Florida International University

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY The proposed research aims to understand and discover the disparity of lung cancer development between African Americans and European Americans, considering race and sex. For example, Among American Males, the highest number of deaths occur from lung cancer, which is more deaths than kidney, pancreas, and prostate cancers combined. African American Males have significantly higher death rates in lung cancer compared to European American Males. Cigarette smoking is considered the strongest risk factor for lung cancer. However, smoking alone cannot explain the disparity in lung cancer development between African American Males and European American Males. The traditional cohort-based genome-wide association studies failed to identify the African American Male-specific genetic locations susceptible to causing lung cancer. These studies are similar to the current standard of medical practice, which largely relies on population-based epidemiological studies in which individuals' genetic and epigenetic variabilities are largely ignored, resulting in population-based conclusions. As a result, similar cancer types respond differently to the same treatment since each tumor has a unique set of mutations. A personalized approach that can identify the patient-specific genetic and epigenetic alterations leading to the disparities in lung cancer incidence and mortality may overcome the issues with population-based studies. Recent advancement in explainable artificial intelligence shows that by applying the local interpretation based on game theory, one can discover the patient-specific significant genes related to a disease condition by analyzing the gene expression profile of a patient. We propose to develop an explainable artificial intelligence- based computational tool to explore multi-omics data in deciphering the lung cancer health disparity by discovering, first, patient-specific disparity information, second, cohort-specific disparity information combining individual disparity information, and third, disparity between two cohorts by comparing cohort-specific disparity information, which will lead to the discovery of cohort-specific risk factors. The proposed tool can be applied to find the cohort-specific risk factors by creating and comparing cohorts based on race and sex, such as African American Males vs. European American Males, African American Females vs. European American Females, etc. Thus, the developed tool will help solve the disparity puzzle that exists in lung cancer incidence and mortality in different races and ethnicities. The proposed work is important since it will identify the heterogeneity of lung cancer at a personalized level, which may help precision medicine's rational design. This improved precision medicine design will help reduce lung cancer health disparities between different ethnic and racial communities and maximize the therapeutic benefit in all communities.

NIH Research Projects · FY 2026 · 2024-02

Abstract: Childhood lead (Pb2+) exposure results in cognitive function deficits and is associated with neuropsychiatric disorders such as schizophrenia (SZ) later in life. Deficits in cognitive function and sensorimotor gating represent core symptoms of chronic early life Pb2+ exposure (CELLE) and psychiatric disease resulting in life-long disability that is currently untreatable. To develop effective treatments, it is critical to understand and integrate neurobiological deficits at multiple levels of analysis. Our proposed studies aim to further understand the effects of CELLE at the cellular level and the resulting effects on brain networks and circuits, regional brain volume and connectivity, and how these changes result in behavioral deficits filling gaps in knowledge on the neurobiology of CELLE as a risk factor for psychiatric disease. Our central hypothesis is that CELLE alters the maturation and function of parvalbumin (PV)-positive GABAergic interneurons (PVGI), disrupting the excitatory/inhibitory (E/I) balance, producing networks and circuits abnormalities and brain dysconnectivity, leading to behavioral and cognitive deficits. We will also test the hypothesis that the brain- derived neurotrophic factor (BDNF)-mimetic and blood-brain-barrier permeable nutraceutical 7,8-dihydroxyflavone (7,8-DHF) is effective in mitigating the negative effects of CELLE with translational implications for the treatment of Pb2+-exposed children. To test these hypotheses, we propose the following specific aims (SA): SA1 will determine the effects of CELLE on behavior and cognitive function and the developmental trajectory of PVGI in the middle prefrontal cortex (mPFC) and hippocampus (HIPP). Behaviors will include reference and working memory in the 8-arm radial arm maze (8-RAM) and pre-pulse inhibition of the startle response (PPI) using a life course approach. We will also examine PVGI development using cell markers including PV (cell identification), GAD67, and perineuronal nets (PNN) in the mPFC and HIPP. SA2 will determine the effect of CELLE in mPFC-HIPP at the network and circuit levels during active 8-RAM and PPI behaviors and relate them to the PVGI markers. CELLE-induced electrophysiological network abnormalities will be examined in delta (1-4Hz), theta (4-8Hz), and gamma (30-120Hz) ranges during behavior. Circuitry contributing to abnormal network activity will be tested in mPFC-HIPP circuitry using a viral-based inhibitory designer receptors specifically activated by a designer drug (DREAADs; retroAAV-hM4Di) approach. We will also perform volumetric MRI and fiber tractography to understand CELLE effects that will complement and augment the electrophysiology studies on brain connectivity. SA3 will test a strategy to restore normal function in CELLE rats. We will use the nutraceutical 7,8-DHF, a BDNF mimetic and TrkB agonist, as a potential therapy for CELLE effects across several levels of analysis as described in SA1 and SA2. The proposed studies will provide new foundational knowledge about the neurobiology of CELLE as a risk factor for psychiatric disease. Furthermore, they will assess the effectiveness of 7,8-DHF as a therapy for translational studies with potential benefits to millions of Pb2+-exposed children.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY The proposed research project addresses an important gap in HIV prevention by applying innovative methods to help bolster uptake of HIV Pre-Exposure Prophylaxis (PrEP), as well as identify ways to improve the delivery of sexual health services among active-duty service members in the US military who are at most risk for HIV acquisition: gay, bisexual, and other men who have sex with men (GBMSM). Annually, the military diagnoses approximately 350 new HIV infections, with 236 new HIV infections occurring in 2020, and another 433 new infections diagnosed between January 1, 2021, through June 30, 2022. HIV PrEP is a highly effective prevention strategy, currently underutilized by active-duty service members. When taken as directed, PrEP is ~99% effective at reducing HIV-seroconversion in at-risk populations, such as GBMSM. Despite authorization to provide PrEP and related care free of cost, PrEP uptake among active-duty service members is low. Prior research has noted psychosocial barriers, such as stigma, may exist from residuals of the ‘Don’t Ask, Don’t Tell’ policy era that emphasized hiding one’s identity as a lesbian, gay, bisexual, or transgender (LGBT) and engagement in same-sex behaviors. Other factors may impede uptake-provision of PrEP, such as one’s comfort level of discussing sex-related topics and identifying whether someone is a candidate for PrEP. Currently, there is limited data describing what factors affect active-duty service members’ demand for PrEP and what factors influence providers’ willingness to prescribe it. The proposed project – from a promising doctoral student with a strong mentorship team – will apply an exploratory sequential mixed-method preference-based study to identify how best to bolster the uptake-delivery of sexual health and HIV prevention, including PrEP, among GBMSM and healthcare providers (HCP) who are active-duty service members in the US military. The integrated behavioral model (IBM) will guide the study to accomplish the proposed Specific Aims: (1) Qualitatively explore preferences for receiving sexual health services, including PrEP, among active-duty GBMSM and explore preferences for receiving sexual health services, including PrEP, among active-duty HCP service members. (2) Quantitatively identify, describe, and compare HIV/STI prevention program preferences among active-duty GBMSM and active-duty HCPs using Choice-Based Conjoint and MaxDiff preference-based methods. Findings from this timely, innovative project will identify ways to tailor sexual health services to the individual’s risk profile, merge overlapping concepts from the patient and provider perspective, facilitate more patient-centered provision of sexual health services, and optimize PrEP uptake among GBMSM service members, and PrEP provision among HCPs in the military.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY: In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. HIV patients die of non-AIDS comorbidities almost a decade earlier that their non-HIV counterparts. cART is unable to eradicate HIV due to established HIV reservoirs. Mounting evidence suggests that exhaustion of the latent viral reservoirs leads to either a complete cure (sterilizing cure) or a remission (functional cure). HIV establishes reservoirs at several anatomical sites like peripheral blood, CNS, lung, etc. Gene therapy has shown enormous promise but its application towards HIV cure is limited due to limitations like viral escape, off-target effects and most importantly delivery and bioavailability to infected cells. Gene editing using CRISPR/Cas9 has tremendous potential in HIV gene therapy and reports have shown excision of HIV from infected cells. However, CRISPR based HIV excision is vulnerable to viral escape as well as off-target effects. P-TEFb, a heterodimer of cyclinT1 and CDK9 is recruited by HIV Tat and plays a pivotal role in releasing the elongation block to allow transcription to proceed from the HIV LTR. Interaction of Tat with CyclinT1 is critical to recruit PTEF-b to turn ON HIV transcription, while CyclinT1 can be substituted by other cyclins for cellular transcription. This criticality for HIV transcription and redundancy for cellular transcription makes CyclinT1 an ideal cellular factor to block HIV with minimal effects on cellular transcription. Inhibition of Cyclin T1 has been shown to completely inhibit HIV transcription. Hence a CRISPR mediated inactivation of CyclinT1 will completely block HIV transcription, locking it in an inactive form in the cell thereby effecting a functional cure. Effecting CRISPR-mediated CyclinT1 knockdown only in HIV infected cells provides an additional insulation from any toxicity or off-target effects. We will restrict CyclinT1 knockdown only in infected cells by co-expressing gRNA targeting Cyclin T1 along with Cas9 from a Pol II mono-promoter based single transcription cassette using our patented LTR-hsp fusion promoter co-expression cassette. Expression is self- limiting as the co-expression cassette is also dependent on HIV Tat-CyclinT1 interaction thereby preventing generation of adaptive immune responses. Upon CyclinT1 knockdown, expression of gRNA and Cas9 will cease from the fusion promoter. We will combine this specific expression with lentiviral vector based in vivo delivery using a regimen that has demonstrated delivery and transduction of bone marrow stem cells and PBMCs. In Aim 1, will determine the efficacy of our self-limiting HIV inducible gRNA-Cas9 co-expression cassette to block and lock HIV proviral transcription in primary cell models of infection and HIV latency. Aim2 we will test the pharmacokinetics, toxicity and efficacy of lentiviral vector based in vivo delivery of our HIV inducible CRISPR targeting CyclinT1 in small animal models of HIV infection and latency. This application responds to key objectives of RFA-AI-20-076 by proposing “in vivo gene therapeutic strategies with selective regulation of genetic payload expression to maximize on-target efficacy and minimize off-target effects.”

