Florida State University

NIH Research Projects · FY 2025 · 2022-09

To strengthen behavioral interventions for improve health, as in cancer prevention and treatment, and increase their dissemination into clinical practice, what is needed is: (1) more attention to phased T1 translation from basic behavioral and social sciences research to applied behavioral intervention development; and (2) more focus on early-phase treatment development by promoting the use of new and innovative methodologies to answer commonly asked questions about basic treatment design. This skills development course aims to train 100 intervention scientists (Fellows) at any academic rank but who have an interest in behavioral treatment development to target cancer and related health behaviors. Training will take place over 6 months including a 3-day workshop followed by biweekly webinars with 25 Fellows per session. Learning will be multi-directional and will feature didactic, interactive, and applied teaching techniques. A train-the-trainer model is integrated throughout the course. Optional follow-up activities include consultation and mentoring with faculty. The curriculum will be offered by expert faculty who will teach a phased approach to intervention development, new and innovative methods that are well-suited to answer common questions that arise during health behavior treatment development. Among the methodologies are dose-finding methods, mixed methods to maximize ecological validity of treatments, approaches for small samples, tailoring and adaptive treatments, and methods to determine the timing and choice of appropriate control groups. The Specific Aims of the course are: 1) To successfully recruit and train 100 Fellows dedicated to behavioral interventions relevant for cancer prevention/treatment and related health behaviors over the 4-year grant period (25 Fellows per year); 2) To increase the skills of Fellows in a phased approach, with associated innovative methods and designs for T1 translation of BSSR. 3) To conduct an ongoing evaluation of the success of the skills development course based upon three basic metrics: (a) perceived value; (b) the reach of the course based upon website hits, number of applications, and train the trainer activities; and (c) the impact of the course on the career trajectories of the Fellows (publications, grants). 4) To conduct ongoing curriculum development and refinement, as well as dissemination via technology, based upon results of quantitative and qualitative evaluations and new methodologies emerging over the grant period.

NIH Research Projects · FY 2024 · 2022-08

Project Summary/Abstract Alzheimer’s disease (AD) is devastating for both individuals and society. Because pathology and neural damage occur so early relative to detectable symptoms, it is important to study early disease progression, with a focus on detection and treatment. One of the earliest symptoms to appear in this disease is impairments in spatial navigation, which could be the result of impairments in navigational computations, memory encoding or retrieval, or some combination of navigational and memory impairments. Both cortex and hippocampus are important for memory encoding and navigational computations, with interactions between these two regions supporting these processes. In navigation, hippocampus is involved in creating a cognitive representation of the environment. Parietal cortex is involved in the translation of this cognitive representation based on body-centered location into the appropriate navigation decision. Furthermore, interactions between these regions have been shown to be impaired during sleep in rodents modeling Tau and amyloid beta (Aβ) aggregation aspects of AD. Thus, we will test the hypothesis that impaired hippocampal-cortical interactions during navigation underlie deficits in spatial navigation in a mouse modeling Tau and Aβ aggregation (TAβA; AIM 1). Additionally, we will test the hypothesis that these interactions can be rescued via 40Hz stimulation of either parietal cortex or hippocampus (AIM 2). This project will expand our knowledge of systems level dysfunction as a consequence of TAβA, and how this impacts cognitive symptoms. Furthermore, this project will provide insight into how new, preliminary treatments for AD designed to ameliorate TAβA effects systems, spatial navigation, and neural function.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY School closures and disruptions to instruction can have long-term impacts on children’s progress towards becoming successful readers (Miller & Hui, 2022). Learning to read is crucial, as reading is a critical indicator of lifetime earnings, general health, and wellbeing (OECD, 2012). Many children are already at risk for reading difficulties, with only 35% of U.S. fourth graders showing proficient levels of reading ability (NCES, 2019). These reading difficulties can be magnified by disruptions to learning, with each day of closure linked to a 0.011 standard deviation decrease in literacy scores (Luo & Xu, 2025), particularly among elementary students (Weir, 2019). Our preliminary data shows that disruptions to schooling have had an immediate impact on children’s reading skills with potentially cascading effects. The overall goal of this project is to uncover the mechanisms through which unplanned school disruptions have short-term and long-term impacts on children’s reading skills. We use a risk-resilience model as the framework for this project, which recognizes children have varying levels of risk factors that make them more or less likely to be affected by disruptions to their sources of resiliency. We will capitalize on an existing active national twin project, the National Project on Achievement in Twins (NatPAT). NatPAT has already enrolled a cohort of 1997 pairs of twins (and growing) and has been tracking them as they progress through elementary school, collecting their reading progress monitoring data three times a year. We will continue to enroll twins into NatPAT using our successful and established recruitment procedures, and collect their ongoing reading data. In addition, every summer for all five years of the grant, any twin family with children in grades kindergarten to 6 will be mailed a survey packet to their homes. This packet will contain a parent and child survey with questionnaires related to their experiences over the last school year related to school disruptions, specifically their social interactions, health status and changes, and their experiences with digital technology. Using methods that allow us to understand causal relations, we are uniquely situated to address the overall goal of the proposed research through three specific aims (SA). First, we will quantify the short and long-term effects that losing social resources due to school disruptions has on reading skills (SA1). Second, we will quantify the short and long-term effects of school disruption related health stressors on reading skills (SA2). Finally, we will quantify the short and long-term effects of the digital-divide on reading skills as a result of school disruptions (SA3).

