Florida International University

NIH Research Projects · FY 2026 · 2022-07

Approximately 70% of Latino men with HIV do not achieve viral suppression—an estimate that has likely worsened due to COVID-19 Pandemic stressors such as unemployment, loss of health insurance, homelessness, and exacerbated mental health and substance use disorders caused by the COVID-19 pandemic. Antiretroviral therapy (ART) adherence is associated with decreased viral load, increased CD4 counts, fewer hospital days, slower disease progression, and longer survival. Adherence also helps prevent drug resistance and reduces HIV transmission risk. The primary objective of this study is to evaluate the efficacy of stepped care strategies to improve ART adherence among adult Latino men with HIV using a sequential, multiple assignment, randomized trial (SMART). The trial will compare a stepped care strategy of delivering TXTXT first and stepping up to remote patient navigation for non-responders vs. a stepped care strategy of delivering TXTXT + e-Navigation first and stepping up to EMA-supported e-Navigation for non-responders. Both, TXTXT (“Treatment Text”) and the foundations of the e-Navigation interventions are CDC evidence-based interventions (EBI). We propose to use a SMART design which explicitly allows building, testing, and optimizing stepped care strategies without compromising rigor or randomization. We propose three specific aims: Aim 1. Compare the immediate (6-month) and sustained (9- and 12-month) efficacy of two static (non-stepped) treatment regimens (TXTXT alone vs. TXTXT + e-Navigation) on ART adherence and viral suppression among Latino men with HIV. Aim 2. Compare the immediate (6-month) and sustained (9- and 12-month) efficacy of two stepped care strategies (TXTXT with added e-Navigation for non-responders vs. TXTXT + e-Navigation with added EMA support for non-responders) on ART adherence and viral suppression among Latino men with HIV. Aim 3. Identify baseline and time-varying moderators on the association between stepped care strategy and ART adherence and viral suppression among Latino men with HIV. The proposed study is innovative by adapting and combining two EBIs, using a stepped care approach, remote patient navigators, adaptive EMA components, and a SMART design. The proposed study is significant because it provides data on the efficacy of two scalable EBIs in one efficient design and provides data on enhanced treatment options for non-responders. The study is also significant because it addresses multiple domains and levels of influence on health and health disparities. It also targets people living in an Ending the HIV Epidemic geographic focus area with the highest HIV diagnosis rate in the nation (South Florida), thereby supporting the objectives of reducing HIV disparities in populations at high risk and living in the Southern US.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY The use of electronic nicotine delivery systems (ENDS; e-cigarettes) has reached epidemic levels among young people in the United States (US). ENDS heat and vaporize a nicotine-containing liquid to produce an inhalable aerosol mist. While generally considered less harmful than combustible cigarettes, ENDS use exposes users to dependence-producing nicotine and respiratory and cardiovascular toxicants such as aldehydes. Flavor is a major factor in getting young people to use ENDS, thus limiting flavors to menthol and tobacco for prefilled cartridge ENDS “pod mods” was the first major action taken by the FDA to reduce the spread of ENDS among young people. Menthol flavor, however, can present a potential risk given its increasing popularity among young people in the US, and its puffing and nicotine-enhancing properties. Yet, the extent of menthol’s ability to affect users' experience and puffing patterns, and how these affect dependence, exposure to toxicants, and clinical outcomes continue to be understudied. Such evidence will be critical to the FDA's ability to set further regulatory standards to reduce ENDS potential harm. Our team of experts in tobacco regulatory science will apply clinical and analytical laboratory methods to address this gap in evidence by conducting a 2x2 (pre-post x menthol vs. tobacco flavor) crossover clinical lab study. We will recruit current/past month ENDS users (n=200, 21-35 yrs), who will come to the lab for two sessions and use their ENDS once with menthol and once with tobacco flavors. While we apply standard and well-tested lab models suitable for regulatory-related research, we have supplemented these with cutting-edge puffing robot technology to detect ENDS-associated emissions of toxicants. The proposed studies will answer two key regulatory questions consistent with FDA’s focus on the role of flavor in tobacco products’ addiction and toxicity; 1) compared to tobacco flavor, does menthol carry additional risk by enhancing puffing, abuse liability, and toxicant exposure in ENDS users, and; 2) is this effect more pronounced among high dependence compared to other users. Other outcomes such as harm perception, satisfaction, clinical responses, intention to use or quit, and group comparisons such as according to race, and sex will allow the FDA a comprehensive assessment of the pros and cons of regulating mentholated ENDS for different segments of the society. Such evidence will help advance FDA regulatory policies with the potential to reduce ENDS harm.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT The opioid crisis has escalated dramatically among women: from 1999 to 2019, the rate of opioid-related overdoses among females increased from 1.4 to 9.3 per 100,000 population. Women face many unique challenges in obtaining treatment for opioid use disorder (OUD). These barriers include caretaking responsibilities and child custody concerns. Additionally, through a phenomenon known as “telescoping,” women have a shorter duration of opioid use before meeting the clinical criteria for OUD compared to men. Further complicating the treatment landscape for women with OUD is that they often present for treatment with more severe comorbidities than men do. These sex-specific differences highlight the importance of women-centered strategies for engagement in care, a critical step in the OUD Cascade of Care. To address these sex-specific needs and barriers to care, a novel women-centered recovery navigation system is proposed. Patient navigator programs are an evidence-based intervention that address disparities and improve seeking care among vulnerable populations. While available for a range of chronic health issues, they have not been widely implemented or evaluated for women with OUD. Ultimately, the proposed recovery navigation system will combine a web-based platform with personalized, women-centered recovery navigator services, and will use a hybrid approach that connects women to both virtual and in-person services. This recovery navigation system will serve as a gateway to services that meet women’s unique needs through increasing awareness of service and resource availability, as well as normalizing seeking treatment for OUD among women. Women in recovery from OUD will guide development through a structured community-engaged intervention development framework. The objectives of this project are to advance understanding of barriers to engagement in care for women with OUD and to create a women-centered recovery navigation system. These objectives will be achieved through the following specific aims: 1) identify key barriers to engagement in care for women with OUD, as well as potential solutions; 2) develop and evaluate a pilot women-centered recovery navigator program; and 3) develop and evaluate a web-based recovery platform to engage women with OUD in care. Analyses will be completed using both qualitative and quantitative methods. Upon completion of the proposed 5-year project and under the guidance of my mentorship team, I will advance my expertise in (1) community-engaged research strategies, (2) the theory and neurobiology of opioid dependence among women, and (3) intervention design. I will also have the data necessary to scale up and refine this women-centered recovery navigation system, and will submit an R01 application to do so by the beginning of year 5 of the award period. Taken together, I will be in a position to establish myself as an independent investigator focused on developing and adapting evidence-based, women-centered interventions that tangibly improve the health outcomes of women struggling with OUD and addiction across the life course.

