus, SES must be accounted for when assessing sleep dysregulation and smoking behavior and cessation outcomes. Although previous studies have examined the relationship between sleep dysregulation and smoking behavior and/or cessation outcomes, they have several methodological limitations, including the use of retrospective survey methods, not using the integrated sleep health dimensions (usually only sleep duration or quality), use of cross- sectional surveys, laboratory-based data collection, omitting low SES smokers, and focusing on a single pathway rather than dynamic associations. Therefore, this proposal will use a Real-Time Data Capture approach among low SES smokers who are attempting to quit. This approach will involve a granular examination of the bidirectional and temporal association of daily sleep dysregulation and smoking cession processes (pre- and post-quit) using smartphone-based ecological momentary assessment (EMA) and wearable sensors among low SES smokers. Specifically, we aim: 1) During the pre-quit period, to examine the within-person and between-person effects of sleep dysregulation on smoking behavior and cessation and 2) During the post-quit period, to identify bidirectional and temporal associations of daily smoking abstinence and sleep dysregulation via EMA and wrist-worn sensors during the first four weeks of a smoking cessation attempt. The proposed research and training plan will take place at Rutgers Cancer Institute of New Jersey. Training will focus on increasing knowledge of the understanding and measuring of sleep dimensions, health disparities in smoking cessation studies, and application of advanced mHealth technologies (including EMA and actigraphy data analyses techniques). It is expected that completion of these aims will yield the necessary preliminary data for developing and implementing Just-in-Time-Adaptive Interventions (JITAI) that aim to improve sleep health during smoking cessation.

NIH Research Projects · FY 2026 · 2024-05

After 4 years, the New Jersey Alliance for Clinical and Translational Science (NJ ACTS), a partnership among four institutions, Rutgers, Princeton Universities, the New Jersey Institute for Technology, and RWJBarnabas Health, has profoundly altered the trajectory of clinical and translational science and research across NJ. Designated as a Hub in 2018, NJ ACTS soon faced a devastating pandemic that served as a springboard to reimagine how we provided our services and facilitated research despite multiple logistic, staffing, recruitment, and safety challenges. From these experiences, NJ ACTS can now reimage its programs and services to catalyze breakthroughs in practices and policies that impact health. In the next 7 years, NJ ACTS will address and overcome challenges and barriers that impede the progress of translation and the adoption of evidence-based processes that will impact the health of NJ. Our approach to providing these solutions will be accelerated by our strengths in dissemination and implementation (D&I) science, informatics, clinical trial performance, and our ability to provide translational science services across the ecosystem. NJ ACTS seeks to advance CTS by developing, demonstrating, and disseminating best-in-class processes, services, and training that incorporate and advance team science, D&I science, health policy, and the learning health system. We will incorporate our communities into our work, understanding their priorities and concerns as Americans. In this way and especially through a participant population representing the totality of the US, we will advance our understanding of the heterogeneity of the disease and response to therapy and address health care delivery. In Aim 1, NJ ACTS will provide a sustainable infrastructure that will provide access to unique study cohorts, tools, and opportunities. Aim 2 will use our strengths in community engagement to develop innovative interdisciplinary approaches to improve population health. Aim 3 will enhance our workforce through targeted training, recognizing their achievements through digital badging and certificates. In Aim 4, we will integrate large and disparate databases with the EHR to provide reliable, comprehensive, and shareable data for interventional or observational clinical trial research, which in turn will provide a roadmap to enhance healthcare delivery in individuals, communities, and populations. In partnership with the Consortium, we will propel CTS discovery, dissemination, and implementation. Success will be defined using rigorous evaluation science approaches that will provide directions for continuous improvement.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract Severe storms, whether hurricanes or other storms with significant wind/precipitation, affect millions of Americans each year, disrupt the delivery of healthcare, and increase the risk for health complications. While severe storms may impact the care and outcomes of any cancer, addressing its impact on patients with breast cancer, a highly prevalent cancer with a good overall survival when treated with high-quality care, is of high public health significance. The primary research objective of this proposal is to recognize treatment disruption and adverse health outcomes experienced by patients with breast cancer and to identify and prioritize strategies to respond to health needs. In this study, we employ a mixed methods framework to accomplish the following aims: (Aim 1) To assess the impact of severe storms on breast care, acute care services, and mortality among patients with breast cancer, identify the most vulnerable populations, and evaluate potential mediators for the three outcomes; (Aim 2) To describe disruptions in breast cancer care, community concerns, perceived care barriers, and strategies to mitigate care disruptions and respond to health needs following storms using depth interviews of key stakeholders; (Aim 3) To identify and prioritize targeted interventions to mitigate disruptions in breast cancer care and respond to post-storm health needs through Delphi methods and community engagement. I am supported by a mentorship team with expertise in oncology, climatology, health services research, geospatial analysis, mixed methods, and disaster preparedness. I will link storm data, including wind speed, flooding, and power outage, with breast databases to quantify the impact of severe storms on the care and outcomes, identify mediators on the causal pathway and create geospatial maps to identify impacted communities and health systems. Then I will conduct depth interviews with diverse stakeholders in cancer care and disaster preparedness. Intervention mapping framework will be used to identify strategies, which are then are assessed and prioritized by stakeholders during Delphi and a community engagement working group. Through mentored training, education, and carrying-out this research proposal, I will accomplish my training goals related to applying new quantitative methods, acquiring skills in qualitative analysis and mixed methods, developing knowledge in implementation science and community engagement to prepare strategies for intervention studies, and developing the skills and network for career independence as a physician scientist. This proposal will provide the foundation for my independent physician-scientist career in health services research focusing on environmental health threats and cancer care and outcomes. By identifying vulnerable subgroups and potential mediators in Aims 1 and describing and prioritizing strategies in Aims 2 and 3, this proposal will support the implementation and evaluation of the most promising strategies in a future R01.