NIH Research Projects · FY 2024 · 2022-08

Project Summary The error-related negativity (ERN) is a biomarker of error processing that can predict future onset and worse outcomes of anxiety disorders in young children and is therefore a potential target to offset the development of anxiety disorders. Therapeutic interventions can reduce the ERN in a single session, but a number of factors make the ERN difficult to measure, such as requiring participants to spontaneously make mistakes on a small fraction of hundreds of trials in simple computer games that are far removed from daily life. Further, the ERN is quite sensitive to interpretation of the task instructions. The balance N1 is a comparable biomarker of error processing that can be evoked by a sudden disturbance to standing balance. Unlike the ERN, the errors that evoke the balance N1 are encountered in daily life, are under full experimental control, and evoke an involuntary behavioral reaction that requires no prior instruction, eliminating many of the problems with measuring the ERN. Further, the balance N1 is substantially larger in amplitude than the ERN and can be robustly observed in single trials. Preliminary data demonstrate that the balance N1 and ERN amplitudes are correlated within younger and older adult populations, suggesting the balance N1 may provide a robust measurement of the same underlying neural system. In the proposed project, the balance N1 and ERN will be measured in 128 children (ages 9-12, N=64 with anxiety disorders and N=64 without). While replicating prior findings that the ERN is enhanced in clinically anxious children, this project will be the first to test whether the balance N1 is similarly enhanced in anxious children (Aim 1). Then, this project will test whether the balance N1 and ERN amplitudes are correlated within and across both groups of children, and assess whether they account for unique or overlapping variance in anxiety status (Aim 2). The anxious children will then be randomized into a single-session computer-based intervention targeting hyperactive error monitoring or a control condition focused on healthy lifestyle choices. Our goal is to demonstrate that an intervention targeting hyperactive error monitoring can reduce the ERN—and test whether this effect transfers to a similar reduction of the balance N1 to test for shared underlying mechanisms (Aim 3). The proposed study may yield a biomarker of anxiety that is more robust and easier to measure than the ERN. Transfer of the intervention effect to the balance N1 would provide insight into prior work demonstrating that balance training can alleviate anxiety in young children, and well-documented benefits of psychotherapy to balance disorders. Collectively, these data may facilitate the development of multidisciplinary interventions for anxiety in children that target activity of the brain’s error monitoring system. This project will provide training in the use of event-related potential based biomarkers to study developmental psychopathology in a clinical research project to support the applicant’s long-term goal of investigating overlapping neural mechanisms of motor, cognitive, and psychiatric problems in children with neurodevelopmental disorders.

NIH Research Projects · FY 2026 · 2022-08

This project will launch a Florida wide effort to promote the delivery of developmentally sensitive and evidence-based DIAGNOSE and PREVENT counseling testing and referral services (CTR) for young men who have sex with men (YMSM). The goal is to leverage implementation science strategies to improve the capacity of the HIV HealthForce to deliver evidence-based practices (risk reduction counseling, PrEP referral and motivational interviewing) within CTR services. Our recent YMSM Mystery Shoppers studies conducted at CTR sites in three cities indicated that providers are woefully unprepared or do not know how to deliver developmentally appropriate, CTR services to YMSM and miss opportunities to deliver these evidence-based practices. Mystery Shopper is a quality management strategy to monitor implementation fidelity to developmentally responsive EBPs in CTR settings. However, assessment and feedback alone are insufficient to improve fidelity; the HealthForce must be properly trained and given technical assistance. We propose integrating two implementation strategies: quality management Mystery Shoppers and HealthForce training in developmentally tailored motivational interviewing with centralized technical assistance. We will test Young Adult Centered HealthForce Training (YACHT) package in Florida’s EHE counties among the Department of Health’s 42 contracted sites who delivered CTR to at least 24 young MSM in the previous 12 months using a Stepped Wedge design. We power on both effectiveness outcomes (# of tests of YMSM) and implementation outcomes (EBP fidelity based on Mystery Shopper Assessments) consistent with a Type 2 Hybrid trial.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT The goal of the current project is to combine two evidence-based treatments for school-aged children with ADHD: Central Executive Training (CET) and Behavioral Parent Training (BPT). CET is a computerized training intervention that improves ADHD symptoms and academic functioning by improving children’s working memory abilities. BPT is a therapeutic intervention that improves family functioning and child ODD symptoms by changing parenting behaviors. Their combined use is expected to provide complementary and additive benefits, particularly if CET is delivered before BPT.

NIH Research Projects · FY 2024 · 2022-08

Men who have sex with men (MSM) are disproportionally affected by HIV and substance abuse in the U.S., Europe, and Latin America. However, as in the general population, identifying and engaging MSM with problematic substance use (PSU) into treatment is a significant challenge, which results in the great majority of MSM with PSU never receiving treatment. The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends Screening (S), Brief Intervention (BI), and Referral to Treatment (RT; SBIRT) as an early intervention for non-treatment-seeking individuals with risky alcohol and drug use, as well as the timely referral to more intensive substance abuse treatment for those with substance use disorders. The need for such an intervention is particularly acute in Argentina and Latin America, where there is little implementation of evidence-based interventions for MSM with PSU. The proposed study seeks to address this glaring gap by developing and piloting an electronic-SBI program tailored for MSM awaiting their HIV test at Nexo Asociacion Civil, our community partners in Buenos Aires. The tablet-based e-SBI will integrate substance use and sexual risk behavior screeners and individually tailored Motivational Interviewing (MI) as the BI. We will also adapt and pilot the implementation of the Young Men’s Health Project (YMHP, now MHP since it will not be limited to young MSM), a four-session MI-based intervention that effectively reduced substance use and condomless anal intercourse among substance using MSM, as a brief treatment provided at Nexo for participants with moderate or high-risk substance use. The Specific Aims of this R34 study are to: 1) develop a tailored e-SBI intervention for MSM in an HIV testing context aimed at reducing substance use and HIV risk behavior (Primary); 2) assess the feasibility and acceptability of integrating e-SBI into the HIV testing process at Nexo as measured by a) percent of MSM testing clients at Nexo who accept entry into the study; b) percent of participants who complete e-SBI; c) e-SBI acceptability ratings (Primary); 3) assess the feasibility and acceptability of implementing adapted YMHP at Nexo, as measured by a) the percent of MSM with moderate or high-risk substance use who enter and/or complete MHP; b) acceptability of MHP among those who received it; and c) percentage of sessions conducted by each MHP counselor that meets criteria for MI fidelity (Secondary). In Stage 1 (Development) we will develop e-SBI, adapt YMHP into MHP, train MHP counselors, and pilot e-SBI with 50 MSM coming to Nexo for HIV testing. In Stage 2 (RCT Pilot), we will randomize 200 MSM coming to Nexo for HIV testing at a 3:1 ratio (eSBI: Screening Assessments Only-SA) to assess the feasibility and acceptability of e-SBI among MSM coming to Nexo for HIV testing and establish and pilot the RCT process for a future trial. As a secondary aim, we will assess uptake, acceptability, and feasibility of delivering MHP to participants with low or moderate risk substance use and subsequent referrals to substance abuse treatment among participants with high-risk substance use or dependence. Lastly, we will explore preliminary findings on substance use and sexual risk reduction outcomes.