NIH Research Projects · FY 2026 · 2022-02

Project Summary Puerto Rico (PR) faces frequent power outages due to damage caused by natural disasters to its electric grid. Aging Puerto Ricans (≥50 years) are a vulnerable population during natural disasters as they are more likely to have multiple chronic health conditions when compared to other non-Hispanic whites and other Hispanic groups in the US. Power outages can increase these disparities, and elevate morbidity and mortality due to co- morbid conditions. Research has demonstrated that energy independence has positive health impacts. Energy independence through direct access to solar power has begun to appear in PR through the work of the non- profit community organization Casa Pueblo (CP). We propose to explore, from a multilevel perspective, the factors that enable local government agencies, communities and individuals to adapt to energy independence in their settings, and their implications for chronic disease management via these aims: Aim 1 – Through our partnership with CP, explore the process experienced by communities and the aging population (≥50 years) living with chronic diseases while adapting to energy independence (e.g., introduction of the technology, training on its use, access to energized communal points) in order to better understand how communal characteristics (e.g., collective identity, perceived individualism) can hinder or foster CDM among those with renal disease, respiratory disease, and diabetes. Aim 2 – Systematically document from a multilevel perspective (i.e., individual, community and structural) the perceived barriers and facilitators for adopting energy independence strategies in PR. Aim 3 – Document resilience related variables at the individual level (e.g., self-efficacy, positive attitudes, knowledge, altruism), communal (e.g., emotional connection, group membership), and structural (i.e., power outages, geographical variables) levels that can foster effective CDM among aging populations in need of electricity-based treatments (i.e., renal disease, respiratory diseases, diabetes). To achieve Aim 1 and 2, we will conduct: (a) a detailed ethnographic observation/mapping of CP, involving 30 months of immersive and ongoing institutional exchange and (b) a multilevel analysis of the community-based energy independence through 45 tiered in-depth interviews with individuals ≥50 years with a range of access to CP’s solar installations: 1) direct access (n=15), indirect access (n=15) and no access (n=15). In addition, we will conduct qualitative interviews with individuals engaged at the policy-, administrative- or technical-levels working within the field of sustainable energy and disaster recovery (n=15). To achieve Aim 3, we will administer a survey to a sample of 345 aging persons in the town of Adjuntas who have direct, indirect and no access to independent energy sources. Our research will contribute to policy development and dissemination regarding the role of community engagement and energy independence in managing chronic diseases among aging populations in areas of the United States and the Caribbean that are vulnerable to health inequities magnified by disasters.

NIH Research Projects · FY 2026 · 2021-12

PROJECT SUMMARY Vascular calcification is the most significant predictor of cardiovascular morbidity and is especially prevalent in individuals with chronic kidney disease. Widespread arterial mineral in these patients disrupts vascular function and increases afterload on the heart. No therapeutic strategies currently exist to prevent or treat vascular calcification. Development of therapeutics is hindered by an incomplete understanding of the mineral formation process. Calcific mineral formation in the vascular wall begins in extracellular vesicles (EVs) that promote interactions between calcium and phosphate ions. Published data show that calcifying EV formation requires the presence of caveolin-1, a structural component of plasma membrane invaginations known as caveolae. However, the mechanisms through which caveolae may initiate calcifying EV formation remain unclear. The proposed study seeks to track the formation of calcifying EVs back to caveolae within vascular smooth muscle cells. We hypothesize that caveolae trafficking into the cell initiates calcifying EV formation and confers mineralization potential to the nascent vesicles. We will study the role of epidermal growth factor receptor (EGFR) as a caveolin-1 interactor and potential novel mediator of calcifying EV formation. Aim 1 of the study explores the caveolae-dependent mechanisms through which EVs form and promote mineralization. We will analyze the evolution of calcifying EVs as mineralization progresses both in vivo and in vitro. Aim 2 will test the therapeutic potential of a clinically-relevant strategy to alter caveolae trafficking and calcifying EV formation to treat vascular calcification.

NIH Research Projects · FY 2025 · 2021-09

Project Summary Since the early days of the epidemic, psychoneuroimmunology research established that there is a bi- directional relationship between depression and HIV pathogenesis. Among people with HIV (PWH), substantial damage to the gastrointestinal tract occurs during acute HIV infection, which is partially responsible for dysregulation of the gut microbiome (i.e., dysbiosis) and translocation of inflammatory microbial products into the periphery. Even among those receiving effective anti-retroviral therapy (ART), these pathophysiologic alterations in the gut drive persistent immune dysregulation that partially explains amplified risk for depression and other neuropsychiatric disorders in PWH. An important gap is that no prior clinical research in PWH receiving effective ART has examined the functional connections between the microbiome, gastrointestinal tract, immune system, and the brain – the microbiome-gut-brain (MGB) axis. Treatment Research Investigating Depression Effects on Neuroimmune Targets (TRIDENT) is a randomized controlled trial that leverages an evidence-based Cognitive-Behavioral Therapy for Adherence and Depression (CBT-AD) treatment as an experimental probe to advance our understanding of how decreasing depression alters MGB axis pathways in PWH. TRIDENT will enroll 120 depressed PWH taking an integrase strand transfer inhibitor (INSTI)-based ART regimen who have an undetectable viral load. TRIDENT will have a brief run-in period (i.e., waiting period prior to randomization) where potentially eligible participants will be asked to complete a baseline psychosocial assessment, provide biospecimens, and attend a separate baseline fMRI assessment. A total of 120 participants who complete the run-in period will be randomized to receive either: 1) CBT-AD (n = 60); or 2) a wait-list control (WLC) condition (n = 60). Immediately following randomization, CBT-AD participants will receive up to 12 individual sessions over 4 months. WLC participants will have the opportunity to receive the CBT-AD treatment after a 6-month delay. During the intent-to-treat period, follow-up assessments at 2 months and 4 months (i.e., during and immediately following the delivery of CBT-AD) will characterize changes in the microbiome, soluble immune markers relevant to HIV pathogenesis, and leukocyte signaling to measure the conserved transcriptional response to adversity (CTRA). These will be examined as plausible mediators of CBT-AD related improvements in the primary outcome – resting state activation and connectivity of the negative valence system at 6 months (assessed via fMRI). Six months after randomization, WLC participants will crossover and have the opportunity to receive CBT-AD, and all participants (both CBT-AD and WLC) will complete a final follow-up assessment at 10 months. TRIDENT will have an exceptional impact by providing an experimental model to advance our understanding of how decreasing depression changes the MGB axis in PWH. TRIDENT will include multi-level, high dimensional data on the MGB axis to catalyze a new generation of pharmacologic and behavioral treatments for depression and its neurobehavioral substrates in PWH.