NIH Research Projects · FY 2026 · 2024-05

PROJECT ABSTRACT Following prison release, individuals with substance use disorders (SUDs) experience high rates of return to substance use and overdose. Justice-involved people account for an important part of the population with high overdose risk; therefore, a high priority for national overdose prevention strategies is to identify and implement better interventions to support them in safe re-entry. Promising strategies include pre-release medication for opioid use disorder (P-MOUD) and peer navigation (PN). To assess implementation and effectiveness, and support translation across the nation's prison systems, it is vital to assess uptake and re-entry outcomes; identify what components are effective, for whom, how and why, and for how long; document barriers and facilitators to program success; and assess PN's effectiveness in supporting post-release MOUD retention and recovery. New Jersey has implemented both interventions at large scale across all of its 11 prisons, with more than 4,000 individuals receiving P-MOUD and 2,500 PN through 2022, creating a unique research opportunity to develop and disseminate knowledge on these interventions when implemented systemwide as standard practice. Use of richly linked clinical and administrative data, for an unprecedently large cohort of individuals with SUD released from 2016-2027, will provide power to assess interactions among interventions and their effects in key subgroups, with longitudinal follow-up to examine long-term outcomes, using state-of-the-art analytic models to produce robust estimates across subgroups of concern. Innovative mixed-methods strategies, leveraging linked data and first-hand experiences, will assess patterns and disparities in pre-release MOUD and PN participation; retention in services during re-entry; and recovery outcomes among participants and non-participants. In-depth interviews during re-entry will document participants' experiences with the programs, in the context of their broader re-entry experience, their decisionmaking about MOUD and illicit drug use, and recovery barriers and facilitators. Interviews with policymakers, providers, and other stakeholders will elicit their perspectives on implementation and generate evidence to support cross-state translation. Among releasees with SUDs, the study will: 1.) examine patterns/predictors of pre- and post-release MOUD and PN; 2.) examine recovery outcomes over the re-entry period and their relationship to PN and MOUD, separately and jointly, utilizing innovative event history analysis strategies incorporating propensity scoring and machine learning strategies; and 3.) utilize qualitative interviews to elicit experiences of implementation and adaptation of PN and MOUD from the perspectives of participants and multiple other stakeholders. Implementation and dissemination will be guided by a Stakeholder Advisory Board including persons with lived experience, providers, correctional leaders, prisoner rights advocates and experts. This study of NJ's innovative, large- scale interventions provides a unique opportunity to build knowledge that can help save lives and improve outcomes during community re-entry, with important implications for intervention in other at-risk populations.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Cancer survivors with cardiovascular disease risk factors (complex cancer survivors) are a growing population and their morbidity and mortality risks are significant. Despite strong clinical evidence bases and established guidelines to manage CVD risks, cancer survivors often forego necessary chronic condition care especially during cancer treatment. A shared care model (when two or more clinicians of different specialties care for the same patient) is the optimal care delivery model for complex cancer survivors and has been shown to produce optimal comorbidity management when primary care is involved. Nevertheless, in the U.S. cancer survivorship focuses on static approaches such as providing survivorship care plans and guidelines for primary care without addressing the implementation context and care delivery processes. These approaches have proven insufficient to shift care paradigms and produce shared care for complex cancer survivors. Many currently proposed and tested cancer survivorship care strategies are considered oncology-centric and do not align with primary care generalist orientations in managing patients with multiple chronic conditions or fit in real-world contexts of primary care practices. Results from our ongoing and recent research studies indicate that survivors managing chronic conditions should not be disconnected from their primary care team. Therefore, feasibility issues must be addressed using stakeholder-informed strategies to enhance the translational potential of shared care that aligns multiple stakeholders (i.e., cancer care team, patients, primary care teams) understandings of this paradigm of care and build team-based care capacities. This study employs a designing for dissemination, theory guided perspective, blending implementation science and care delivery conceptual frameworks Exploration, Planning, Implementation, and Sustainment (EPIS) and Cancer Multi-team System (cMTS) to understand and address the multi-level factors of implementing shared care in a health system. These perspectives will shape tailoring and implementation of Primary Care Connect (PC2), a health system intervention designed to align complex cancer survivors, healthcare team members, and health system implementation actors’ understandings, capacities, and practices to promote the adoption of shared care delivery models for complex cancer survivors. Using a hybrid type III effectiveness-implementation study design it aims to: (1) engage diverse primary care and health system stakeholders to tailor PC2 to maximize implementation strategies fit to the health system and primary care practice contexts; (2) conduct a randomized controlled trial (n=266 patients) to test the effectiveness of PC2 on primary care connection, chronic disease management, and patient-reported outcomes; and, (3) evaluate PC2 implementation using a mixed methods approach to inform sustainable usage of the intervention. Study results are poised to have a profound impact on the adoption of shared care delivery models throughout the U.S. to optimally mitigate complex cancer survivors CVD risks.