NIH Research Projects · FY 2026 · 2022-08

The Southeastern Center for Microscopy of MacroMolecular Machines (SECM4), at Florida State University (FSU) will be a service center that will enable sample preparation and cryogenic electron microscopy (cryo-EM) imaging of specimens for high-resolution biomolecular structure determination. The center will be led by Dr. Scott Stagg and Dr. Kenneth Taylor and will feature two staff members with complimentary expertise. This will be the second generation of the SECM4. The first generation provided high-resolution cryo-EM data collection for cryo-EM experts. In the new generation of the SECM4, we are expanding the scope of the resource by offsetting the cost of collecting high-resolution data on the microscope for all users with a very modest usage fee and also by offering a large number of new services including cryo-EM specimen optimization, specimen preparation, specimen screening, high-resolution data collection, routine single particle data analysis, and training for all aspects of cryo-EM from specimen preparation to processing. We will target users in the greater Southeast to be clients for the center, specifically focusing expanding into the IDeA states that have not benefitted from the current explosion in cryo-EM due to the extraordinary costs that serve as an entry barrier. Our approach will enable exceptional economies of scale because we will: 1) enable users at universities across the Southeast to gain entry the cryo-EM field without making multi-million dollar investments in instrumentation, 2) by offering screening and specimen optimization services, we will address the biggest bottleneck in cryo-EM right now, which is preparation of cryo-EM samples that will reconstruct to high-resolution, 3) by offering in person training and offsetting the travel costs, we will enable interested users to gain entry into the field of cryo-EM without having to seek out a collaboration with an already saturated cryo-EM expert.

NIH Research Projects · FY 2026 · 2022-07

Project Summary/Abstract Compromised olfactory function is associated with the aging process, as well as a number of human diseases. Our incomplete understanding of the brain makes it challenging to comprehend the mechanisms that underlie these sensory deficits and other psychiatric disorders. Understanding how sensory information is encoded and transformed by neural circuits will help define the basic mechanisms that underlie these challenges. For many animals, smell is critical for recognizing and locating food, mates and dangers. Odor recognition requires the identification of a specific smell that can vary in intensity, while localization involves detecting a concentration profile that varies in time and space. Both processes must be carried out while the stimulus is embedded in a complex chemical context. This requires that the olfactory system recognize and maintain a concentration- invariant representation of the odor, while detecting its changing concentration gradient and segmenting its percept from other chemical stimuli present in the environment. Understanding how the brain carries out these processes is key to understanding perceptual stability. The goal of this proposal is to define the neural circuits that support odor recognition and the ability to adjust sensitivity to complex olfactory scenes in vivo. First, we will define how changes in odor concentration are encoded and transformed across the olfactory bulb circuit. Next, we will examine how different concentrations or durations of odor exposure impact olfactory bulb responses to future odor stimulation. We will then test the hypothesis that olfactory bulb adaptation underlies dynamic range adjustments involved in maintaining sensitivity in different odor backgrounds. This proposal will answer these questions using an imaging approach to measure the neural activity from the olfactory receptor neuron input, and the mitral/tufted cell output that innervate olfactory bulb glomeruli. We will pair this strategy with a mechanistic toolkit to dissect the underlying mechanisms that drive functional transformations in the bulb. The impact of this proposal will be to generate a comprehensive mechanistic description of how two perceptual functions are carried out by the olfactory bulb, which are the critical first steps that will ultimately link physiology with naturalistic behavior.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY/ABSTRACT CANDIDATE: Joseph Watso, PhD, is a postdoctoral fellow at the University of Texas Southwestern Medical Center within the Institute for Exercise and Environmental Medicine. Dr. Watso seeks mentored research training with an NHLBI K01 to facilitate achieving his long-term career goal of directing an extramurally-funded clinical laboratory. Dr. Watso’s research interest is to examine cardiovascular disease prevention and treatment strategies in clinical populations. CAREER DEVELOPMENT PLAN: Dr. Watso’s training objectives are to: 1) Master new technical skills, such as “gold-standard” respiratory function assessments and measuring circulating cardiovascular biomarkers; 2) Establish independent research expertise in human obesity through meetings, coursework, and workshops; 3) Improve technical writing skills through co-writing grants with his mentors and UT-Southwestern’s ‘Successfully Obtaining an R’ program; and 4) Refine professional skills through journal club participation, mentoring trainees, and presenting at regional/national scientific meetings. RESEARCH: Obesity affects four-in-ten American adults and is associated with hypertension and greater all-cause mortality. Irrespective of weight loss, aerobic exercise reduces arterial blood pressure (BP) and improves cardiometabolic health. However, nearly half of adults with obesity do not perform aerobic exercise because of low leisure time availability and exertional dyspnea secondary to high chest wall mass-related inspiratory muscle dysfunction. In other clinical populations, emerging data demonstrates time-efficient high-resistance inspiratory muscle strength training (IMST) reduces BP and improves respiratory muscle function. Therefore, we will determine whether eight weeks of daily high-resistance IMST reduces BP, improves respiratory muscle function, and concomitantly reduces exertional dyspnea in a randomized, double-blinded, sham-controlled (i.e., very low-resistance IMST) clinical trial among adults with obesity. ENVIRONMENT: Dr. Watso will train in a world-leading research environment and receive mentoring from a multidisciplinary team. Internationally-recognized human physiologist Craig Crandall, PhD, has completed four NHLBI-R01 grants as the principal investigator and mentored >20 postdoctoral fellows into independent research positions. He is exceptionally-suited to serve as Dr. Watso’s primary mentor. Expert pulmonary physiologist Tony Babb, PhD, and pulmonologist Andrew Tomlinson, MD, (co-mentors) will provide training in respiratory function assessments in adults with obesity. IMST expert Fiona Bailey, PhD, (advisor) will provide training in implementing an IMST clinical trial. Vascular physiologist Kerrie Moreau, PhD (advisor) will provide training in assessing circulating cardiovascular biomarkers. Endocrinologist Jaime Almandoz, MD, (advisor) will provide training in obesity physiology and medicine. Biostatistician Linda Hynan, PhD, (advisor) will provide biostatistical support and training. World-renowned cardiologist and institute- director Ben Levine, MD, (advisor) will ensure Dr. Watso has the resources necessary for success as a junior faculty member and will provide assistance with future NHLBI R01 grant submission(s) from the resultant data.