NIH Research Projects · FY 2025 · 2021-09

Children with attention-deficit/hyperactivity disorder (ADHD) experience profound, sustained, and severe impairments in academic functioning and long-term progress, making the identification and evaluation of effective approaches critical. Therefore, it is surprising that such little empirical work has explored effective intervention approaches related to learning. This proposal will investigate the efficacy of common academic accommodations (extra time, frequent breaks, low-distraction environment, and adaptive furniture) provided for children with attention- deficit/hyperactivity disorder (ADHD) as well as classroom behavior management positive supports and medication. There has not yet been a rigorous trial that investigates these interventions alone and in combination with one another for children with ADHD in standard educational settings. Thus, in this proposed study, the efficacy of commonly employed academic accommodations, behavioral support interventions, and medication will be rigorously evaluated in a within-subject design in a classroom setting conducted under well- controlled conditions in a summer treatment program setting. Specific aims for the project include an evaluation of the single and combined effects of behavioral supports, medication, and academic accommodations. Further, the moderating effect of child characteristics using standard diagnostic procedures as well as baseline neurocognitive functioning will be explored. Participants will be 288 children (grades K-5; 72 per year for four years; 36 per site), diagnosed with ADHD. At baseline, information on comorbidities (specific learning disability, disruptive behavior disorder) and neurocognitive impairments (processing speed, working memory, reaction time variability, inhibitory control and attention) will be measured and evaluated as moderators. Then, in a within-subject design, all children will receive each level of the behavior modification accommodations (i.e., no positive behavioral supports, positive behavioral supports), each level of medication (i.e., placebo, .3 mg/kg methylphenidate) and each level of the academic accommodations (i.e., extended time, adaptive furniture, frequent breaks, preferential/low distraction seating vs. a standard classroom environment). Measures of key outcome will include objective measures of behavioral and academic functioning. These include observations of behavior in the classroom (i.e., on-task behavior) and academic productivity (i.e., work completion) in independent seatwork and group instruction settings.

NIH Research Projects · FY 2023 · 2021-08

PROJECT SUMMMARY/ABSTRACT Statement of problem: Chlorine (Cl2) gas is the most common inhalational irritant in the United States, which results in serious adverse effects including lung injury and death. Previous studies by the PI and others have demonstrated that migration and homing of leukocytes (neutrophils and macrophages) into lungs play a critical role in lung morbidity and mortality post Cl2 gas exposure. The binding of the chemokine ligand, stromal- derived-factor-1 (SDF-1), to the C-X-C chemokine receptor type 4 (CXCR4) on lung immune, epithelial, and endothelial cells promote the migration of leukocytes from the circulation to lungs. The SDF-1/CXCR4 axis also propagates the activation and survival of leukocytes in the lungs. Our preliminary data shows that both SDF-1 and CXCR4 levels are elevated in the lungs of Cl2 exposed animals. Therefore, our hypothesis is that SDF- 1/CXCR4 axis is involved in the migration, homing, and survival of leukocytes in lung post exposure to Cl2 and therefore inhibiting this axis by an FDA approved compound, AMD3100 (Plerixafor), would attenuate Cl2- induced lung morbidity and mortality. Specific aims: 1) Establish the role of SDF-1/CXCR4 axis in Cl2-induced lung leukocyte migration, activation, and survival. 2) Optimize the dosage regimen of AMD3100 for Cl2 toxicity. 3) Delineate the mechanisms of SDF-1/CXCR4 regulation post-Cl2 exposure. Experimental approach: C57BL/6 mice will be exposed to Cl2 gas (500ppm, 30min) and then the SDF-1 concentration in broncholaveolar lavage fluid and the CXCR4 surface expression on the alveolar leukocytes and whole lung tissue will be measured over time. It will also be analyzed whether, the SDF-1/CXCR4 axis mediates Cl2 dependent migration, activation, and survival of lung leukocytes. Next the Cl2 exposed mice will be administered a clinically safe dose (0.01-0.16 mg/kg) of AMD3100 intramuscularly and the indices of acute and chronic lung injury and mortality will be measured. Finally, the role of Cl2-induced hemolysis and hypoxia in the regulation of lung SDF-1 and CXCR4 levels post Cl2 exposure will be studied in vitro and in vivo. Anticipated results: We anticipate that AMD3100 will attenuate leukocyte translocation to lungs and subsequently mitigate lung injury and improve survival in mice exposed to Cl2. Innovation: The study is the first to propose the use of a novel, FDA-approved, small molecule compound, AMD3100, to mitigate lung injury and mortality post exposure to Cl2 gas. AMD3100 may be beneficial in mitigating lung injury post exposure to other toxic gases such as bromine and phosgene, which are also associated with hemolysis and increased migration of leukocytes into lung.

NIH Research Projects · FY 2025 · 2021-08

Project Summary With the failure of nearly all clinical trials for AD drugs in the pipeline to date, identification of a new class of drug candidates has become imperative to bring about effective AD therapies. A major obstacle is the lack of promising new drug targets unrelated to the events leading to the accumulation of the amyloid-beta (Aβ) and tau- protein. We recently reported that linear peptide epoxyketones targeting the immunoproteasome (iP), an inducible variant of the 20S constitutive proteasome (cP), may represent a new class of AD drugs that can ameliorate cognitive deficits, independently of Aβ or tau accumulation. While displaying promising efficacy, however, the prospect of these linear peptide epoxyketones for clinical use in AD appears limited at this time, due to potential issues of having a poor brain accessibility, in vivo metabolic instability, and short circulation time (largely attributable to the ABCB1-mediated drug efflux at the BBB and enzymatic hydrolysis by peptidases and epoxide hydrolases). Yet, the family of peptide epoxyketones (‘short peptides with C-terminal α′,β′-epoxyketone warhead’) remain attractive drug candidates considering their pharmacological advantages conferred by their proven target specificity for the proteasomes and long-term safety in the clinic. Our current findings reveal that some of the peptide epoxyketone family members containing a macrocycle have the ability to resist the ABCB1-mediated efflux and metabolic stability superior to their linear counterparts, and the potential to be a meaningful new treatment for patients with AD. Our objective in this application is to identify and characterize one of these macrocyclic compounds best suited for brain iP inhibition in vivo and proceed to the next phase of drug development. To do this, in aim 1 we will prepare the current sets of promising macrocyclic peptide epoxyketones with different structural features that displayed comparable target inhibition and biological activity in vitro and in cellulo on a gram scale. In aim 2, we will characterize in vivo properties of each macrocyclic peptide epoxyketone to identify a lead drug candidate. In aim 3, we will verify in vivo efficacy and the proposed mechanism of action of the lead drug candidate [iP inhibition → (NLRP3 inflammasome) → suppression of microglial IL-1α release → blockade of astrocytes transformation (to A1 subtype) → neuronal survival] using two mouse models of AD (APP/PS1 and PS19 tau transgenic mice). By completing the proposed study, we will have identified a lead candidate with the best attributes for IND enabling studies and novel mode of action. These results are expected to have an important positive impact by examining the validity of the previously untapped iP-targeting approach for AD therapy and potentially offering a new direction for AD drug discovery.