NIH Research Projects · FY 2024 · 2023-09

Project Summary This R01 project proposes to test a developmentally informed, mechanistic model of the relations between social media (SoMe) use and social anxiety symptoms (SA) in adolescence, examining attention perturbations and sleep as key variables that impact risk. There is a steep increase in both SoMe use and SA in adolescence. Although total self-reported time spent using SoMe has been associated with SA in adolescence, findings are mixed and the literature suffers from well-documented assessment and design limitations. Consequently, “little is known about the mechanisms by which SoMe use may impact risk” (RFA-MH-23-115). There is a critical need for longitudinal research using sophisticated approaches to assess SoMe use and test a mechanistic model of its influence on SA in adolescents. This project responds directly to that need. Guided by developmental cognitive neuroscience, our model posits perturbed attention to social content and key features of sleep disturbance (poor perceived sleep quality and poor sleep efficiency) as central variables on the path from SoMe use to SA. Attention acts as a gatekeeper through which social information is selected for processing, thus shaping how adolescents experience their social world. Exciting data from members of our team document that perturbed attention to social content is related to higher levels of SA and sleep disturbance. Additional data document that SoMe use, especially at bedtime, is related to sleep disturbance and sleep disturbance is related to SA in adolescence. Hispanic/Latine adolescents are particularly impacted, as they experience anxiety and sleep disturbance at higher rates and are more likely to report using SoMe “almost constantly,” compared with other ethnic groups. Together, these data position us to provide the first test of a developmentally informed, mechanistic model wherein: bedtime SoMe use predicts SA and sleep disturbance (Aim 1) -- when adolescents show perturbed attention to social content (i.e., moderation) (Aim 2) -- and sleep disturbance mediates the relationship between SoMe use and SA (Aim 3). We will test this model in 252 biologically male/female, predominately (75%) Hispanic/Latine adolescents ages 13-17 years, using an accelerated longitudinal design, assessing adolescents four times over 18 months. Addressing assessment limitations that characterize prior work, we will use passive sensing and ecological momentary assessment to characterize the timing, location, and behaviors of SoMe use; established eye-tracking paradigms to measure attention to social content; and subjective (daily diary) and objective (actigraphy) methods to measure sleep disturbance. This project will provide a rigorous test of a mechanistic model of the escalation of SA in adolescents. It also will identify modifiable targets (features of SoMe use, sleep, and attention) that we would pursue in future projects to prevent the escalation of social anxiety symptom severity in adolescence.

NIH Research Projects · FY 2025 · 2023-09

Project Summary This R01 project proposes to test a developmentally informed, mechanistic model of the relations between social media (SoMe) use and social anxiety symptoms (SA) in adolescence, examining attention perturbations and sleep as key variables that impact risk. There is a steep increase in both SoMe use and SA in adolescence. Although total self-reported time spent using SoMe has been associated with SA in adolescence, findings are mixed and the literature suffers from well-documented assessment and design limitations. Consequently, “little is known about the mechanisms by which SoMe use may impact risk” (RFA-MH-23-115). There is a critical need for longitudinal research using sophisticated approaches to assess SoMe use and test a mechanistic model of its influence on SA in adolescents. This project responds directly to that need. Guided by developmental cognitive neuroscience, our model posits perturbed attention to social content and key features of sleep disturbance (poor perceived sleep quality and poor sleep efficiency) as central variables on the path from SoMe use to SA. Attention acts as a gatekeeper through which social information is selected for processing, thus shaping how adolescents experience their social world. Exciting data from members of our team document that perturbed attention to social content is related to higher levels of SA and sleep disturbance. Additional data document that SoMe use, especially at bedtime, is related to sleep disturbance and sleep disturbance is related to SA in adolescence. Hispanic/Latine adolescents are particularly impacted, as they experience anxiety and sleep disturbance at higher rates and are more likely to report using SoMe “almost constantly,” compared with other ethnic groups. Together, these data position us to provide the first test of a developmentally informed, mechanistic model wherein: bedtime SoMe use predicts SA and sleep disturbance (Aim 1) -- when adolescents show perturbed attention to social content (i.e., moderation) (Aim 2) -- and sleep disturbance mediates the relationship between SoMe use and SA (Aim 3). We will test this model in 252 biologically male/female, predominately (75%) Hispanic/Latine adolescents ages 13-17 years, using an accelerated longitudinal design, assessing adolescents four times over 18 months. Addressing assessment limitations that characterize prior work, we will use passive sensing and ecological momentary assessment to characterize the timing, location, and behaviors of SoMe use; established eye-tracking paradigms to measure attention to social content; and subjective (daily diary) and objective (actigraphy) methods to measure sleep disturbance. This project will provide a rigorous test of a mechanistic model of the escalation of SA in adolescents. It also will identify modifiable targets (features of SoMe use, sleep, and attention) that we would pursue in future projects to prevent the escalation of social anxiety symptom severity in adolescence.