NIH Research Projects · FY 2026 · 2022-05

Project Summary/Abstract To understand mental health and disease, we need to understand the function of the brain at the level of genes, gene regulatory networks, neurons, circuit structure, and physiology. Drosophila has emerged as one of the most powerful model systems for these questions, given the range of tools and the tractability of analyzing complex behaviors at all these levels. This proposal seeks to understand Drosophila reproductive behaviors. One reason Drosophila is such a powerful system is that the sex- specific master regulatory transcription factors that direct reproductive behaviors are known. This has provided a powerful molecular inroad into identifying and manipulating the neurons that underlie these behaviors. These tools can also be used to perform neuron-specific mutational studies to discover the functions of genes that direct behaviors, which leverages one of the biggest strengths of the Drosophila model system. In addition, this system affords an unparalleled model to both examine the sex-specific development of these neurons and how they are modified by adult experiences. Research using the Drosophila model has continued to uncover biologically important processes that have informed on human health and disease, including studies of the nervous system and behavior. The work will build off of my laboratories 15-year NIGMS funded research program. We will continue to address these behavioral questions using cutting-edge molecular-genetic, genomic, proteomic, behavioral and microscopy tools to gain insights into complex behaviors.

NIH Research Projects · FY 2026 · 2022-03

Project Summary/Abstract Currently, about 4 million Americans are living with the effects of stroke, but there is no effective treatment to improve functional recovery. The stroke-damaged site is especially cytotoxic to neurons because of the high susceptibility to reactive oxygen species and pro- inflammatory enzymes. It was recently realized that cellular secretome may be the major contributor during stem cell therapy. Extracellular vesicles (EVs), the membrane-bound microvesicles, represent an active component of the cell secretome. And a major contributor to the activity of EVs is the microRNA cargo. Since 2013, derivation of brain organoids from human induced pluripotent stem cells (iPSCs) has emerged as a promising approach for mimicking three- dimensional human brain tissue. However, current knowledge on the therapeutic benefits of EVs secreted by iPSC-derived brain organoids is limited. The objectives of this research are to engineer EVs of brain organoids derived from human iPSCs (iNPCo) and investigate the impacts of iNPCo-secreted EVs on the survival, biosynthesis of trophic factors and extracellular matrices, and functional neural differentiation in vitro and in vivo. The central hypothesis is that iNPCo, unlike naïve iPSCs and monolayer neural progenitors, secrete EVs carrying brain-specific microRNA cargo that can target ischemic brain tissue both by providing neuroprotection from injury and by promoting recovery after injury; in particular, heparin- hyaluronic acid hydrogel encapsulation will allow for the sustained delivery of iNPCo-EVs in the ischemic environment, promoting their therapeutic effects. Based on these hypotheses, we propose three aims: (1) Aim 1 will test the hypothesis that iNPCo-EVs express exosomal markers and promote cell survival under oxidative stress in vitro; (2) Aim 2 will test the hypothesis that the microRNAs in iNPCo-EVs regulate the Wnt pathway and the secretion of trophic factors and extracellular matrices to stimulate neurogenesis in vitro; and (3) Aim 3 will test the hypothesis that iNPCo-EVs promote in situ neural differentiation and tissue regeneration in an ischemic stroke model. To date, no EV study has been performed for brain organoids derived from human iPSCs yet. The novelty of our study in contrast to previous EV study is the use of three-dimensional brain region-specific organoid system and the tunable heparin-hyaluronic acid hydrogel encapsulation for therapeutic EV delivery. This project will advance our understanding of the effects of paracrine signaling on neural regeneration and establish a transformative approach to modulate extracellular microenvironment to attenuate ischemic-associated neuropathology toward the goal of promoting neural regeneration through novel therapeutics.

NIH Research Projects · FY 2026 · 2022-03

In humans, social attachment with partners, relatives, or friends act as a protective buffer against many negative consequences of life stress, whereas lack of social attachments can lead to serious pathologies including dysphoria, anxiety, depression, sleep disturbance, cardiovascular problems, and immune system deficits. In the social prairie voles, acute and chronic social isolation as well as partner separation induce anxiety and depression-like behaviors, enhance stress response, and alter activities of several neurochemical systems, including the oxytocinergic system. Data from our group and others have shown that oxytocin (OT) is involved not only in the formation of pair bonds in this specie, but also in the response to social isolation/ partner separation as well as social buffering of stress responses. In this proposal, we will verify the overall hypothesis that breaking bonds in voles alter the OT circuitry projecting from the hypothalamic PVN to the nucleus accumbens (which represents 90% of OT projections to nucleus accumbens) and leads to negative consequences on social behaviors in male and female prairie voles.

NIH Research Projects · FY 2026 · 2022-02

PROJECT SUMMARY Spinal cord injury (SCI) progression can be divided into acute and chronic phases. Following the primary injury, bone marrow-derived macrophages (BMDMɸ) infiltrate to the injured epicenter where they engulf myelin debris to become proinflammatory myelin-laden macrophages (Mye-Mϕ). Mye-Mɸ accumulate in the injured core densely and occupy almost entire epicenter of injured area indefinitely, which would consequently result in: 1) They prevent the entry and growth of axons, which inhibits remyelination. 2) They lose their normal phagocytic capacity for dead cells and cellular debris, which may exacerbate the inflammatory microenvironment. 3) They release inflammatory mediators, which trigger an inflammatory cascade that prevents tissue regeneration. Our data indicated that the migratory potential of BMDMɸ is directly suppressed when they engulf myelin debris. We resently reported that newly formed microvessels and their lining endothelial cells (ECs) in the injured cord are able to engulf myelin debris. Myelin debris engulfment by ECs (Mye-ECs) significantly increased deposition of extracellular matrices (ECM) such as collagen and fibronectin which may serve as extrinsic factor to promote the adhesive interaction between Mye-Mϕ-ECs and lead to Mye-Mϕ retention in the injured lesion. Our central hypothesis is that Mye-Mϕ retention in the injured core is mediated by intrinsic and extrinsic mechanisms which promote Mye-Mɸ retention through ECM adhesion. The objective of the proposed project is to investigate the underlying mechanisms of Mye-Mϕ sequestration and identify treatment strategies that target Mye-Mɸ in the injury site, which may restore normal Mφ functions and lead to improvements in lesion resolution. The rationale for the proposed research is based on preliminary investigations that demonstrate Mye-Mɸ become ‘trapped’ via a mix of intrinsic (Mɸ produced) and extrinsic (environmental) mechanisms within the lesion. Our central hypothesis will be tested in the following specific aims: 1) To study whether myelin debris, either directly or via autocrine pathways, inhibits BMDMϕ migration ability which promotes their lesion retention; 2) To determine whether adhesive ECM produced by Mye-ECs in the injured core aggravates Mye-Mɸ retention; and 3) To investigate whether targeting Mye-Mφ and subsequently switching their phenotype toward a reparative phenotype promotes tissue healing. This research is innovative because we propose that inflammatory Mye- Mɸ trapped within the injured spinal cord lesion contribute to the chronic SCI lesion, preventing full resolution of the injury. This work is significant because Aims 1 and 2 will identify the underlying mechanisms governing Mye-Mφ retention, while Aim 3 will demonstrate novel strategies for the resolution of chronic SCI inflammation and lesions. This will have the positive impact of identifying novel therapeutic strategies for therapeutic interventions not only to treat SCI but also to other demyelinating disorders that generate myelin debris.