NIH Research Projects · FY 2025 · 2021-08

SUMMARY Neuronal activity leads to increases in local cerebral blood flow (CBF) to allow adequate supply of O2 and nutrients to active neurons. This process, termed neurovascular coupling (NVC), is essential for survival and its disruption is associated with cognitive decline and dementia. Despite significant findings, we are still far from reaching a comprehensive understanding of NVC. This prohibits us from a thorough understanding of normal brain function and from identifying critical failures in disease and hinders investigations into the vascular origins of cognitive impairment. The objective of this application is to investigate how K+-mediated local CBF control emerges from the integration of neuronal inputs and autoregulatory feedback. This will be accomplished by pursuing two specific aims: In Aim 1, models of endothelial and smooth muscle cells will be developed and examine K+-mediated electrical signaling in capillaries and arterioles. We propose that the inward rectifying K+ channel acts as bistable, “on-off”, switch to hyperpolarize cell membranes when extracellular K+ increases. Multi- cellular models of microvascular networks will examine communication between capillaries and their feeding arteriole, and the significance of capillary-level NVC for local CBF control. We propose that regenerative signal propagation enables this communication and we will test this hypothesis using modeling and an ex-vivo intact arteriole-capillary preparation. In Aim 2, simulations in a geometrically accurate vascular network will predict macroscopic changes in blood flow following functional activation. We will integrate theory and experiments to analyze channelopathy-like defects, in animal models of cerebral small vessel and Alzheimer's disease. We will test the hypothesis that impaired capillary-arteriole communication and altered myogenic response lead to a NVC deficit and propose optimal strategies for restoring this deficit. The proposed work will provide a paradigm for comprehensive examinations of cerebral blood flow control, for interpreting altered cellular signaling in disease and for elucidating vascular underpinnings in cognitive impairment.

NIH Research Projects · FY 2025 · 2021-07

1 SUMMARY / ABSTRACT 2 3 Between one to two-thirds of new HIV infections among MSM are attributable to sex with main partners (i.e., 4 male couples).1,2 48% of HIV-positive MSM in 5 US cities who were HIV tested in CDC's NHBS project were 5 unaware of their status,3 suggesting the potential for high levels of unknown sero-discordance among male 6 couples. Research has also illustrated the role that relationship dynamics (e.g., HIV-specific social support, 7 constructive communication, sexual agreements) have in shaping male couples' risk for HIV4-41; this has also 8 been shown longitudinally, strongly suggesting that promoting positive relationship dynamics is a significant 9 intervention point for reducing HIV transmission among male couples.42-44 There is also evidence at-risk male 10 couples can work together towards shared HIV prevention and care-related goals, including PrEP and U=U/TasP 11 that rely on adherence and resultant viral suppression, leading to increased health and reduced likelihood of 12 onward HIV transmission.45-55 Innovative and tailored solutions are needed to meet the HIV prevention and care 13 needs of at-risk male couples. Our solution is to leverage our strong findings from the preliminary work we 14 conducted in the US (R34 pilot RCT & mixed method acceptability project)59-62 to propose a highly novel, 5-year 15 project to revise and update an existing, eHealth couples-based HIV/STI prevention toolkit intervention that 16 showed promise for reducing couples' HIV risk. The intervention is theoretically grounded in Couples 17 Interdependence Theory for health behavior change.63,64 We will first apply the remaining stages of the ADAPT- 18 ITT model65 with elements of human-centered design66-69 to incorporate at-risk, sero-concordant negative and 19 sero-discordant male couples' prevention and relationship needs while also including the latest science in 20 HIV/STI prevention. We will then conduct a 16-month RCT with 300 at-risk male couples using a delayed, 21 educational control condition of 8 months. Our Specific Aims are to: 1) examine efficacy of the intervention on 22 couples' a) formation and adherence to a risk-reduction plan and agreement, b) relationship functioning, c) self- 23 reported and biomarker confirmed indicators of risk (sexual behavior and STI), and engagement in HIV 24 prevention (PrEP adherence) and care (ART adherence); 2) evaluate use of the intervention over time by using 25 three different data sources; 3) explore moderating and mediating effects on couples' outcomes a-c. Our proposal 26 has high Public Health significance given the HIV disparities and importance of attending to couples' unique 27 relationship and prevention needs. Our innovative, accessible, and tailored intervention will fill a gap in current 28 prevention services by offering couples a personalized program. We believe results from the fully powered RCT 29 will show efficacy toward improving sustained HIV prevention outcomes among at-risk male couples in the US. 30 The scientific premise and rigor will further allow us to understand the processes that couples work together 31 to manage HIV/STIs in their relationships. Our next steps may include conducting a Type 1 Hybrid Trial to assess 32 for effectiveness and explore best practices for future implementation.70

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY/ABSTRACT The advent and access to new treatments have made infection with human immunodeficiency virus (HIV) a chronic disease, allowing patients to have a nearly normal life expectancy. However, the prevalence of chronic widespread pain (CWP) in individuals infected with HIV is high, ranging from 25% to 85%, despite low viral load and adequate CD4 count. CWP is one of the most common associated comorbidities of HIV infection and is associated with high rate of disability and decreased quality of life. However, the specific mechanisms that contribute to CWP in HIV are not understood. Thus, pharmacological and non-pharmacological approaches to mitigate CWP have had minimal benefits, contributing to an overreliance on opioids and alarming rise in addiction and overdose. The overall objective of this proposal is to address the gap in the knowledge of the pathogenesis of CWP and identify potential biomarkers and therapeutic targets to mitigate CWP in HIV. Specifically, we will explore the role of cell-free heme in impairment of endogenous opioid synthesis/release from peripheral leukocytes in HIV patients with CWP. Our novel preliminary findings demonstrate that HIV patients who self- report having CWP have elevated plasma levels of cell-free heme, coupled with decreased leukocyte β- endorphin levels, relative to HIV patients without CWP. Heme is a pro-inflammatory molecule that can induce endoplasmic reticulum stress, as well as inhibit function of leukocytes. Heme also promotes the transition of M0 macrophages toward an M1-like pro-inflammatory rather than M2-like proresolution phenotype. Compared to M2 cells, M1 macrophages contain and release lower amounts of opioid peptides. Therefore, we hypothesize that cell-free heme reduces endogenous opioid peptide-dependent analgesia and enhances pain sensitivity in PWH. We will accomplish our overall objective by addressing the following specific aims: 1) establish a direct link between plasma concentration of cell-free heme and peripheral endogenous opioid peptides with quantitative sensory measures in HIV patients with CWP, 2) to determine in a translational manner the mechanisms through which heme contributes to diminished peripheral opioid release and pain, and 3) test whether heme scavenging is a therapeutic option to increase leukocyte endogenous opioids and attenuate pain hypersensitivity. This work is novel as the impact of endogenous opioid peptide synthesis and release by leukocytes on CWP in HIV has never before been directly examined. Furthermore, the proposed work is innovative in that it combines clinical and preclinical experiments, including the use of the HIV-1 transgenic rat model, to identify potential biomarkers and mechanisms of CWP in HIV. The proposed research is significant because, if our hypotheses are confirmed, we will identify: 1) heme as a major driver of pain in HIV, and 2) heme scavenging by hemopexin as a novel, non-opioid therapeutic for HIV-associated pain.