NIH Research Projects · FY 2026 · 2024-05

School entry is an important developmental stage during the life course. Developmental and behavioral health at this stage, which includes cognitive, communication, and social-emotional development, are powerful predictors of later educational attainment, a social determinant of health (SDOH), and long-term health and wellbeing. Pediatric professionals in primary care have near-universal access to young children, frequent contact with their families, and opportunities to build trusted caregiver-clinician relationships making primary care the right place to support optimal developmental and behavioral health. Neuroplasticity makes early childhood the right time to intervene since developmental and behavioral health promotion interventions can have large effects during this developmental stage. However, to date, healthcare interventions have largely missed the opportunity to support optimal developmental and behavioral health in primary care settings. Primary care literacy promotion, a pediatric standard of care supported by the American Academy of Pediatrics and the National Association of Pediatric Nurse Practitioners, represents an exception and is an exemplar prevention and health promotion intervention that can promote optimal developmental and behavioral health at scale. However, prior work by our team and others points to inconsistent implementation that threatens to dilute its impact. Patient-oriented research that applies SDOH and prevention and health promotion lenses is needed to help address this gap. The overall objectives of this K24 application are to provide Dr. Manuel E. Jimenez with mentorship-focused protected time to: (1) augment his research capabilities building on his funded patient-oriented research program that uses community-engaged research and implementation science to address SDOH in primary care, and (2) mentor the next generation of interprofessional clinician investigators and enhance their capabilities to apply SDOH and prevention and health promotion lenses on patient-oriented research. To achieve these objective Dr Jimenez proposes the following specific aims: (1) To examine which literacy promotion components are most important and why from the perspective of literacy promotion experts and caregivers, (2) To identify consensus on literacy promotion core components among intervention experts and other key partners including families, and (3) to develop an intervention that supports tailored literacy promotion implementation strategies and test the feasibility of the intervention in community health centers. The application addresses multiple NINR priority areas and will help train the next generation of clinician scientists in SDOH, community health, and intervention research that positively impacts practice and policy to help address the pressing health challenges facing the nation.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT This K23 proposal integrates research and training to characterize how genetic, neural, and environmental risk factors impact treatment outcomes for adolescents using substances and engaged in related externalizing behaviors. While substance problems and associated externalizing behaviors (i.e., violence, delinquency) have a significant negative impact on health and development, empirically-supported treatments are time- and resource-intensive, placing a high burden on youth and families engaged in treatment as well as the therapists providing these services. Using knowledge from neuroimaging and psychiatric genetics can inform personalized clinical practice, ultimately improving the precision and potency of treatment for these youth. The training in advanced network neuroscience methods, advanced quantitative and statistical genetic methods, and clinical and translational research, complement the research aims, which examine how neural and genetic risk markers, identified from a large sample of adolescents, can be evaluated as targets and moderators of treatment outcomes for youth with substance problems. The candidate will work towards this goal through the completion of a