NIH Research Projects · FY 2026 · 2022-01

PROJECT SUMMARY Recent studies on the gustatory portion of the insular cortex (gustatory cortex, GC) have demonstrated its role in integrating sensory, affective, and cognitive signals associated with the experience of food. Indeed, GC neurons do not just encode the chemosensory features of gustatory stimuli but can also process hedonic value (i.e. liking or disliking) and information on multisensory stimuli anticipating taste. Understanding how GC performs the complex integration of chemosensory, affective, and anticipatory information is one of the major efforts in the field. It is generally believed that GC achieves this level of integration by processing inputs from sensory and limbic areas including the gustatory thalamus (VPMpc), the basolateral amygdala (BLA), and the mediodorsal thalamic nuclei (MD). While the functions of VPMpc and BLA have been studied, very little is known regarding the contribution of MD in taste. Using mice as a model system, the proposed research will rely on multiple experimental approaches to test the general hypothesis that the MD conveys taste quality, reward-related, and associative signals that contribute to processes in the GC that can impact taste-related behaviors. Specific Aim 1 will use electrophysiological recordings and behavioral training to characterize the taste and taste-predicting cues response profile in the MD. Specific Aim 2 will combine neural recordings, behavioral training and chemogenetic manipulation to unveil the effect of MD inputs on GC response profiles pertaining to taste quality and taste-predicting anticipatory cues. Finally, the experiment in Specific Aim 3 will rely on a behavioral task and chemogenetic manipulation to determine the role of the MD-GC connection in helping to establish incentive values of neutral auditory cues in the acquisition of cue-taste associations. Altogether, the results obtained from these experiments will provide a comprehensive system-level investigation on the role of MD in taste processing. If successful, this work will lead the way for the MD thalamus as a potential crucial brain region involved in the integration and communication of behaviorally relevant chemosensory information.

NIH Research Projects · FY 2025 · 2021-12

PROJECT SUMMARY Increasing evidence indicates that both zona incerta (ZI) and paraventricular thalamus (PVT) play important roles in the regulation of feeding. Our previous study reported that activation of ZI GABA neurons and their projections to PVT rapidly evokes binge-like eating. Food deprivation activates ZI GABA neurons and selective ablation of ZI GABA neurons suppresses daily food intake and body weight gain in mice, supporting the importance of ZI GABA neurons in the physiological feeding control. However, it remains largely unknown how the ZI-PVT pathway is innervated and controlled by other brain areas for the feeding regulation. In this application, we propose to study how central serotonin (5-HT) signaling targeting both ZI and PVT for the feeding control. Although the importance of central 5-HT signaling in the satiety regulation is well-known, little is known what raphe 5-HT projections regulate feeding motivation. Our pilot data show that both ZI and PVT receive dense 5-HT projections from raphe nuclei, including both dorsal and medial raphe. Food deprivation depressed the activity of dorsal raphe neurons that project to ZI and PVT. In addition, 5-HT excited PVT neurons but inhibited ZI neurons as well as ZI-PVT GABA transmission. Based on the significant role of the ZI- PVT neural pathway in feeding control, we hypothesize that: 1) raphe neurons send 5-HT signaling to modulate both ZI and PVT neurons, and inhibit ZI-PVT GABA transmission. 2) raphe 5-HT projections to ZI and PVT regulate feeding motivation and food intake. 3) chronic high-fat high-sugar (HFHS) diet alters 5-HT inhibition on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Aim 1 of the proposal is focused on the study about the functional 5-HT neural projections from raphe to both ZI and PVT, and the modulatory effects of 5- HT signaling on ZI and PVT neurons. Using slice electrophysiology in combination with optogenetics to target specific neurons in brain slices, we will corroborate the differential modulation of 5-HT signaling on ZI and PVT neurons as well as ZI-PVT GABA transmission. In Aim 2, we will examine how raphe 5-HT projections to both ZI and PVT regulate feeding motivation and food intake. In the proposed experiments for the behavioral study, we will use optogenetic tools to manipulate raphe 5-HT neurons and their projections to ZI and PVT. We will also use slice electrophysiology and c-fos immunoreactivity to study how ZI- and PVT-projecting 5-HT neurons respond to the metabolic states, revealing the role of raphe 5-HT projections to ZI and PVT in the physiological feeding regulation. In Aim 3, we will study how chronic HFHS diets alter 5-HT inhibition on PVT-projecting ZI neurons and ZI-PVT GABA transmission. Together, the proposal in this application will elucidate a novel role of 5-HT signaling in the regulation of food intake by targeting both ZI and PVT. Also, the findings from this project will help further understand how dysfunctional brain 5-HT signaling is involved in overeating and obesity.