NIH Research Projects · FY 2025 · 2021-06

Developing and Testing Health Warnings for ENDS PROJECT SUMMARY The use of electronic nicotine delivery systems (ENDS or e-cigarettes) has reached epidemic levels among young people in the United States (US). ENDS emit toxic substances, including nicotine that irreversibly affects youth’s developing brain leading to dependence and increased risk of cigarette smoking initiation, yet misperceptions about their safety are widespread. Therefore, health communication of ENDS-related risks through Health Warning Labels (HWLs) has been considered as a priority by leading health and regulatory bodies in the US to reduce ENDS use among young people. We have developed and pilot-tested a clinical lab model to examine the potential effects of pictorial HWLs on young (21-29 yrs) ENDS users’ experiences. In this proposal, we will use this model coupled with a systematic development of ENDS pictorial HWLs to test their effect when they are placed on the device on a variety of subjective (e.g. satisfaction, harm perception, nicotine dependence, intention to quit) and objective outcomes (e.g. plasma nicotine, puff topography). This will be done in three stages. First, we will review the literature and develop candidate messages and their associated pictures for the HWLs (n=45). This initial set of HWLs will then be revised and ranked through a Delphi study among tobacco control, regulation, and health communication experts. Second, we will conduct focus groups with young ENDS (21-29 yrs) users to adapt the candidate HWLs to our target population and device itself. Third, we will test HWLs on the ENDS device in a clinical lab cross-over study, where each subject uses ENDS in 2 sessions; 1) their preferred product without HWL (control), and 2) their preferred product with pictorial HWL on the ENDS device. This design will allow us to test our main hypothesis; compared to control, using ENDS with the HWLs is associated with decreased satisfaction, dependence suppression, and puffing behavior, but increased knowledge about harm and intention to quit. This project will guide policymakers into the application of effective HWLs for ENDS and will develop warning messages and pictorials that national and state stakeholders can use through different modalities in counter-marketing campaigns to protect young people and discourage harmful ENDS use.

NIH Research Projects · FY 2025 · 2021-02

Project Summary/Abstract Type IA topoisomerases are ubiquitous in the three kingdoms of life, and play critically important roles in maintaining proper DNA topology during the vital cellular processes of replication, transcription, recombination, and repair. The PI’s research activities have provided seminal biochemical and structural findings for this class of essential genome regulator, and continue to address key questions on the catalytic mechanism of type IA topoisomerases and provide new insights into their functional and regulatory interactions. This information is needed to utilize type IA topoisomerases present in every bacterial pathogen as a novel therapeutic target for finding new antibiotics to help face our serious global health challenge of antibiotic resistance. Type IA topoisomerases catalyze the relaxation of negatively supercoiled DNA by cleaving a single DNA strand in the underwound duplex DNA and passing the complementary DNA single strand through the break before religation of the cleaved strand to change the DNA topology. The molecular mechanism of the large enzyme conformational changes that are required for the coordinated movement of the passing DNA in and out of the DNA gate is the critical barrier for elucidating how bacterial TOP1 can relax negatively supercoiled DNA with high efficiency to prevent hypernegative DNA supercoiling and R-loop stabilization that can arise during transcription. This important function of bacterial TOP1 is facilitated by the direct TOP1 interaction with RNA polymerase that we have characterized and found to be targeted by endogenous toxin in mycobacteria. For future studies, we will create new TOP1 mutants perturbed in interdomain interactions at a distance from the active site and investigate the effect on the in vivo relaxation activity and in vitro interactions with DNA substrate. Mutants with reduced catalytic efficiency will be further studied to determine if the mutations affected the gate opening-closing dynamics and DNA strand passage. We will capture new structural conformations of the TOP1-DNA complex that may represent different stages of the catalytic cycle with X-ray crystallography and measure the gate opening-closing dynamics with single molecule assays. Structural studies will also incorporate other ligands including RNA. Type IA topoisomerases have evolved to include TOP1 and TOP3 enzymes in all three kingdoms of life that possess dual activities on both DNA and RNA substrates. The RNA topoisomerase activity of human TOP3B has been shown to be required for neurodevelopment and the enzyme is also involved in R-loop suppression and genome stability. We are modeling the RNA interaction of type IA topoisomerases with molecular dynamics simulations to determine how the DNA and RNA substrate may be accommodated differentially by change in enzyme conformation and interacting residues. We have initiated studies to identify a separation of function mutation or small molecule probe that can be used to distinguish between the DNA and RNA topoisomerase activity in vivo. Such research tools for study of cellular RNA topoisomerase activity and regulation will have an important and lasting impact on the field.

NIH Research Projects · FY 2024 · 2020-09

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by progressive degeneration of dopaminergic neurons in the midbrain. At present, PD is incurable. A roadblock halting development of effective therapy for PD is the limited understanding of PD pathogenesis. While most PD cases are sporadic without an ascertained cause, about 10% of PD cases are likely caused by mutation of a known or unknown gene. Genetic clues not only help define the molecular pathways leading to neurodegeneration but also help identify biomarkers for monitoring disease progression and therapeutic effectiveness. Compared to the other neurodegenerative diseases, genetic discovery for PD is significantly deferred. One reason for deferred genetic discovery in PD is the incomplete penetrance of disease phenotypes in PD and it is particularly true for late-onset PD. A compelling need for PD research is identifying and validating the genes segregating with late-onset PD. Recently the new gene TMEM230 was reported to cosegregate with disease in a large family affected by late-onset PD. Once after a novel disease gene is identified, enormous efforts are required to validate the authenticity of the pathogenic role of the mutant gene in the disease. First, genetic variants cosegregating with the disease must be verified in independent families afflicted with the disease. Second, disease phenotypes observed in patients carrying the genetic variant must be reproduced in animal models expressing the disease-associated mutation. Third, mechanistic studies must be fulfilled to reveal how the disease-linked mutation impairs cellular functions and thus to determine how these new mechanisms are integrated into existing pathways leading to cell death in the disease. Validating process often takes many years to consolidate the authenticity of a genetic mutation after a disease gene is identified. In the proposed studies, we will take comprehensive approaches to validating the pathogenic role of TMEM230 mutation in late-onset PD by using both cell culture and animal models. Upon completion, our study will determine the effect of TMEM230 mutation on neuronal functions at both systemic and molecular levels.