research project with three parts. The first aim focuses on using data from the Adolescent Brain Cognitive Development (ABCD) study to identify key neural networks associated with early externalizing and examining how genetic and environmental risk are associated. The second part (Aims 2 & 3) involves collecting neuroimaging, genetic, and phenotypic data from youth enrolled in Multisystemic Therapy (MST), an empirically-supported treatment for substance problems in youth with severe behavior problems. Third, comprehensive pilot data on family trios will be used to support future grant submissions examining transmission of risk and impact of treatment on family systems. Etiologic findings from ABCD, will be translated and applied in this clinical sample, addressing the following research aims: 1) Identify the neural networks and genetic and environmental factors that relate to externalizing outcomes in youth, 2) Examine the impact of MST on multimodal indices of inhibitory control, reward responsivity, and socioemotional functioning in treatment seeking youth, and 3) Examine how genetic and environmental risk are associated with MST treatment outcomes and 4) Examine the impact of MST on the family system. The following training objectives will be completed during the award period to equip the candidate to carry out the proposed project and establish herself as an independent investigator ready to conduct future projects following from this work: 1) Training in advanced multivariate network neuroscience methods; 2) Training in advanced quantitative and statistical genetics methods; 3) Further develop clinical and translational research skills; 4) Improving professional skills essential for an independent patient-oriented investigator. The proposed K23 will allow the candidate to become an independent clinical investigator specializing in the application and integration of multimethod data analysis with treatment for substance use.

NIH Research Projects · FY 2026 · 2024-04

Project summary/abstract Carbapenem-resistant Klebsiella pneumoniae (Kp) strains belonging to sequence type (ST) 258 have spread globally in the past decades. Their association with often-fatal ventilator-associated pneumonia is of urgent public health concern especially in light of the current COVID-19 pandemic. While numerous studies have focused on investigating antimicrobial resistance strategies, there is still a lack of effective therapeutic agents, which urges the need to better understand other factors that are crucial for Kp ST258 persistence. Kp ST258 strains differ from hypervirulent strains that induce rapidly fatal infections by instead causing subacute chronic infections. Failure to clear Kp ST258 is associated with the recruitment of monocytes (myeloid-derived suppressor cells, MDSCs) with anti-inflammatory properties similar to those that promote the growth of tumor cells during oncogenesis. Given that metabolic activities govern the function of immune cells, we hypothesize that Kp ST258 metabolism in a manner similar to tumor metabolism generates host metabolic stress and a milieu conducive to the generation and expansion of immunosuppressive cells. We found that Kp ST258 stimulates a unique host metabolic response during pulmonary infection that is characterized by the rapid depletion of glucose, stimulation of glutaminolysis and fatty acid oxidation (FAO) pathways that fuel oxidative phosphorylation (OXPHOS) and reactive oxygen species (ROS) production, and the accumulation of the antioxidative metabolite itaconate. This project offers a novel approach to develop therapeutic strategies drawing upon the host metabolic response to Kp ST258 as the main factor promoting chronic pulmonary infection. Specifically, aim 1 explores the dynamics of the host immunometabolic response to Kp ST258. Aim 2 seeks to investigate how this response promotes immunosuppression while aim 3 focuses on its direct effect on bacterial adaptation to and survival in the airway by driving global changes in bacterial gene expression including the upregulation of the Type Six Secretion System (T6SS) to counteract oxidative stress.