NIH Research Projects · FY 2026 · 2021-09

PROJECT SUMMARY Several factors contribute to FSU’s potential to create cultural transformation through an innovative approach to hiring, supporting, and retaining URM faculty. First, our College of Medicine was founded in 2000 to train physicians to serve rural communities throughout the panhandle region and the State of Florida. Given the racial and ethnic diversity of these areas, we have created a rich community-based network upon which to integrate academic health-science efforts across our Colleges of Medicine, Nursing, and Arts and Sciences. Second, in 2013, the Florida Board of Governors designated FSU as one of two "preeminent universities" which triggered an increased state commitment of $75 million from 2013 to 2018. FSU leadership invested these funds to advance health-science research, including the creation of the Equity Research Corner (a consortium of eight centers and institutes) with the mission to address equity issues related to health, social, and educational barriers at the levels of individuals, families, and communities . Third, FSU has created resources to support faculty conducting clinical translational research through our NIH-funded Clinical Translational Science Award subaward. Fourth, FSU has committed in its Strategic Plan (Goal III) to institutional change to foster diversity, inclusion, and equity at all levels and through the President’s Task Force of Anti-Racism, Equity, and Inclusion. We will leverage these resources to test the robustness of The FLORIDA-FIRST BRIGADE for promoting a self-reinforcing community of scientists committed to inclusive excellence. In response to RFA-RM-20-022, we propose three specific aims for the Overall Core: Aim 1. Achieve significant and sustainable cultural change at FSU to ensure inclusive excellence and diversity at the macro (institutional), meso (hiring unit/Center/department), and micro (faculty) levels. Aim 2. Recruit, hire, and retain 6 new URM faculty within the clusters of chronic disease prevention and management or mental health to form The FIRST Cohort as a replicable model for promoting diversity, equity, and inclusive excellence in health-science research at FSU. Aim 3. Develop and implement a systems-levels approach (macro, meso, micro) to establish individual research and career development plans and mentorship plans for each member of The FIRST Cohort. By recalibrating the standard institutional practices for URM faculty recruitment, development, and retention, The FLORIDA-FIRST BRIGADE has the potential to promote diversity and inclusive excellence1 for The FIRST Cohort and serve as an innovative model for the next generation of FSU health-science faculty.

NIH Research Projects · FY 2025 · 2021-09

Project Summary This project will address the question of how abnormal synaptic development emerges in neurodevelopmental disorders. Our overall hypothesis is that disorganized synaptic adhesion and delayed functional assembly of synaptic vesicles (SVs) impair the formation and physiological maturation of presynaptic terminals, which triggers subsequent developmental deficits in synaptic connectivity and function. We will test this hypothesis in Fragile X syndrome (FXS), a leading inheritable form of autism and intellectual disability caused by functional loss of Fragile X mental retardation protein (FMRP). Experimental observations will utilize the evolutionally conserved endbulb terminals that are readily accessible for in vivo cell-autonomous characterizations in chicken embryos. We will pursue two specific aims to test several important hypotheses derived from our preliminary studies. · In Specific Aim 1, we will determine the role of FMRP-regulated synaptic adhesion in presynaptic terminal formation. We hypothesize that axonal FMRP promotes terminal formation, stabilization, and selective retraction through developmentally profiled synaptic adhesion. To test this hypothesis, we will use cell-group specific and temporally-controlled genetic manipulations combined with in vivo live imaging to identify the exact actions of FMRP-mediated axon transport vs. protein translation in dynamic terminal turnover. We will also identify FMRP-regulated synaptic adhesion elements in developing terminals and assess the effects of correcting these elements on FMRP loss-induced presynaptic and axon alterations. · In Specific Aim 2, we will determine the role of FMRP-regulated synaptotagmin (Syt) in functional maturation of presynaptic terminals. Syt1/2 are primary calcium sensors on SVs that trigger vesicle fusion and neurotransmitter release. We hypothesize that FMRP regulates presynaptic functional maturation by controlling the timely upregulation of Syt2 in nascent terminals. To test this hypothesis, we will determine the effects of expressing Syt2 on FMRP loss-induced deficits in SV activity, presynaptic protein machinery, and glutamate release. We will also determine the interplay between synaptic adhesion regulation and SV assembly under FMRP control using rescue studies. Together, these results will identify an origin of defective synaptic phenotypes, a hallmark of neurodevelopmental disorders. This knowledge is of vital importance because it will help establish a sensitive time window and identify novel therapeutic candidates for preventing, or at least reducing, the progress of synaptic deficits in FXS and other neurodevelopmental disorders.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY/ABSTRACT The long-term goal of our research program is to decipher the molecular mechanism of “non-canonical” protein- RNA interactions studying a particularly fascinating and disease-relevant family of proteins, called the La-related protein (LARP) superfamily, on a molecular level. Cytoplasmic LARPs play a pivotal role in post-transcriptional gene control by regulating the delicate balance between active translation, degradation, and storage of mRNAs. Hence, many LARPs are intimately implicated in various cancers and fibroproliferative diseases rendering them an important class of druggable targets. However, the development of therapies has been stunted by the lack of detailed molecular-level information. Our research will elucidate the molecular mechanism of RNA recognition exhibited by LARPs, in particular, to explain the intricacies of commonality and individuality, i.e. how their com- mon RNA-binding motif, called the La-module, has individually evolved to allow specific RNA recognition and thus achieve its distinct function. The investigation is based on our unique strength in solution and solid-state NMR spectroscopy and their close coupling with other biochemical, biophysical, computational, and functional approaches. Our initial efforts will follow two lines of inquiry, simultaneously focusing on two members of the LARP superfamily, hLARP6 and hLARP1. In the first line of inquiry, we will explore how the La-module of hLARP6 achieves the exclusive recognition of the highly conserved 5' stem-loop (5'SL) motif, which is found in all verte- brate mRNAs encoding type I collagens. This line of study will provide a detailed molecular-level map on how individual elements of the La-module contribute to the specificity and affinity of 5'SL binding. The detailed insights to be gained, together with currently available biochemical and biophysical data, will provide essential insights into the molecular “symbiosis” of the individual elements of the La-module and close this critical gap in knowledge required for the development of therapeutic strategies against fibroproliferative diseases. In the second line of inquiry, we will analogously dissect how the La-module of hLARP1 recognizes a distinctly different type of RNA compared to hLARP6. hLARP1 was found to be heavily involved in proliferation and cell cycle defects and to be significantly upregulated in malignant cells and tissues. Very recent biochemical studies revealed that the La- module of hLARP1 sequentially binds to the 3' poly(A) and then to the 5ʹ terminal oligopyrimidine (5ʹTOP) motifs of mRNAs. Notably, this peculiar two-step behavior has not yet been observed for any other LARP. We will uncover this unusual molecular mechanism by investigating the structural and dynamic changes of hLARP1 upon binding of the poly(A) and 5'TOP motifs. This study will for the first time reveal how the initial binding of one RNA to its La-module elicits structural and dynamic changes required for the binding of a second RNA target. Overall, these two lines of comparative investigations will synergistically lead us to understand the fundamental principles that connect the co-evolution of the individual elements of the La-module and their specific role in RNA recognition, thus explaining how structural and dynamic plasticity contribute to functional plasticity.