NIH Research Projects · FY 2025 · 2023-08

The alarming emergence of multidrug-resistant (MDR) pathogenic microorganisms worldwide and the lack of next-generation portfolios of novel antimicrobials threaten human and public health. Therefore, it is a worldwide priority to expedite the development of novel antimicrobial therapies to control MDR bacteria effectively. Natural and synthetic antimicrobial peptides (AMPs) exhibit great potential as therapeutic agents because of their unique modes of action in fast-killing bacteria through membrane permeation. However, several barriers to AMP development limit its clinical application. This application aims to overcome current AMP limitations to develop a safe and effective broad-spectrum antimicrobial against MDR Gram-negative bacterial infection. Our novel peptide therapeutics A4-AMP antibiotics (A4X) is a new generation of computationally engineered AMPs (eAMPs) derived from the antimicrobial motif, alpha-4, of a natural human host defense protein SPLUNC1 with negligible toxicity to mammalian cells. The extensive results from our studies demonstrate that our current lead candidate displays superior antibacterial activity to standard of care (SoC) antibiotics in over 500 clinical isolates of difficult-to-kill MDR Gram-negative pathogens obtained from hospitals and the CDC & FDA Antibiotic Resistance Isolate Bank. Our A4X lead also has a much lower tendency to develop resistance than SoC antibiotics. The A4X lead is safe and well tolerated when intravenously administered to mice and rats, with a four times higher maximum tolerated dosage than colistin, a last resort antibiotic, in mouse blood circulation. Moreover, we have demonstrated the efficacy of the A4X lead against Klebsiella pneumoniae and Acinetobacter baumannii in mouse models of bacteremia and respiratory infection. In this project, we will carry out preclinical and pre-IND non-clinical development activities and perform structure-activity relationship (SAR) based optimization of the current A4X lead to advance the preclinical development and to determine the clinical utility. We will extensively examine the safety, pharmacokinetic/pharmacodynamic, and efficacy of these novel antimicrobial agents in small and large animals of the most effective A4X. The targeting bacteria are the MDR strains of Gram-negative species on the CDC's urgent pathogen threats list and WHO's the most critical global priority 1 pathogens list (carbapenem-resistant Acinetobacter baumannii, Klebsiella pneumonia, and Escherichia coli) and, including resistant strains to colistin. This proposal targets the urgent unmet global medical need for novel antibiotics and addresses the U.S. National Action Plan for Combating Antibiotic-Resistant Bacteria in a timely manner. Successful completion of these studies will have an enormous impact on developing a novel class of antibiotics capable of fighting MDR "superbugs."

NIH Research Projects · FY 2025 · 2023-08

Among all age cohorts in the United States, emerging adults have the highest prevalence of alcohol use and about one-third (32%) engage in binge drinking (4 to 5 drinks in two hours females/males). While Hispanic emerging adults report lower rates of heavy alcohol use compared to their non-Hispanic White counterparts, Hispanic emerging adults who do drink are at greater risk for transitioning to substance use disorders and experience more severe negative consequences. Relative to other racial/ethnic groups, Hispanic emerging adults who engage in problematic drinking are (a) less likely to seek treatment, and (b) have less access to innovative and accessible health promoting resources. Increasing evidence supports the utility of mindfulness-based interventions (MBIs) for reducing problematic alcohol use and promoting a sustainable healthy lifestyle. However, research on MBIs to address alcohol use problems is limited by (1) minimal racial/ethnic minority representation and (2) low rates of program adherence and retention. The long-term goal of this research is to decrease alcohol misuse among Hispanic emerging adult drinkers through a culturally and developmentally adapted mindfulness-based intervention program targeting self-regulatory processes. The primary aims of the study are twofold. Primary Aim 1 - Use Community-Engaged Research methods guided by the five stages of cultural adaptations of behavioral health interventions to ensure a culturally and developmentally appropriate adaptation of mindfulness-based stress reduction (MBSR) for Hispanic emerging adults (18-25 years-old) who report 2 or more binge drinking episodes in the prior 30 days. These formative stages of the research will include an expert advisory panel review, key informant interviews (n=15), focus groups (n=30), and a pilot trial (n=10; 8-weeks with weekly hour-long adapted MBSR sessions). Formative data will be analyzed to obtain information on structure, duration, acceptability, and cultural appropriateness and further refinement of intervention protocols. Primary Aim 2 – Conduct a Cultural Adaptation Trial to evaluate the acceptability and feasibility of the adapted MBSR intervention among a community sample (n=120) of Hispanic emerging adults who report 2 or more binge drinking episodes in the prior 30 days. Participants will be randomly assigned to an MBSR condition (8 weekly 1-hour adapted MBSR sessions) or an assessment-only control condition. Secondary Aim 2.1 - Examine initial evidence of the efficacy of the MBSR intervention. We hypothesize that, relative to the participants in the control condition, participants in the MBSR condition will report: (a) greater reductions in frequency of binge drinking episodes and number of drinks per drinking occasion, and (b) greater impacts on putative mechanisms of change (e.g., reduced stress, greater self-regulation, and enhanced well-being). The proposed study has significant public health implications by contributing to translational efforts to reduce alcohol misuse among Hispanic emerging adults who would otherwise not seek treatment.