NIH Research Projects · FY 2024 · 2020-09

Currently, approximately 5.8 million Americans have Alzheimer’s disease and related dementias (ADRD) and are cared for by 16 million family members, friends or other unpaid caregivers. Communication deficits are common among persons with ADRD and are due to a variety of symptoms associated with ADRD, including (but not limited to) various types of primary progressive aphasia, memory loss, word-retrieval anomia, and decreased attention span. For the persons with ADRD, these deficits can lead to a number of poor outcomes, such as depression, social isolation, mood and behavioral disturbances, and premature institutionalization. Communication deficits also pose challenges to caregiving and clinical care, which is already complex. Our team has previously developed and tested an information technology (IT) intervention, called CareHeroes (CH) app that assists caregivers with common caregiving challenges and to improve clinical communication between ADRD caregivers and providers. The team has successfully integrated CH into clinical care at two memory clinics and have translated CH into Spanish. The proposed project builds on this previous work by modifying CH to include an Assistive Alternative Communication (AAC) device that relies on touchscreen technology to increase communication by the persons with ADRD about their daily care preferences, experiences, and habits. This new interface is customizable and grounded in evidence on AAC and touchscreen-use by persons with dementia. Essentially, the CH AAC would compensate for the persons’ communication deficits by using photographs, graphics and text to promote engagement of the person with ADRD, promote personhood, and offer providers access to real-time, tracked behavioral trends that support early detection, intervention, and monitoring of community dwelling older adults. The study has two Specific Aims: (1) Develop a novel, electronic AAC interface for an existing IT intervention (CH) that assists the person with dementia in communicating their daily care preferences with caregivers; and communicate everyday habits and behaviors (e.g., sleep quality, appetite, daily activities) with providers involved in their care; (2) Examine the impact and conduct a pilot study that evaluates biopsychosocial outcomes of 120 triads (person with dementia/ caregivers/providers) utilizing the CH3.0 intervention as an adjunct to care and caregiving for 12 months. Triads will be recruited from two memory clinics (Miami, Alabama) where we have already integrated the current version of CH into care for use by caregivers and providers. These clinics serve several disadvantaged ADRD populations (e.g., African American, Hispanic, rural-dwelling). Measures will be administered at baseline, 6 month, and 12 months and focus on psychosocial and communication/engagement among members of the triad and we will track all CH3.0 user actions for the 12 month study. The project design is highly feasible and cost efficient, given that the infrastructure has already been established through the team’s currently funded (AHRQ R21 HS026571- 9/18- 09/20) study.

NIH Research Projects · FY 2025 · 2020-08

PROGRAM SUMMARY Pulmonary vascular disease (PVD) is one of the most critical complications of children born with congenital heart disease (CHD) that results in increased pulmonary blood flow (PBF). Metabolic reprogramming is increasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascular morphology studies in our model demonstrate a >2-fold increase in pulmonary arterioles in Shunt compared to control lambs. This is opposed to decreased arterial counts in humans with advanced disease. This early increase in angiogenesis represents an adaptation to increased PBF. Developing a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for this angiogenic response and requires a dramatic metabolic reprogramming that supplies these cells with the requisite biosynthetic precursors. A consequence of these metabolic changes is the loss of NO signaling, the development of endothelial dysfunction, and increased vascular remodeling. We will extend our investigations into a new metabolic pathway—proline biosynthesis and collagen deposition—in this competitive renewal. This will significantly boost the impact on three levels: first, mechanistically, the proline- collagen axis is receiving renewed interest in the PVD field, but little is known of its role in the endothelium; second, functionally, collagen is a critical regulator of cell proliferation, survival, and angiogenesis; and third, pathologically, changes in collagen alter the mechanical properties of the vessel leading to increased stiffness. Proximal pulmonary artery stiffness is increasingly recognized as an early marker of advancing PVD. Overall, this PPG will continue to focus on increasing our understanding of i) the transcription factors that drive the metabolic rewiring of pulmonary endothelium, ii) post-translational modifications (PTMs) that influence metabolic reprogramming, iii) interactions between mitochondrial network dynamics, metabolism, and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NO signaling; and v) novel therapeutic strategies for treating CHD with increased PBF. These represent the thematic underpinning of this PPG. Project 1 will investigate the paradigm-shifting hypothesis that the mechanically regulated transcription factor, SOX18, metabolically rewires the endothelium to stimulate proline biosynthesis, leading to collagen deposition and increased vascular stiffness. Project #2 will continue to build on ongoing studies investigating the role of mitochondrially localized pp60Src and PTM-mediated regulation of cellular energetics. Project #3 will continue investigating the role of disrupted mitochondrial network dynamics in developing PVD, focusing on persistent MFN2 loss in a metabolic reprogramming favoring glutamine-proline metabolism. Each project, along with the supporting scientific Cores, will focus on integrated and synergistic investigations to continue to increase our understanding of how the metabolic rewiring of the pulmonary endothelium leads to the hyperproliferative, anti- apoptotic angiogenic EC phenotype, the loss of NO signaling, endothelial dysfunction, and vascular remodeling.

NIH Research Projects · FY 2024 · 2020-07

There is an urgent need to optimize the unprecedented clinical and public health benefits of pre-exposure prophylaxis (PrEP) to prevent HIV with men who use stimulants (i.e., methamphetamine, cocaine, and crack- cocaine). Men at risk for HIV who use stimulants display 3-6 fold faster rates of HIV seroconversion, and one- in-ten men with newly diagnosed HIV infection report recent stimulant use. Findings from our team and others also demonstrate that stimulant use is a key obstacle to PrEP adherence and persistence. Stimulant-using men have a 3-fold greater rate of disengagement from PrEP care and 5-fold greater odds of sub-optimal PrEP adherence. The proposed multi-site randomized controlled trial (RCT) will leverage a promising intervention model of delivering a positive affect intervention during contingency management (CM), which we have recently demonstrated achieves durable and clinically meaningful reductions in viral load among men with HIV who use methamphetamine. In the proposed multi-site RCT, we plan to test whether delivering a Positive Affect Regulation Treatment Innovation (PARTI) intervention during remote CM for directly observed PrEP doses achieves more durable reductions in HIV acquisition risk over 12 months. HIV acquisition risk (the primary outcome) will be operationalized as tenofovir diphosphate (TFV-DP) levels < 900 fmol per punch and self-reported recent condomless anal sex (CAS). Up to 300 men on PrEP who report stimulant use and CAS in the past 3 months as well as any PrEP non-adherence in the past month will be recruited from social networking applications as well as PrEP clinical services in South Florida and San Francisco. Participants who meet the inclusion and exclusion criteria at an in-person baseline assessment will provide a dried blood spot (DBS) specimen that will be stored to measure TFV-DP levels and begin 3-months of remote CM that includes financial incentives for completing up to four directly observed PrEP doses per week (48 doses total over the 3 months). Participants will complete a run-in period (waiting period) where they will complete 4 directly observed remote CM PrEP doses prior to randomization. At a separate randomization visit, 240 participants (120 South Florida and 120 San Francisco) will be randomized to receive their first individually delivered PARTI intervention or attention-control session. All 5 individually delivered intervention sessions will be delivered during the 3-month CM intervention period. Follow-up assessments will be conducted at 3, 6, and 12 months after beginning CM, with DBS collected to measure TFV-DP at 6 and 12 months. Consistent with the NIH OAR high priority area of “reducing the incidence of HIV/AIDS,” this clinical research will meaningfully inform the targeted deployment of limited public health resources to optimize the unprecedented clinical and public health benefits of PrEP men who use stimulants, one of highest priority populations for decreasing HIV incidence.