NIH Research Projects · FY 2025 · 2021-09

Anhedonia - the inability to seek-out and experience pleasure - is a common symptom in depression that predicts treatment resistance and is sometimes exacerbated by first-line antidepressants. Anhedonia falls within the "Positive Valence System" of the Research Domain Criteria framework that comprises two primary components: "liking" and "wanting." The "liking," or consummatory, component reflects the evaluation of rewards reliant on the medial prefrontal cortex and ventral striatum. The "wanting," or anticipatory, component modulates the degree to which effort is expended in goal-directed behavior reliant on the lateral prefrontal cortex and dorsal striatum. Previous research found decreased neural activity in both of these neural circuits in depressed patients with anhedonia but has not causally investigated the role of these neural circuits, or their temporal dynamics, in different components of reward-based decision-making. The preliminary data found decreased goal-directed behavior in depressed patients with anhedonia and reduced cross-frequency coupling between the phase of delta oscillations (2-4 Hz) in lateral prefrontal cortex and task-modulated beta oscillations (15-30 Hz) ( delta-beta coupling). The objective of this research plan is to dissect the causal role of frontal-striatal circuity in different components of reward-based decision-making and their impairment in anhedonia. The central hypothesis is that anhedonia arises from decreased goal-directed behavior and disruption of delta-beta coupling in lateral prefrontal cortex and dorsal striatum. The rationale is that spatially and temporally-targeted non-invasive brain stimulation during performance of a reward-based decision-making task will provide causal evidence for which network dynamics are impaired in anhedonia. In the K99 phase, this research (1) Causally dissociated the neural circuits that implement goal-directed behavior and reward-evaluation in decision-making and (2) Increased goal-directed behavior in depressed patients with anhedonia using network-targeted non-invasive brain stimulation. Now, the R00 phase will (3) Investigate target engagement of delta-beta coupling in a potential treatment paradigm with network-targeted stimulation in a randomized clinical trial for depressed patients with symptoms of anhedonia. This proposal is significant because it causally evaluates mechanistic models of the networks and cognitive processes that are disrupted in anhedonia. The work is innovative because it uses concurrent neurophysiology and neurostimulation, integrates high-resolution spatial and temporal investigation tools, and utilizes individualized stimulation parameters such as subcortical-targeting with functional-connectivity and task-specific frequency targeting. The positive impact of this proposal is a refined definition of anhedonia based in biological mechanism that may have transdiagnostic relevance for other psychiatric illnesses such as schizophrenia and substance use disorder. The implication of this proposal is that the knowledge gained can be directly used for the development of novel interventions using precision medicine.

NIH Research Projects · FY 2025 · 2021-09

The purpose of the SHARE P01 research program project is to address HIV and alcohol use around three themes; 1) Emerging adulthood (ages 18 -29); 2) Self-management of HIV and alcohol; and 3) Translational behavioral science. Emerging adulthood is a developmental stage marked by significant changes in social roles, expectations as a new adult, and increased responsibilities. It is also marked by poor HIV self- management and increased alcohol use. Emerging adults with HIV (hereafter called young people living with HIV; YPLWH) may face encounter additional challenges due to their diagnosis. This age group continues to have very high rates of new HIV infections. Interventions designed specifically for the unique developmental challenges of emerging adults are needed, yet emerging adults are often included with older adults in intervention programs. The concept of self-management emerged concurrently within both the substance abuse and chronic illness literatures and fits well with the developmental challenges of emerging adulthood. Self-management, a framework we have utilized in our work with YPLWH, refers to the ability to manage symptoms, treatments, lifestyle changes, and consequences of health conditions. Current research now identifies individual-level self- management skills such as self-control, decision-making, self-reinforcement, and problem solving as that protect against substance use and improve other health outcomes and can be embedded in the Information-Motivation-Behavioral Skills model. Although we have conducted multiple studies with YPLWH, only one intervention to date (Healthy Choices conducted by our team) improved both alcohol use and viral suppression in YPLWH in large trials. The goal of the SHARE P01 is to utilize advances in translational behavioral science to optimize behavioral interventions and define new intervention targets to improve self-management of alcohol and HIV in YPLWH. We will focus our efforts in Florida, a state hardest hit by the HIV epidemic but with a particularly strong academic- community partnership to support translation. We have assembled research teams to conduct self- management studies across the translational spectrum to address self- management and improve alcohol use and viral suppression (and thereby reduce transmission) in YPLWH in Florida. The P01 will consist of three research projects (DEFINE, ENGAGE, and SUSTAIN), representing different stages on the translational spectrum and targeting different core competencies, supported by two cores (Community Engagement Core and Data Science Core). If successful, the SHARE P01 has the potential to greatly advance programs promoting self-management of HIV and alcohol use among emerging adults living with HIV. SHARE also has a high potential for scale-up and implementation beyond Florida and across the United States.