NIH Research Projects · FY 2025 · 2023-08

Project Summary The proposed studies focus on the design, synthesis, and development of a range of vanadium- based catalysts to perform carbon isotope exchange via =*CH2 (*C = 11C, 13C, and 14C) group transfer between terminal olefins. Carbon isotope exchange is an emerging area that allows incorporating carbon- 14 isotope directly into target compounds for metabolic and pharmacokinetic studies. Furthermore, the integration of carbon-11 into pharmaceuticals is an indispensable tool in positron emission tomography. The innovation of the proposed work is the development of olefin metathesis catalysts based on the first-row transition metal, vanadium, to take advantage highly polarized V=C bond. These V alkylidenes feature enabled regioselective formation of metallacyclobutane, resulting in reversible =CH2 transfer between terminal olefins without formation of cross-products and ethylene, which is supported by our preliminary results and DFT studies. Therefore, V-catalyze carbon isotope exchange can serve as a new platform to incorporate labeled carbon atoms into a wide range of pharmaceuticals and natural products without developing new multi-step synthetic strategies. The proposed approach uses accessible labeled iodomethane (*CH3I) as a carbon isotope source and can be applied to compounds containing various common functional groups. The method will be expanded to alkyl-containing bioactive molecules utilizing a tandem dehydrogenation/olefin metathesis strategy. Therefore, the first example of carbon isotope exchange involving the methyl group will be introduced. The utility of the new concepts, catalysts, and protocols will be emphasized through applications to the concise synthesis of isotopically labeled pharmaceuticals and natural products.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY The primary goal of the present proposal is to explore the role of pathway-specific RE neurons in the synchronized activity of the prefrontal-hippocampal circuit (mPFC-HC) and memory related rhythms in wake (episodic-like sequence memory) and in sleep states (REM/NREM). To accomplish this, Aim1 will determine if and how excitation of RE neurons can drive memory related mPFC-HC coherent states. The first experiment will test a range of relevant frequencies in RE-pathway specific neurons to identify a stimulation capable of driving mPFC-HC coherent modes in freely behaving rats. Using a closed-loop optogenetic approach, the second experiment will stimulate RE neurons to induce mPFC-HC coherence during different endogenous coherence states to boost memory performance while rats perform in a nonspatial sequence memory task. As I transition to my independent career (R00), Aim2 will explore the role of pathway-specific RE neurons in driving theta and delta related sleep oscillations (REM/NREM) using a closed-loop setup. Two new technical skills will be acquired during the K99 training phase which include 1) learning to run a sophisticated rodent sequence memory task capable of testing multiple RE-dependent memory dimensions, and 2) implementing a cutting edge closed-loop optogenetic control system capable of detecting neurophysiological coherence modes between the hippocampus and medial prefrontal cortex in `real-time' to trigger RE optogenetic stimulations. My previous training in anatomy, optogenetics, multisite electrophysiological recordings, and my theoretical background on RE-related mnemonic processes and arousal provides me with the foundation and technical skills necessary to pursue these goals with this additional training. Florida International University, a research- intensive and Hispanic-serving institution, is the ideal place to complete my training because it offers all the resources (mentor, equipment, facilities, and professional development programs) necessary to carry out the proposed experiments and training plan. The mentoring team is composed of two well-established and highly successful scientists, who together are committed to my success and will adequately prepare me for a career as an independent research investigator. The K99 phase of this award would allow me to enter the independent stage of my career with the theoretical, technical, methodological, networking, and laboratory management skills necessary to answer scientific questions at the circuit and network level, establish my own laboratory, and independently pursue future scientific directions. As a MOSAIC awardee and future principal investigator, one of my goals is to become a role model and mentor to other underrepresented students and scientists, so that I can enhance diversity, equality, and inclusion in the biomedical field. Overall, this research will shed new light on the role of RE in driving network-wide memory states, while the training plan will equip me professionally to launch my independent career.

NIH Research Projects · FY 2025 · 2023-07

The proposed Training in Environmental Neuroscience (TEN) is a program based at Florida International University (FIU), a designated Carnegie Research 1: Very High Research Spending and Doctorate Production University. FIU has a leadership committed to providing institutional resources to ensure successful student outcomes. The TEN program aims to provide training to a new generation of interdisciplinary scientists working at the unique interface of environmental health and neuroscience termed Environmental Neuroscience. As the burden of neurological disease and disorders increases at an alarming rate, especially among underserved minorities, environmental factors are recognized as significant determinants. Thus, there is an urgent need for a new generation of scientists trained at the interface of environmental health and neuroscience. The existing Brain, Behavior, and Environment (BBE) center at FIU is uniquely poised to provide this research training and provides strong institutional support and a home for the proposed program. As a designated Emerging Preeminent Program at FIU, BBE brings together faculty and students from the Robert Stempel College of Public Health, the College of Arts, Sciences, and Education, and the College of Engineering and Computing. The mission of the proposed TEN program is to provide talented and motivated predoctoral and postdoctoral trainees with rigorous didactic and laboratory training in contemporary environmental health and neuroscience. Program Objectives are for trainees to 1) acquire fundamental knowledge in environmental health and neuroscience; 2) become proficient at integrating concepts of environmental health and neuroscience into cutting edge basic, clinical, and translational research; and 3) gain the necessary skills and tools to leverage this unique training to achieve their next career objective. The Program proposes to support a cohort of 2 pre- and 2-post-doctoral trainees in Year 1, increasing to 3 pre- and 3 post-doctoral trainees/year thereafter. The core curriculum for PhD students includes didactic coursework in environmental neuroscience, environmental health, neuroscience, neurotoxicology, advanced methods in neuroscience/neurotoxicology and research design and analysis. This didactic training is complemented by career development activities, training in Responsible Conduct of Research and Rigor and Reproducibility, and rogrammatic/networking opportunities. Postdoctoral trainees will also participate in selected components of the didactic program, depending upon their background, and be provided with additional career development activities. At the end of the program, trainees will have a deep understanding of interdisciplinary Environmental Neuroscience research, demonstrated ability to carry out independent research in this challenging multidisciplinary area, and achieved state-of-the-art preparation for this rapidly evolving discipline.

NIH Research Projects · FY 2025 · 2023-07

The U.S. is home to a significant Caribbean population, yet little is known regarding Caribbean-born individuals living with HIV beyond what was known in the pre-TasP era. No evidence-based engagement and retention intervention strategies have been developed for this group. For Caribbean-born individuals in the U.S., the HIV care continuum frequently faces disruption. Delays in diagnosis and treatment are prevalent; disruption in care due to unmet needs is commonplace. The threat of a virus hidden from view competes with more immediate socioeconomic threats. Late entry into care further compounds stigma; intersecting forms of stigma create additional barriers to effective healthcare engagement. The recent emphasis in research prioritizes understanding the longitudinal and experiential aspects of care and tailoring engagement strategies to groups not yet benefiting from biomedical advancements. Notably absent from this current era of intervention development are Caribbean-born individuals living with HIV . Based on two decades of research in both the Caribbean region and S. Florida, we propose a study that will integrate this population into the current generation of research frameworks. This proposed R34 stems from our recent work with the first community adaptation of the Integrating Engagement and Adherence Goals upon Entry (iENGAGE) intervention for implementation in a federally qualified health center serving people living with HIV. The brief engagement intervention model is designed to address the HIV care cascade comprehensively, problem-solving unmet needs, stigma, mental health and other comorbidities within a social-ecological information-motivation-behavioral framework, that incorporates motivational interviewing components. Previous iterations have shown effectiveness in reducing internalized stigma. We propose to adapt the engagement intervention model with Caribbean-born people living with HIV in Miami. The aims of our study include: (1) utilizing mixed methods to produce multi-level formative data on barriers to engagement, retention, and viral suppression among affected individuals, stakeholders, and providers; (2) culturally adapting and evaluating a Caribbean-specific engagement intervention for preliminary efficacy in a quasi-experimental pilot among recently diagnosed or nonvirally suppressed adults; and (3) identifying multi-level implementation factors affecting outcomes using mixed methods. We will adapt photovoice techniques sensitive to sociocultural constraints within this community. The study will aim to integrate a previously overlooked group into longitudinal HIV Care Cascade research, adapting and testing a promising intervention specific to their unique and persistent poorer HIV outcomes. The study fills critical gaps for this population, responds to NIH’s recent joint publication prioritizing adaptation of interventions for stigmatized populations, and establishing a foundation for future R01-level research of national significance.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Dual use of e-cigarettes and cigarettes (i.e., dual use) is a common tobacco use pattern among adults in the United States. The most common use for e-cigarettes among dual users is for harm reduction (i.e., the complete transition to e-cigarettes or total cessation). Dual use may reduce the burden of tobacco use if it is a temporary stage, i.e., cigarette smokers using e-cigarettes to quit, transition to e-cigarette use only, or total cessation (i.e., harm reduction). However, this does not always translate in real life. A significant number of dual users still maintain dual use, and evidence is mixed as to the effectiveness of e-cigarettes as a cessation tool. Furthermore, dual users face barriers to and facilitators of harm reduction that are not clearly understood. As such, we must understand these barriers/facilitators to develop effective interventions to help dual users quit or reduce their harm. This study aims to identify these contextual and individual barriers that prevent dual users from quitting cigarettes and the daily triggers associated with cigarette smoking and identify some facilitators that may promote harm reduction. I will recruit two separate groups of adult users of e-cigarettes and cigarettes (n= 50 each; 50% women; age ≥21years) to 1) use ecological momentary assessment (EMA) in a longitudinal within-subject study design to identify daily triggers and settings of cigarettes smoking for 14 days and 2) conduct focus group discussions to explore the contextual barriers/facilitators of harm reduction. Combined, the proposed studies will give real-world evidence on the barriers that prevent adult dual users who use e-cigarettes with the intent to quit but do not quit or reduce their harm. Though I have expertise in tobacco research, I lack formal training in qualitative and EMA methodology. The mentoring team has outstanding experience in epidemiological research of tobacco product use, qualitative methods, and EMA methodology and is committed to supporting Dr. Osibogun in her training and professional development. Through this K01, Dr. Osibogun will develop the skills to achieve her long-term goal of becoming an independent researcher with expertise in tobacco research, which will position her to develop and submit a R01 intervention grant proposal that can leverage EMA and other techniques learned through the K01 training experience to improve cessation outcomes among dual users.