NIH Research Projects · FY 2026 · 2019-07

PROJECT SUMMARY The long-term goal of this proposal is to arrest or reverse lung inflammation and aging in HIV-associated COPD. Lung comorbidities are important determinants of morbidity and mortality in people living with HIV (PLWH) and COPD is a major lung comorbidity in PLWH and is exacerbated by smoking. Lungs are important HIV reservoirs and we, and others have shown that airway epithelial cells express canonical HIV receptors and can be infected with HIV. Majority of the HIV reservoir is transcriptionally active even with suppressive cART. The Cystic Fibrosis Transmembrane Conductance regulator (CFTR) plays an important role in airway health by maintaining optimal mucociliary clearance (MCC). CFTR suppression and impaired MCC is an important pathophysiology in chronic bronchitis. The proposal identifies two autoregulatory feedback loops involved in maintaining H₂O₂ homeostasis which provide the enzyme and substrate for reduction and scavenging of H2O2. Our data identify HIV Tat and cigarette smoke (CS)-induced CFTR dysfunction as a key molecular driver of emphysema. CFTR tightly regulates H2O2 in the airway through a negative feedback loop where H2O2 activates CFTR which then secretes reduced glutathione. A second, circadian-regulated loop, the NRF2/GPX axis, drives glutathione peroxidase 1 expression constituting the intracellular H₂O₂ scavenging system. HIV Tat and CS disrupt both loops: Tat suppresses CFTR via miR-145-5p and downregulates the circadian deacetylase SIRT1, destabilizing BMAL1 and NRF2. Elevated H₂O₂ has pleotropic downstream effects. It promotes neutrophil infiltration, mitochondrial dysfunction, senescence, and chronic inflammation. We show that that HIV Tat also inactivates alpha1-antitrypsin (A1AT) an important disease modifier of emphysema with consequent increase in neutrophil elastase activity. Together this leads to inflammation, airway remodeling, and airspace enlargement which are hallmarks of emphysema. Given that each miRNA regulates multiple genes using different target site sequences, editing the miR-145- 5p target site on the CFTR 3’ untranslated region (UTR) preserves CFTR levels without affecting the broader TGF-β signaling or regulation of other genes by miR-145-5p. Combining this approach with clock augmenters can restore both loops restoring H₂O2 homeostasis and mitigating lung inflammation and airway remodeling. Aim 1 will assess how HIV-mediated suppression of CFTR and the NRF2/GPX axis promotes H₂O₂ accumulation, A1AT inactivation, and emphysema pathogenesis. Aim 2 will provide a spatiotemporal map linked to disease progression that will help us identify HIV Tat and CS-induced pathways in emphysema progression. Aim 3 will test CRISPR-based gene-specific CFTR rescue combined with clock modulators to reverse redox imbalance, inflammation, and alveolar damage.

NIH Research Projects · FY 2025 · 2019-07

Project Summary The NIDA T32 Training Program in Adolescent Substance Use Disorders and Co-Occurring Mental and Behavioral Disorders, established five years ago, has become increasingly vital due to rising youth mental health disorders and evolving substance use patterns. Rates of mental health disorders in youth have increased and patterns of substance use have changed. Our training mission aligns with the current U.S. Surgeon General’s focus on youth mental health and NIDA’s Strategic Plan on training the next generation of scientists and accelerating research on the interaction of substance use and related comorbidities. It also addresses the AAP-AACAP- CHA’s declaration of a national emergency in child and adolescent mental health. Our program has adeptly addressed training in the complexities of research on SUD, mental health disorders, and how they co-occur. With a team of multidisciplinary research faculty, renowned for their expertise in adolescent substance abuse and related mental health disorders, the program trained 9 predoctoral and 6 postdoctoral fellows from several disciplines. T32 graduates have procured positions at top internship and training sites, as academic researchers, clinician researchers, principal investigators of NIH-funded grants, and producers of high-quality empirical studies. The renewal moves forward the program's comprehensive leadership, diverse training experiences, administrative oversight, and continuous enhancement of trainee resources. The Training Steering Committee, the External Advisory Committee, and exceptional Institutional Support have played pivotal roles in maintaining high standards and updating the program to meet emerging challenges in the field. Lessons learned from the initial funding cycle have led to a focus on training 15 predoctoral students from various related disciplines relevant to substance and mental health in youth in the renewal. Each trainee, under the guidance of a Primary Mentor and supported by Affiliated Faculty, will craft personalized training roadmaps through Individual Development Plans that focus on four key domains: developmental psychopathology, preventive interventions and dissemination, treatment and dissemination, and health services practices and implementation. Relevant additional training in neuroscience and advanced statistics is incorporated into the program along with robust training in in the responsible conduct of research and methods for enhancing reproducibility. As we seek renewal, our vision is to serve as a national exemplar in training the next generation of researchers in the intersection of substance use and adolescent mental health. The renewed T32 program at FIU will further expand its impact, integrating novel research methodologies and emerging trends in adolescent SUD and co-occurring disorders.

NIH Research Projects · FY 2026 · 2019-06

Project Summary The long term goal of our laboratory is to study the pathogenic mechanisms induced by environmental toxicants, genetic mutations and gene-environment interactions in Parkinson’s disease (PD) with the ultimate goal of developing disease-modifying therapeutics for this brain disorder. Overall, our research projects address the following fundamental questions: 1) Gene- environment interactions: Do mutations linked to PD render dopamine neurons more susceptible to environmental toxicants? 2) Glia-neuron interactions: How do glial cells contribute to the vulnerability of dopamine neurons in PD? 3) Excessive mitochondrial fission has been demonstrated in genetic and toxicant-induced models of PD. Can mitochondrial fission and fusion be targeted for PD treatment? These research projects have been supported by NIEHS since 2006. This R35 proposal will be built upon the strength, expertise, experimental models and other resources generated from the NIEHS funded projects in our laboratory to take our work to the next transformative level. The primary goal of this R35 proposal is to demonstrate that neurotoxicity induced by neurotoxicants such as manganese (Mn) alone or in combination with other factors (α-synuclein and gastric bacteria) linked to PD can be mitigated by reducing the function of dynamin related protein-1 (Drp1), which is typically known as a mitochondrial fission protein. However, our recent findings have led us to unexpected and exciting mechanism of Drp1 through autophagy. Combined with our recent discoveries that neurotoxicants such as Mn and paraquat impair autophagy at a low and sub-lethal concentration, our vision is that Drp1 plays a central role in pathogenic mechanism and this protein can be targeted for PD therapy. Over the next eight years, this R35 will give us the flexibility and power to fully investigate the extensive involvement of Drp1 in neurotoxicity mediated by glia-neuron interactions, gene-environment interactions and gastric bacteria that have been linked to PD. This proposal utilizes a transdisciplinary approach from a team of accomplished investigators with relevant established track-records, a wide range of chemical and genetic tools, high standard techniques and innovative experimental models for molecular target manipulations with functional studies at cellular, circuit and whole animal levels. Completion of this project will provide paradigm shifts in our understanding of how Drp1 mediates neurotoxicity through a wide range of toxic insults.