NIH Research Projects · FY 2025 · 2024-04

Project Summary/Abstract BACKGROUND: Integrated behavioral health (IBH) holds great promise for improving care quality and outcomes for patients with co-occurring mental and physical health conditions by embedding mental health and substance use treatment services into primary care settings. Despite over two decades of effort, however, there still lacks widespread IBH implementation due to insufficient leadership skills to overcome organizational, attitudinal, and financial challenges. This study develops and tests an evidence-based IBH intervention that incorporates leadership concepts to prepare primary care teams to overcome IBH challenges and lead IBH implementation initiatives. SPECIFIC AIMS: Aim 1 is to identify IBH implementation challenges, strategies, and leadership skills needed to successfully implement IBH. Aim 2 is to develop an intervention that uses IBH implementation strategies and leadership training to accelerate IBH into primary care settings. Aim 3 is to conduct a preliminary effectiveness, feasibility, and acceptability pilot by implementing and evaluating the intervention in practice settings. METHODS: I use sequential, complementarity mixed methods and draw upon a conceptual model that blends the implementation science EPIS (Exploration, Preparation, Implementation, and Sustainment) framework with AHRQ’s Integration Framework. Aim 1 uses depth interviews with nationally-renowned IBH stakeholders to develop an inventory of IBH challenges, strategies, and leadership skills. Aim 2 uses a 4-round modified Delphi approach with IBH stakeholders to develop the intervention. Aim 3 uses the New Jersey Primary Care Research Network to recruit 5-10 primary care practices serving health disparity populations. The intervention is delivered to all practice members using practice facilitation, and I will conduct a series of assessment to determine the preliminary effectiveness, feasibility, and acceptability of the intervention in improving leadership skills to address IBH challenges (intermediary outcome) and integrated care processes (primary outcome). IMPACT: This study is novel because it draws upon national IBH experts to develop an intervention that identifies and consolidates IBH strategies and leadership skills that have been effective with IBH implementation in real-world settings. Second, this study produces a systematically-developed intervention that pairs IBH implementation challenges with specific leadership skills for overcoming them, refined and prioritized for action. Third, this is the first study to map the AHRQ Integration Framework to an implementation science framework. Resulting data informs future refining and testing of the intervention in additional clinical settings.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT Medications for opioid use disorder (MOUD; methadone, buprenorphine, naltrexone) are highly efficacious treatments for OUD; risk of fatal and nonfatal overdose is significantly reduced during their use. However, MOUDs are vastly underutilized, and MOUD adoption is particularly low in residential treatment programs (RTPs). Individuals with OUD are particularly vulnerable to overdose directly following discharge from controlled environments such as RTPs when tolerance is greatly diminished. RTPs therefore represent a novel touchpoint for initiating MOUD treatment for individuals with OUD, and additional research is urgently needed to identify key factors that support scaling-up of MOUD in these settings. Recent policy changes by the Centers for Medicare and Medicaid Services (CMS) allowed state Medicaid programs to reimburse services delivered in Institutions for Mental Disease (IMDs; “IMD waiver”), i.e., RTPs with 16 or more beds, and required RTPs ensure access to MOUD. This presents a unique opportunity to study MOUD adoption in RTPs and learn about the factors that support its uptake by a particularly vulnerable population, Medicaid beneficiaries with OUD. The overall goal of this K-99/R-00 Pathway to Independence application is to supplement the candidate’s existing skillset by providing structured, intensive training in implementation science frameworks and study design, integration and analysis of large data sets to study state policies targeting adoption of evidence-based addiction treatment, and career development activities during the K-99 phase of the award. This training will take place in an outstanding training environment, fostered by an exceptional mentoring team including Dr. Stephen Crystal (Primary Mentor) and co-mentors Drs. Shawna Hudson, Frederick Altice, and Ayse Akincigil. The candidate will work closely with her primary mentor to gain expertise in working with “big data” including national Medicaid claims to study state policy natural experiments. Drs. Altice and Hudson will provide training in implementation science frameworks and study designs including mixed methods. Dr. Akincigil will support skills development in the application of novel advanced econometric methods relevant to observational study designs. The applicant will also complete formal coursework and workshops in these subject areas and participate in career development activities. Applying these newly acquired skills, this research proposes to: characterize state strategies for scaling-up MOUD in RTPs nationally (K-99 Aim 1), define national trends in MOUD utilization trajectories during RTP episodes in early-adopter states (K99 Aim 2), describe NJ RTP provider experiences with MOUD scale-up (R00 Aim 1), identify predictors of trajectory group membership in all IMD-waivered states and test the effects of a New Jersey Medicaid RTP MOUD pay-for-performance incentive (R00 Aim 2). The proposed training and research program aligns with the candidate’s long-term goal of developing an independent research program focused on the implementation of state policy interventions targeting the scale-up of evidence-based practices in addiction treatment settings.