NIH Research Projects · FY 2024 · 2023-06

PROJECT SUMMARY/ ABSTRACT There is an urgent need to increase the numbers and diversity of prepared graduates joining the biomedical workforce, through reasoned, evidence-based approaches that follow scientific practices. Florida International University's Engaging and Mentoring through Biomedical Research And Career Exploration (EMBRACE) project will leverage existing evidence to increase the diversity of the biomedical research workforce through coordinated activities including, intentional career development opportunities, authentic student research experiences, and strategic faculty professional development. FIU is an urban Hispanic-serving research-intensive (R1) public institution with over 58,000 students, 80% of which are from groups that are underrepresented in biomedicine. EMBRACE centers on programming that will leverage FIU's extensive expertise in student success, diversity, equity, and inclusion and focus on programming that transforms students' access to biomedical research experiences and career awareness and preparation. EMBRACE aims to 1) support the development of essential biomedical career skills to ensure students are prepared to pursue future biomedical research paths; 2) increase student access to authentic research experiences to promote development of essential research skills; 3) provide leadership opportunities for undergraduate students, and 4) create an informed, proactive institutional community that collectively supports STEM students in biomedical career exploration and development. EMBRACE will offer a novel research and career development experience sequence to increase access to research opportunities, starting with a 1-week research exploration, continuing with increasingly immersive experiences in a Course-based Undergraduate Research Experience (CURE) and follow-up novel Course- based Undergraduate Research Internship Experience (CURIE), and culminating in research leadership opportunities as undergraduate research peer mentors. Students will receive career professional development to promote essential professional skills, awareness of biomedical research career paths, and create opportunities for students to network with faculty, alumni, and scientists. The research curriculum will focus on investigating infectious diseases through the lens of bioinformatics, considering the importance to improve bioinformatics skills among the biomedical workforce and the possibility of providing access to safely conduct infectious pathogen cutting-edge research. Additionally, the project will provide faculty professional development to faculty teaching across the biology degree program to become effective mentors in their large-enrollment classrooms and provide students with guidance and strategies to support their readiness for potential biomedical careers. The integrated research and career support activities, organized longitudinally through the biology degree program, will support a diverse group of undergraduate students to pursue advanced studies and join the biomedical research workforce.