NIH Research Projects · FY 2026 · 2018-06

PROJECT SUMMARY Sleep is essential to our well-being, yet sleep problems are pervasive across mental health disorders and are heightened during adolescence – a developmental window of notable biological and social changes coinciding with escalations of anxiety disorders and depression. Consistent with the NIMH strategic plan, we aim to map the longitudinal course of sleep neurophysiology, brain maturation, emotion reactivity, and memory generalization and their relation to emotional health from the onset of adolescence through mid-late adolescence to inform novel treatments and minimize emotional health risks during this critical developmental window. In our ongoing R01, we have focused on mechanisms related to negative overgeneralization – a core dimension of anxiety that is poorly understood. We have found that sleep fails to depotentiate the response of the amygdala to negative stimuli in participants with elevated anxiety and negative overgeneralization emerges from an interplay between the amygdala at encoding and pattern completion supported by activity in the CA1 subfield of the hippocampus during retrieval. This proposal builds on and extends our ongoing R01 by longitudinally following the same individuals to investigate our hypothesis that altered emotional reactivity, sleep neurophysiology, and overgeneralization of negative memories arise from an imbalance between the amygdala and the hippocampus. Further, we posit that the amygdalo-hippocampal imbalance, exacerbated by the emotional and social changes prevalent during adolescence, contributes to the escalation of internalizing symptom severity often noted during this developmental window. The current renewal proposal tests this model using an accelerated longitudinal approach combining multiple methods – detailed clinical assessment, neuroimaging, polysomnography, and emotional memory task – across three time points, collected every ~18 months, in each participant to examine longitudinal maturation from peri-adolescence through mid-late adolescence. Youth (retained: n=140; newly recruited: n=80; total: N=220) across a continuum of anxiety symptoms, assigned to one of four cohorts based on their age at baseline will be enrolled in the proposed renewal study. Aim 1 will utilize the nocturnal polysomnography and structural and functional neuroimaging data collected at baseline and the two follow-up sessions to evaluate the longitudinal relation between amygdalo-hippocampal function and changes in sleep. Aim 2 will focus on behavior from the emotional memory task and functional neuroimaging data collected across waves to evaluate the longitudinal relation between amygdalo-hippocampal function and changes in negative overgeneralization. Aim 3 will incorporate the detailed clinical assessments collected across waves to investigate the longitudinal relation between amygdalo-hippocampal function, sleep neurophysiology, negative overgeneralization, and internalizing symptom severity. This project will provide critically needed data to advance mechanistic understanding of how sleep and neuromaturation influence emotional health in this sensitive period.

NIH Research Projects · FY 2025 · 2017-09

The Research Center in Minority Institutions at Miami Dade’s Florida International University (FIU-RCMI) is supported by the largest NIH Award in the history of FIU. Since 2017, the FIU-RCMI has been devoted to developing and sustaining a national, clinical and behavioral research program primarily focused on HIV and substance use problems. We have provided extensive research support and training for early-stage investigators (ESIs), partnered with South Florida communities to develop and conduct health research, and capitalized on our community connections to develop supplementary large-scale research. FIU, our ESIs, and our South Florida community partners all have benefitted from the NIMHD-funded FIU-RCMI. We are enthusiastic about submitting this competitive renewal proposal for our Center, which builds upon our earlier achievements, refines our approaches to ESI mentoring and community research partnership, and broadens our scope. Our scientific focus areas will include basic biomedical research, behavioral research and population science, and clinical/health services research, with two research projects. During the initial funding cycle of the FIU-RCMI, we concentrated on behavioral and clinical research primarily regarding HIV and substance use problems. More recently, with supplemental research funding, the hiring of new investigators, and the growth of our pilot studies and community research enhancement programs, FIU-RCMI research concentrations have grown to include behavioral, clinical, population, and basic biomedical research regarding Alzheimer’s Disease, the microbiome, app-based HIV prevention approaches, and precision cancer therapeutics. Our competitive renewal proposal reflects this growth. The FIU-RCMI is well positioned relative to FIU’s priorities, long-range goals and vision for health-related research. Overarching goals of our proposed Center renewal include: 1. enhancing institutional health research capacity, 2. increasing investigator success in obtaining competitive extramural research support, 3. fostering an environment conducive to career development for ESIs, 4. disseminating research generally and specifically for advancing and improving health, and 5. establishing sustainable relationships with community-based organizations.

NIH Research Projects · FY 2025 · 2016-04

PROJECT SUMMARY The long-term objective of the proposed Florida International University-Health Disparities Initiative (FIU-HDI) is to enhance and expand FIU’s capacity for health disparities research and training. These efforts will have a direct impact on reducing health disparities in communicable and noncommunicable health conditions in vulnerable, underserved communities in South Florida and the Caribbean region. The proposed FIU-HDI will advance foundational efforts of the original FIU-HDI (S21MD010683) and other health disparities programs and centers at the University, including: FIU’s P20 Center for Substance Use and HIV/AIDS Research on Latinos in the United States (C-SALUD; P20MD002288); FIU’s U54 Center for Latino Health Research Opportunities (CLaRO; #U54MD002266), which is a continuation of FIU’s P20 Center, and; FIU’s Emerging Preeminent Health Inequities and Disparities Program. The proposed FIU-HDI will utilize community-engaged multidisciplinary approaches to further strengthen the University’s capacity to train the next generation of public health, clinical, biomedical, and behavioral researchers at FIU’s Robert Stempel College of Public Health & Social Work (hereafter Stempel College) and Herbert Wertheim College of Medicine (hereafter HWCOM) to address health disparities in communicable and noncommunicable heath conditions—and advance health equity—among underserved populations in South Florida and the Caribbean. Thus, the three objectives of the proposed FIU-HDI are: Objective 1: Expand the breadth and scope of FIU’s existing Health Disparities Doctoral Concentration to include doctoral students across all departments/schools within Stempel College, and doctoral students in Biomedical Sciences at HWCOM, enabling them to earn doctoral degrees in their respective fields with a concentration in Health Disparities; Objective 2: Expand the FIU-HDI post-doctoral training program allowing early stage investigators to receive training, mentoring, and professional development opportunities in their chosen focus area with the goal of becoming independent health disparities researchers; Objective 3: Expand and strengthen the HWCOM Research Scholarship Course by continuing to train the next generation of physicians to understand the role of social and cultural determinants of health in the diagnosis, treatment, and care of patients in vulnerable and underserved communities. The proposed FIU- HDI will build on the expertise available across Stempel College, whose faculty (a) possess extensive experience in conducting NIH-funded community-engaged health disparities research with underserved communities in South Florida; and (b) have cultivated and sustained ongoing community-based collaborations with distinguished research institutions in the Caribbean. This application expands on the success of the current program to establish a permanent investment by the University in continuing to build research and training infrastructure leading to a reduction in health disparities in vulnerable, underserved communities in South Florida and the Caribbean region as well as a diversification of the health disparities scientific workforce.

NIH Research Projects · FY 2026 · 2015-09

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child’s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.