NIH Research Projects · FY 2025 · 2021-09

Project Summary Purpose in life is the belief that one’s life and activities are goal-oriented, directed, and worthwhile. This belief is associated consistently with better outcomes, including greater engagement in health promoting behavior (e.g., less smoking, more physical activity), fewer chronic diseases (e.g., cardiovascular disease, diabetes), and ultimately greater longevity. Independent of behavioral and clinical factors, purpose in life is associated with better cognitive outcomes, including lower risk of Alzheimer’s disease and related dementias (ADRD). ADRD remains a significant challenge to patients, their families, and the healthcare system, as it is one of the leading causes of death that lacks disease-modifying treatments or cures. There is a growing literature that shows that purpose in life is protective across the arc of the ADRD disease spectrum: It is associated with better performance on cognitive tasks and less cognitive decline prior to dementia onset, it is protective against cognitive impairments, both mild and severe, and, even after diagnosis, it is associated with fewer behavioral and psychological symptoms of dementia. In a parallel literature, there is consistent evidence from randomized controlled trials that purpose in life is malleable and can be increased through intervention. Purpose in life is thus poised to be a powerful target of intervention to improve cognitive outcomes, from maintaining cognitive function in middle adulthood to improving outcomes in dementia care. The next step in intervention development is to identify the putative mechanisms of action hypothesized to change in response to the intervention and explain the relation between purpose and better cognitive outcomes. Once these mechanisms are identified, interventions that increase purpose to improve cognitive outcomes can be developed and tested. As a step toward this long-term goal, the present study will use ecological momentary assessments (EMA) to identify the daily mechanisms responsible for the association between purpose in life and healthier cognitive outcomes. In particular, we will test the hypothesis that purpose in life is associated with greater momentary engagement and better momentary cognition, which will support healthier cognitive function over time. We will address these associations in three groups considered critical populations for intervention: older adults with subjective cognitive impairment, older adults with healthy cognition, and middle-aged adults. This research will provide much needed information on putative mechanisms of action that explain how purpose protects cognition. Such information is critical to develop purpose interventions that promote healthier cognitive aging.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Deficits in chemosensory processing are associated with healthy aging, as well as numerous neurodegenerative disorders including Alzheimer’s Disease (AD). In many cases, chemosensory deficits are harbingers of neurodegenerative disease, and understanding the mechanistic basis for these changes may provide insight into fundamental dysfunction associated with aging and neurodegeneration. The genetic and physiological accessibility of chemosensory neurons and their defined higher order processing centers provide a unique opportunity to investigate the effects of aging-related processes on neural function, including sensory responsiveness, plasticity, and synaptic connectivity. The fruit fly, Drosophila melanogaster, is a powerful model for studying chemosensation, aging, and aging-related pathologies, yet the effects of aging on chemosensation remain largely unexplored in this model, particularly with respect to taste. A large genetic toolkit combined with functional imaging allow for cell-type specific manipulation of taste circuits. Numerous models of AD been developed in Drosophila that largely phenocopy two hallmarks of AD: amyloid beta (Aβ)-mediated toxicity and tauopathy caused by hyperphosphorylation of the Tau protein. My preliminary findings reveal that taste perception and taste memory deteriorate with age, and this is exacerbated in a fly model of AD. Here, I will examine the physiological and molecular basis for age-associated reduction in taste and taste memory in models of natural and pathological aging. These experiments build on my expertise in chemosensory processing and functional imaging, while providing training in aging and genomic approaches.

NIH Research Projects · FY 2025 · 2021-08

Contextual factors create significant health disparities in prevalence, diagnosis, and treatment of the comorbid physical and mental health conditions that are typically managed in primary care settings. The current NIH Director’s unified strategy calls for moving beyond documenting such disparities to focus on a solution-oriented approach. There are shockingly few evidence-based interventions to address such contextual factors. New paradigms are needed to intervene on, and not just document, health disparities in primary care where behavioral health is managed. We propose to develop and test a transformative paradigm for translating basic behavioral and social science into new interventions to improve health disparities in primary care settings. The proposed paradigm is the first of its kind to integrate community-based participatory research, systems science, diffusion of innovation theory, and item response theory, leveraging an established framework of early phase translational behavioral and social science to rigorously define new strategies to address contextual factors within complex health systems and rigorously develop measures to assess impact. Addressing contextual factors in integrated primary care systems in the United States is an innovation that can be rigorously mapped using community-engaged systems science methods. This map identifies “inflection points” likely to result in the most impactful intervention targets, and then established pathways can be used to translate fundamental behavioral and social science discoveries into new interventions at these points. Systems science modeling can then simulate potential interventions and produce mathematical standards for intervention efficacy in future trials. This transformative paradigm will also detail innovative methods to develop efficient and effective measurement tools to ensure scientifically valid, measurable health outcomes as delineated in the unified strategy.

NIH Research Projects · FY 2025 · 2021-07

Very little is known about how the prevalence of eating disorders (EDs) has changed across generations or the trajectory of EDs over the course of adult development. This study offers a unique opportunity to 1) examine ED point prevalence and mean scores on dimensional ED measures across 5 cohorts of college students randomly sampled from the same university population in 1982, 1992, 2002, 2012, and 2022, 2) examine the longitudinal course of eating pathology from late adolescence to midlife (18 to 62+ years), and 3) identify predictors of course focusing on factors unique to adulthood. This project will offer new insights into how generation impacts gender differences in EDs and how both gender and generation impact longitudinal trajectory. This project builds on a study initiated in 1982 and replicated with the addition of new cohorts and extended with follow-up of well-characterized, established cohorts every 10 years since its inception. In the spring of 2022, 1600 undergraduates (800 women and 800 men) will be randomly sampled to complete surveys of weight, height, body image disturbance, dieting, disordered eating behaviors, and EDs. In addition, participants who completed these assessments in college will be sought for 10-, 20-, 30-, and 40-year follow- up. We project collecting 20-year follow-up data in over 1,700 adults (>70% retention), including nearly 500 men and over 400 participants from ethnic/racial minority groups. These data will allow us to examine generation X age effects to determine whether course of eating pathology differs across Baby Boomers (1982 cohort), Generation X (1992 cohort), and Millennials (2002 cohort). The investigation will be conducted in two stages: a survey phase and an interview phase. The survey phase will replicate methods employed for data collection in all prior waves to ensure comparability of data. Surveys include detailed items about demographic background; height and weight; dieting, body image, and exercise; 5 scales of the Eating Disorders Inventory (Bulimia, Drive for Thinness, Maturity Fears, Perfectionism, and Interpersonal Distrust); and symptoms of anorexia nervosa, bulimia nervosa, binge-eating disorder, and permit DSM-5 ED diagnosis and diagnoses of their partial and subthreshold variants. In addition, beginning in the 3rd wave, surveys included the Eating Disorder Diagnostic Scale which is included as a core ED assessment for the NIMH. On the basis of self-report survey data, all subjects diagnosed with an ED and controls matched to these subjects on age, sex, race, and ethnicity will be recruited for participation in the interview phase of the study. Interviews will establish the validity of survey assessments, as well as provide data on psychosocial function, suicidality, comorbidity, and treatment history for a nonclinical sample, similar to their use in the 3rd wave, 20 years ago. The long-term objectives of this project are to evaluate whether we are making progress in reducing the public health burden associated with EDs, determine the adult developmental course of EDs, and identify predictors of ED trajectory that can be translated into targets for intervention, including what to modify, in whom, and when.