NIH Research Projects · FY 2026 · 2023-06

SUMMARY/ABSTRACT The overarching goal of this proposal is to identify and characterize mechanistic pathways in astrocytes responsible for changes in drug-evoked structural and synaptic plasticity that underlie the maladaptive behavior in opioid drug abuse. Astrocytes are a logical focus for these studies, as they are intimately involved in diverse neuronal function, including modulation of synaptic function and plasticity, regulating concentrations of the excitatory neurotransmitter glutamate, and yet secrete and response to neuroinflammatory cytokines, chemokines, and growth factors. These processes are themselves regulated by autophagy: the process by which cells both engage in orderly degradation and recycling of cellular components as well as balancing energy metabolism. Although astrocyte-mediated excitation and inflammation have been implicated in neuroadaptations and drug-seeking behavior, the role of astrocytes autophagy in the mechanism underlying the intersection between the glutamate system and neuroimmune signaling, is not well understood. Findings from our lab showed that a key autophagy protein, Beclin1, is strongly associated with the secretion of cytokines, chemokines, and growth factors released from glia and neurons. We also showed that activation of autophagy increases glutamate uptake along with glutamate transporters expressed in astrocytes, collectively establishing a strong premise for the current proposed investigations. Extending our initial studies, here we hypothesize that autophagy- mediated neuroimmune signaling and glutamate metabolism in astrocytes ± HIV alters neuronal circuitry to promote opioid use disorder (OUD) and abuse. Since opioid and HIV-infection are common comorbidities, and opioids are commonly prescribed to HIV-infected individuals experiencing pain, studies will include assessment of HIV-infection through use of EcoHIV in a series of mouse models, facilitating the needed behavioral, neuroanatomical, and mechanistic studies to address the current knowledge gap. In Specific Aim (SA) 1 we will use Becn1+/- and Becn1+/+ mice to define the role of astrocyte autophagy with or without HIV and/or chronic opioid exposure on the progression and magnitude of opioid addiction, withdrawal, long-term abstinence, and relapse in validated behavioral models. In SA 2 we will use brain tissue harvested from mice tested in Aim 1 to decipher the interlink between excitation and inflammation-evoked changes in neurochemical and neuroanatomical plasticity and maladaptive behavior in opioid drug abuse (with or without HIV), through the lens of astrocytes autophagy. In SA 3 we will use brain cells to further investigate the mechanisms by which Beclin1 interacts with the μ-opioid receptor and/or associated proteins and analyze how Beclin1 activity modulates endolysosomal trafficking and degradation of MOR intracellular trafficking in brain cells in response to opioid (with and without HIV). Findings are expected to produce mechanistic insights into how autophagy regulates the underlying crosstalk between astrocytes and neuronal circuitry mediating OUD and abuse behaviors, yielding both novel therapeutic targets for development and strategies for preventing OUD in at risk HIV populations.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY The long-term goal of this proposal is to identify the pathophysiology underlying HIV associated COPD. People living with HIV (PLWH) show increased incidence of COPD even when compensated for smoking status. MicroRNAs manage the cellular transcriptome and play important roles in health and disease. We have shown that HIV Tat and Transforming Growth Factor-beta (TGF-β) signaling dysregulate the airway microRNAome. Dysregulation of the microRNAome can effect multiple signaling pathways and this can affect cellular homeostasis. COPD is a multifactorial pathology and involves dysregulation of diverse signaling pathways that converge towards airway mitochondrial disfunction, circadian dysregulation, remodeling, inflammation, etc. TGF- β signaling is induced by both HIV Tat and cigarette smoke and this is significant since a significant proportion of PLWH are addicted to nicotine and smoke tobacco/cigarettes, possibly exacerbating their progression to COPD. Hence, Tat and TGF-β-induced aberrant microRNAome and its effects on the airway transcriptome can serve as an initiating events with downstream consequences on critical signaling nodes and pathways. Identifying these pathways and these critical signaling nodes can help tailor interventions to improve long-term pulmonary outcomes in PLWH. 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. A recent study shows that the bulk of HIV reservoirs are transcriptionally active even with suppressive cART. Hence, silencing HIV transcription can decrease HIV proteins like Tat in the airway. Gene editing using CRISPR/Cas9 has tremendous potential in eliminating HIV reservoirs and reports have shown excision of HIV from infected cells. However, CRISPR based HIV excision is vulnerable to viral escape as well as off-target effects. Cyclin T1, a component of P-TEFb, (heterodimer of cyclinT1 and CDK9) is bound by HIV Tat and plays a pivotal role HIV transcription and its inhibition abolishes HIV transcription. Hence CRISPR mediated CyclinT1 inactivation will completely block HIV transcription, locking the HIV proviral DNA in an inactive form. We will use our patented Pol II HIV LTR-drosophila hsp70 fusion monopromoter to co-express CyclinT1 gRNA and Cas9 (and effect CyclinT1 inactivation) only in HIV infected cells. Expression is self-limiting as our fusion promoter also requires CyclinT1 thereby minimizing off- target effects. Aim 1 will determine the mechanism by which HIV Tat and TGF-β dysregulate the airway microRNAome and its effects on the transcriptome to identify signaling pathways involved in HIV associated COPD. Aim 2 will use an inducible CRISPR syste to inactivate CyclinT1 only in HIV infected cells and lock the proviral DNA in a transcriptionally inactive state. Understanding the signaling pathways that promote HIV- associated COPD and silencing HIV transcription in reservoirs will prevent lung function decline and development of COPD in PLWH.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Adolescence is a key developmental period during which educational experiences shape long-term mental and physical health. Youth who disengage from school are at increased risk for mental health concerns and substance use. School-related factors, including exclusionary disciplinary practices, play an important role in influencing both academic engagement and health trajectories. The effects of these school-based experiences may be further shaped by early life stressors. Childhood adversity, such as exposure to violence, can contribute to increased sensitivity to stress and disrupt behavioral regulation, in part through its impact on neurodevelopment. These neurobiological adaptations may interact with educational factors to influence health outcomes during adolescence. This K01 proposal will leverage data from the Adolescent Brain Cognitive Development Study, a large, longitudinal study of youth in the United States, to examine how individual, community, and school-related factors shape adolescent mental health and substance use outcomes. The project will pursue the following three research aims: (1) Examine how school discipline is associated with adolescent mental health and substance use, while accounting for broader contextual influences (e.g. neighborhood resources, educational environments) and individual characteristics (e.g., prior behavioral concerns, socioeconomic characteristics), (2) Assess the role of early adversity in shaping the associations between school discipline and adolescent health outcomes; and (3) Evaluate the interactive effects of neurobiological functioning and early adversity on the associations between school discipline and youth health outcomes. Findings from this work will contribute to a broader understanding of how modifiable school-related risk factors, such as school discipline, and contextual experiences influence adolescent health. This award will support training in developmental neuroscience, advanced statistical modeling, and the integration of schoolbased influences on adolescent development. The proposed research builds on prior training in clinical and developmental psychology and will support the establishment of an independent research program focused on promoting adolescent health and well-being through modifiable educational experiences.

NIH Research Projects · FY 2025 · 2022-09

Abstract Social anxiety disorder (SAD) is a chronic, impairing condition that typically emerges during adolescence and affects about 10% of the population. Treatment response rates for SAD are markedly lower than for other anxiety disorders, thus presenting an urgent need to identify novel therapeutic targets that can inform new interventions for this difficult-to-treat disorder. We propose to address this need by testing a developmentally-informed, mechanistic model of the escalation of impairing social anxiety symptoms (SA) in early-to-mid adolescence; our model centers on Fear of Negative Evaluation (FNE) and Hypervigilance for Errors in the presence of peers, with a focus on frontal brain oscillations as central to this escalation. Adolescence represents a sensitive period for the development of social cognition and cognitive control. At the psychological level, social fears and FNE exhibit normative increases across adolescence, given the increasing importance of peers during this developmental window. At the neural level, frontal brain systems underlying social cognition and cognitive control exhibit protracted development across adolescence, including development of the frontal cortex and associated 4-8 Hz “theta” oscillations causally implicated in cognitive control. Our central hypothesis is that adolescent increases in FNE, alongside development of the frontal cortex, create a maladaptive feedback loop: adolescents become Hypervigilant to Errors in social settings, further increasing FNE, and ultimately, impairing SA. Our model predicts (Aim 1) that developmental increases in FNE lead to increased concerns over performance in the presence of peers, which in turn amplifies Hypervigilance for Errors (that is, increased strength of error-related theta oscillations). We further predict (Aim 2) that increased Hypervigilance for Errors leads to more critical self- evaluations and confirmations of initial fears, which worsen FNE/SA over time. Moreover, we predict adolescents who exhibit greater synchrony in theta oscillations across medial-lateral frontal cortex are at greatest risk and will display the largest increases in FNE/SA. To test our model, we will collect an accelerated longitudinal study of 256 adolescents, spanning ages 11-15, biologically male/female, and ranging in FNE/SA. Participants will complete a modified cognitive control task in peer presence/absence (via Zoom) as EEG is recorded. With an eye toward future translational work, we will also (Aim 3) establish the ecological validity of our neural measures by testing links to micro-coded behaviors indicative of SA within a social interaction task. Given that escalation of SA occurs during puberty and within a broader social context, we will also measure, control for, and explore the possible moderating roles of puberty, as well as effects of social and demographic variables. A key strength of this proposal is that our team has a proven record in developmental psychopathology and experimental therapeutics, providing a clear path for translating findings from this project into novel, brain-based therapeutics and thereby shortening the distance “from bench to bedside.”