NIH Research Projects · FY 2026 · 2024-04

Tuberculosis (TB) is the second leading cause of death due to infectious disease worldwide and is notoriously difficult to treat. This is partially due to the emergence of drug-tolerant populations of Mycobacterium tuberculosis (Mtb), the causative agent of TB. Drug tolerance, defined as a non-heritable phenotypic state of reduced growth induced by stressors such as antibiotic treatment, differs from drug resistance, which is permanent and heritable. The transient nature of drug tolerant populations provides a major barrier to identifying drug targets that kill Mtb. Our lab identified a key glycerol kinase gene (glpK) as a major determinant of drug tolerance in Mtb driven by reversible mutations in a homopolymeric region. These mutants are found in clinical samples and are associated with poor clinical outcomes. Identifying novel drug targets against these clinically significant glpK mutants may significantly improve the outcomes of TB treatment. However, little is known about the bacterial and host factors that confer drug tolerance to glpK mutants in vivo. To study this clinically important phenotype, we generated a H37RV glpK strain with a permanent drug tolerant phenotype. We found that glpK strain mimics classic phenotypes of drug tolerant Mtb; glpK strain forms small colony variants, exhibits drug tolerance, overexpresses genes related to dormancy, differentially expresses carbon metabolism genes, and accumulates intracellular lipids. Given that glpK strain lacks a functional glycerol kinase, it is likely that glpK strain depends on carbon sources other than glycerol for drug tolerance. However, most experiments are performed in glycerol-containing media. As drug tolerance in Mtb is often associated with cholesterol accumulation and Mtb persistence requires host cholesterol, we selected this biologically relevant condition to test the role of lipid metabolism on drug tolerance in glpK strain. Furthermore, preliminary data suggest that macrophage infection can induce glpK strain drug tolerance, but not all macrophage environments are equally likely to have a high drug tolerance induction phenotype. We hypothesize that drug tolerance in Mycobacterium tuberculosis glpK mutants is connected to alterations in lipid metabolism, which occur in vitro as well as in infected macrophages. The goal of this project is to identify new drug targets in Mtb glpK mutants under biologically significant conditions to improve translatability and unlock novel therapeutics that enhance the overall efficacy of TB treatment. To identify novel drug targets under biologically significant conditions, we propose two models: a cholesterol- containing media model (Aim 1) and a macrophage infection model (Aim 2). We will probe the essentiality of relevant genetic pathways and genes within Mtb that are required for drug tolerance and then use specific macrophage mutants as well as a library of genetically diverse macrophages to study how specific host environments as well as a variable host genetic background affect bacterial drug tolerance. Together, these studies will identify within pathogen, within host, and host-pathogen interactions, including genetic and metabolic cross-talk, that regulate Mtb survival and drug tolerance, leading to novel drug targets against drug tolerant Mtb.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Prostate cancer (CaP) is the leading non-cutaneous cancer in men, accounting for roughly 1 in 5 new cases and 1 in 10 deaths from cancer per year. Few modifiable risk factors have been identified for CaP, limiting opportunities for primary prevention. In the US, Black men experience over twice the rate of mortality from CaP compared to White men, disparities that are partly explained by differences in neighborhood environmental context. Black men are often exposed to higher burden of environmental pollutants due to segregation and neighborhood disinvestment, which may contribute to disparities. Per- and polyfluoroalkyl substances (PFAS) are synthetic industrial chemicals of public health concern due to their ubiquitous presence and persistence in the body and environment, as well as growing evidence of their adverse health impacts. Certain PFAS have been classified as Group 2B (“possible”) carcinogens by the Institute of Agency for Cancer. Some studies in populations with high occupational or community exposures to PFAS have shown elevated risk of CaP, but few studies have examined these associations in large racially-diverse, population-based studies. I propose to study three commonly measured PFAS (PFOA, perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA) as potential risk factors for aggressive CaP and CaP disparities in New Jersey. I will develop a spatiotemporal model of drinking water PFAS exposure using multiple geographic datasets capturing business, hydrology, meteorologic, and census variables. Modeled PFAS exposure will be linked to masked residential address histories collected from men diagnosed with CaP in the New Jersey State Cancer Registry to estimate the risk of advanced CaP associated with increasing levels of PFAS. I will then conduct a pilot study among patients seeking CaP treatment at the Rutgers Cancer Institute of New Jersey. I will evaluate differences in PFAS souces by different sociodemographic groups, and study associations between serum PFAS and risk of biochemical reccurrence among men treated for CaP. This research will be complemented by a training program to develop knowledge and skills in health effects of endocrine-disrupting chemicals, spatiotemporal modeling of environmental chemicals, primary data collection and biospecimen collection, and molecular alterations involved in prostate carcinogenesis. I have invited a multidisciplinary team of environmental and cancer researchers to support my training. My short-term goals are to develop expertise in pathways through which PFAS and related endocrine-disrupting chemicals influence CaP, and disseminate findings through conference presentations and publications. My long-term goal is to become an independent scientist and expert in multilevel environmental and biological pathways that influence CaP progression and outcomes. Preliminary data generated through this project will support the development of an R01 proposal to clarify mechanisms through which PFAS and other endocrine-disrupting chemicals influence tumor biology and risk of recurrence following treatment for CaP.

NIH Research Projects · FY 2026 · 2024-03

Abstract: All individuals with type 1 and >30% of those with type 2 diabetes mellitus (T1/2DM) require intensive insulin therapy to manage their blood glucose levels. This therapy comes at a great price: increased incidence of iatrogenic insulin-induced hypoglycemia. Insulin-induced hypoglycemia is not only acutely life-threatening, repeated hypoglycemia (RH) impairs the ability of the brain to detect and correct subsequent hypoglycemia allowing glucose levels to fall to dangerous, even lethal, levels. Declining glucose first triggers the hormonal (e.g., glucagon, epinephrine) counterregulatory response (CRR) to stimulate gluconeogenesis. Further glucose decline leads to the behavioral response known as hypoglycemia awareness which includes neurogenic (e.g., palpitations, anxiety) and neuroglycopenic (e.g., tiredness, confusion) symptoms that alert the individual of hypoglycemia. RH impairs these hormonal and behavioral responses leading to hypoglycemia associated autonomic failure (HAAF) and hypoglycemia unawareness, respectively. While the CRR and HAAF have been studied extensively, little is known about the mechanisms underlying hypoglycemia awareness/unawareness. This oversight was due to lack of an animal model. However, the Levin lab recently developed a rat model for hypoglycemia awareness which we have translated into the mouse. This model enables us for the first time to investigate how RH causes hypoglycemia unawareness. Our data suggest that orexin expressing neurons in the perifornical hypothalamus (PFH) which are inhibited by glucose (glucose inhibited or GI) play a role in hypoglycemia awareness. We find that RH blunts activation of PFH orexin-GI neuron in low glucose. Using our mouse model of hypoglycemia awareness/unawareness we have shown that the dopamine reuptake inhibitor modafinil restores hypoglycemia awareness after RH. Modafinil also restores glucose sensing by PFH orexin-GI neurons. In this proposal we will test the hypothesis that RH increases the inhibitory effect of glucose on PFH orexin-GI neurons leading to hypoglycemia unawareness. Modafinil, via the dopamine 1 receptor, restores both glucose sensitivity of PFH orexin-GI neurons and hypoglycemia awareness. We will determine how RH alters the glucose sensitivity of PFH orexin-GI neurons and how this is corrected by modafinil. We will also determine the role of dopamine receptors in modafinil’s effect. Finally, we will determine the role of diabetic hyperglycemia per se in hypoglycemia awareness/unawareness. These studies are the first to shed light on the mechanisms of hypoglycemia awareness/unawareness and as such are of critical importance for patients with T1/2DM.