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Mutation is the ultimate source of genetic and genomic variation and the relationship between mutation and evolution- ary change is a fundamental question in biology. Mutations can occur as single nucleotide polymorphisms (SNPs) or larger structural variants (SVs) like duplications, deletions and copy number variants. Molecular studies have focused extensively on SNP variation but DNA sequencing technologies are increasingly demonstrating the prevalence and im- portance of genomic SVs. The recency means that there is little understanding of SVs in evolution and few theoretical predictions to guide empirical investigations. For example, organisms with holocentric chromosomes, characterized by diffuse centromeres spread across the length of the chromosome, can have high rates of intrachromosomal rearrangements and SVs segregating in populations. The sojourn time of a mutation fundamentally affects the dynamics of natural selection and may differ for SNPs and SVs. Understanding the evolutionary significance of SVs requires greater understanding of the ways in which population genetic forces of drift, selection and recombination act on SVs, the long-term outcomes of SVs in genomes and the mechanisms that generate segregating SV mutations. This application proposes to address these gaps in scientific understanding by addressing 3 questions: 1) What are the population genetics of SV mutations? 2) How do SV mutations accumulate to differences in genome size and content? 3) Does the frequency spectrum of SVs vary between organisms with holocentric and metacentric chromosomes? To answer these questions my lab group will pursue a synergistic set of theoretical and comparative genomic projects. We will study a theoretical graph-based model of SVs and formulate a comprehensive population genetic theory of SV evolution. We will use our theory to formulate predictions regarding SV evolution and test our predictions by analyzing empirical genomic change in a phylogenetic comparative framework and studying the spectrum of SVs in holocentric and monocentric organisms. My research program uses an innovative combination of theory and comparative computational genomics to address fundamental evolutionary questions. The research proposed here will result in exciting discoveries unlocking the rules of eukaryotic genome evolution.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY STATEMENT We have identified a previously overlooked problem regarding a possible drug-drug interaction (DDI) among patients with opioid use disorders (OUDs) with high risk to HIV that are using Pre-Existing Prophylaxis (PrEP). Morphine and cabotegravir are metabolized by the enzyme, uridine diphosphate glucuronosyltransferase (UGT) and when combined, can influence the rate of drug metabolism, creating a potential risk for toxicity in people with comorbid HIV and OUD. Opioids are the cornerstone of pain management, and as long as they are continuing to be widely prescribed for chronic pain and/ or illicitly abused, the opioid epidemic in the United States (US) will continue to soar. OUDs are often comorbid with HIV infection, and studies have shown that individuals who misuse opioid analgesics, as well as other illicit drugs, are most likely to have difficulty adhering to antiretroviral (ART) medication regimens. Adverse DDI between ART and opioid abuse and/or medications to treat OUDs are frequently reported. In a recent publication, we showed that co-exposure with morphine and ART in HIV-infected brain reservoirs led to failure in the attenuation of viral load and increased secretion of viral- induced inflammatory molecules. Co-exposure with morphine and ART caused an increase in several histone- modifying enzymes which correlated with an increase in the mRNA expression of different variants of the μ- opioid receptor; suggesting that changes in epigenetic and opioid receptors may be involved in the regulation of DDI. Gap in Knowledge: Not much is known about the potential DDI among cabotegravir and morphine and/or medications to treat opioid use disorders (naltrexone). On that note, we hypothesize that when taken in combination, cabotegravir and morphine and/or naltrexone exhibit synergism that can influence the pharmacokinetic (PK) and pharmacodynamic (PD) responses, resulting in drug toxicity. We further posit that epigenetic variations due to the combined exposure of cabotegravir and opioids control the PK/PD responses by regulating drug-metabolizing enzymes, transporters, and/or the μ-opioid receptors. The goal of this new application is to evaluate potential interactions among opioids and cabotegravir. Specific Aim 1 will evaluate the PK responses among the three groups of drugs (cabotegravir - morphine - naltrexone) in healthy mice model. Specific Aim 2 will evaluate the PD responses, and toxicological interactions among the three groups of drugs in non-infected or HIV-infected humanized mouse model. Specific Aim 3 will evaluate the PK/PD, and toxicological interactions among the three groups of drugs in non-human primates. Impact: Findings will provide novel insights in the potential mechanisms involved in the adverse DDIs among cabotegravir and opioids which are used in clinical settings. Furthermore, an understanding of the pharmacoepigenetics will identify new targets that might help in the interference with pharmacokinetics or pharmacodynamics of opioids and cabotegravir.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY It is critical to improve the reach and efficacy of psychosocial treatments for childhood attention-deficit hyperactivity disorder (ADHD), the single most prevalent pediatric mental health disorder (9% prevalence; Danielson et al., 2018a). Evidence-based treatments for ADHD, such as behavioral parent training (BPT), produce moderate effect sizes on clinical outcomes including parenting skills, parent stress, child impairment, and child academic functioning when targeted (Evans et al., 2018; Merrill et al., 2017; Power et al., 2012). However, the impact of BPT in the community is attenuated by poor transportability and high therapist involvement in standard treatment. The magnitude of treatment need is far beyond the capacity of the current mental health system, with only about 30% of parents receiving BPT (Danielson et al., 2018b). Technology- delivered interventions, and specifically mHealth applications, can overcome this gap as 81% of Americans own a smartphone (Pew Research Center, 2019), and many minoritized and low-income individuals rely on smartphones for internet access. The current study aims to leverage an established data collection and intervention development smartphone application to develop and pilot a mobile BPT intervention for parents of children with ADHD and academic difficulties. The intervention will target candidate mechanisms of child behavioral and academic success including parenting skills, parent academic management, and engagement with treatment material. mBPT will include: 1) online, asynchronous treatment videos, 2) survey data collection, 3) prompts to complete between session parent practice, and 4) personalized adaptive components to enhance parenting skills. Following intervention development and refinement, 60 children with ADHD will be recruited from area pediatric practices and randomly assigned to (1) business and usual (BAU) or (2) mBPT. Within the mBPT group, adaptive components of the intervention will be evaluated in a microrandomized trial. Primary aims are to demonstrate the feasibility and acceptability of the intervention approach. Further, the hypothesized mechanisms (e.g., parent skill use, user engagement) will be measured and correspondence to hypothesized outcomes (e.g., improved child behavior and homework performance) will be evaluated. Data collected will be used to justify a larger effectiveness trial to evaluate mBPT effects on child behavior and academic impairment.

NIH Research Projects · FY 2025 · 2022-09

Enter the text here that is the new abstract information for your application. There is an urgent need to increase the number of prepared graduates joining the biomedical workforce through systematic and impactful evidence-based approaches that follow scientific practices. Florida International University's Project iCREATE (investigating Career & Research Experience Access Through Evidence) will increase awareness of biomedical careers as well as workforce readiness for future biomedical careers by designing, implementing and testing innovative interventions; as well as investigating the effect of high-impact practices (e.g., different research experience formats and career development opportunities) on students' career goals, career strategies, and key student career intent and action outcomes. FIU is an urban research-intensive (R1) public institution with over 4,000 biology students. iCREATE centers on generating evidence for two scalable interventions that will leverage FIU's extensive expertise in student success and focus on programming that transforms students' access to biomedical research experiences and career awareness and preparation. iCREATE aims to 1) develop and implement the following interventions: Careers+, a workshop for students focused on career development strategies and biomedical career awareness, and CURE+ which expands a one semester CURE into a two-semester advanced course-based research experience; 2) evaluate the effectiveness of the proposed interventions and current research experiences available to students at our institution; and 3) perform a qualitative longitudinal study of undergraduates’ development of career goals and strategies and the impact of research experiences and career development opportunities on student career goal trajectories. iCREATE will advance our understanding of best-practices in preparing a qualified biomedical workforce by 1) developing and testing evidence-based programs, thus, laying the groundwork for implementing similar efforts in life science curricula to increase student preparation for the biomedical workforce; 2) conducting comparative analyses across research experience formats to directly compare the impact of various experiences on student outcomes; 3) focusing on the impact of research experiences and career development opportunities on students, and 4) following students longitudinally to comprehensively understand how students develop career strategies and factors that trigger the intent and actions to pursue a career in biomedical research.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY This proposal describes a five-year career development program to prepare Dr. David Marciano for a career as an independent investigator. This program builds on Dr. Marciano’s extensive background as a molecular pharmacologist by providing him with the training to establish expertise in extracellular vesicle biology, in vivo surgery, state-of-the-art imaging and iPSC to investigate new therapeutic strategies to treat pulmonary arterial hypertension (PAH). Dr. Marciano’s primary mentor is Dr. Michael Snyder, a Professor and chair of the Genetics department at Stanford University and his Co-mentor Dr. Marlene Rabinovitch is a clinical professor in the pediatrics department and expert in PAH. Drs. Snyder and Rabinovitch have a long standing collaboration and are excellent mentors with many former trainees now established as independent investigators. The K99 phase of Dr. Marciano’s studies will focus on supporting his investigation into the role of BMPR2 in mediating the hypoxic cellular response and its dysfunction in PAH. Specifically, in AIM 1 of Dr. Marciano’s proposal he seeks to determine the therapeutic potential of BMPR2 enriched extracellular vesicles (EV) in reversing disease progression. The therapeutic application of EV is an emerging field that Dr. Marciano is being trained in as a future leader. In AIM 2 of Dr. Marciano’s proposal he will investigate the effect of laminar shear-stress, the frictional force of blood flow on EV signaling. He will apply live PET imaging to track the bioidistriubtion of EV and the effect of different cellular perturbations on their targeting. In Aim 3 of the proposed studies, Dr. Marciano will initiate studies towards the development of autologous ‘personalized’ EV derived from a patient’s own stem cells as a strategy to reduce adverse immune reactions. Dr. Marciano is uniquely positioned to leverage his background in translational medicine to extend the exciting preliminary findings from which this proposal builds to identify new PAH therapies. This work will also provide the foundation for future studies, which will be carried out by Dr. Marciano as an independent investigator.

NIH Research Projects · FY 2025 · 2022-08

One in three people with diabetes mellitus is at risk of diabetic foot ulcers (DFUs), with over 10% amputated. The current global pandemic has driven a significant change in healthcare delivery and disrupted DFU care and limb preservation, leaving many patients with limited or no clinical care. Clinicians must adopt a paradigm shift from the hospital and clinic care to community-based point-of-care (POC) - to best triage chronic DFU cases that are high-risk lesions requiring clinical care or hospitalization. There is an unmet clinical need for smart health assessment tools for POC treatment of patients with DFUs onsite, where no wound care expertise is available. Smartphone technologies for wound care are limited to 2D/3D wound image analysis for size/depth. They are insufficient as stand-alone tools to assess and triage high-risk DFU lesions without wound expertise onsite. Hence, additional clinical assessments (e.g., the extent of oxygen supply to wound) are required during POC of DFUs onsite. Oxygenation measurements provide a sub-clinical physiological assessment that complements clinical visual assessment. We recently developed a smartphone-based NIR imaging approach or SmartPhone Oxygenation Tool (SPOT) to obtain visual tissue oxygenation measurements in wounds. Systematic assessment of the skin tone and wound characteristics is critical during physiological imaging and has not been investigated to date. Hence, our objective is to develop and validate a smartphone-based imaging approach (or Smart Scanner) capable of visual and physiological analysis of DFUs across the spectrum of skin tones and wound features via automated machine learning (ML) algorithms. Developing a smartphone-based optical device via integration of existing NIR imaging technology, but towards smart health platform for physiological assessment of DFUs, while accounting for varying skin colors and wound types using ML algorithms is innovative. The specific aims are: (i) Account for the effect of skin tones on oxygenation measurements by applying light propagation models and machine learning algorithms and validate via phantom and in-vivo studies. (ii) Analyze tissue curvatures and account for depth variations in-vivo oxygenation maps via studies on control subjects (~15 cases). (iii) Differentiate wound tissue types and validate physiological imaging using the SPOT device via DFU studies (~25 cases). The expected outcomes are: (i) Develop our Smart Scanner (SPOT device + app) to obtain accurate tissue oxygenation maps across different skin tones and wound tissue types; (ii) Validate our SPOT device to differentiate DFUs with high-risk lesions that require clinical care, from low-risk cases. Incidence of DFUs and related amputation rates differ across people of different skin tones. In the long term, SPOT can be used as a smart health tool to pre-screen or triage DFUs with high-risk lesions to clinical care and thus minimize potential amputations in people with any skin tone.

NIH Research Projects · FY 2025 · 2022-07

Title: Resetting the Clock on HIV associated COPD PROJECT SUMMARY The long-term goal of this proposal is identifying the role of aberrant circadian-coupled gene expression linking HIV and lung inflammation as a fundamental starting point to understand the pathophysiological mechanism in HIV associated COPD. People living with HIV demonstrate increased lung inflammation and incidence of COPD even when compensated for smoking status. Disruption of the lung molecular clock has been implicated in increased lung inflammation observed in COPD and smokers. SIRT1 is a principal circadian deacetylase that serves as a critical link between core clock function and inflammatory responses in the lung. HIV Tat, an immediate early protein of HIV that is secreted extracellularly, upregulates miR-142-5p in primary bronchial epithelial cells. This upregulation results in suppression of SIRT1 and circadian disruption of core clock genes BMAL1 and PER2. Likewise, cigarette smoking has also been shown to suppress SIRT1/BMAL1 pathway and dysregulate the lung molecular clock with consequent increase in secretion of proinflammatory cytokines. A significant proportion of people living with HIV smoke tobacco/cigarettes, possibly exacerbating their lung molecular clock dysfunction. This could be one of the core mechanisms that results in COPD exacerbations in HIV smokers. Therefore, determining the role of lung molecular clock dysfunction in HIV associated lung inflammation and COPD is the goal of this proposal. Resetting the molecular clock could thus help reduce underlying inflammation and/or arrest the lung function decline observed in HIV smokers. We propose three aims. Aim 1 determine that lung molecular clock is dysregulated by HIV Tat and identify the mechanism involved and its impact on inflammation. Aim 2 will test the role of miR-142-5p/SIRT1/BMAL1 axis in lung molecular clock dysfunction in HIV smokers/non smokers and in transgenic mouse models. Aim 3 will test clinically feasible strategies with established potential to neutralize HIV Tat and reset the lung molecular clock in vitro and in transgenic molecular clock mouse models in vivo. Understanding the pathophysiological mechanisms by which HIV disrupts the lung molecular clock will provide therapeutic targets for HIV-associated COPD.