University Of Alabama At Birmingham

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY This NIH F30 application describes a four-year plan for mentored research and career development for the PI, Matthew Cheung. The scientific premise of this proposal is focused on the role of kidney resident macrophages and their responses to acute kidney injury (AKI). AKI is a major complication affecting up to 20% of hospitalized and 60% of critically ill patients. Despite the high mortality rate and frequency of occurrence, targeted therapies to treat AKI have not been successfully developed. The innate immune system, particularly macrophages, are important in the pathogenesis and healing in AKI and will likely be an important component of future therapies. Studies involving kidney resident macrophages (KRMs) are increasing in number as preliminary studies suggest that they are crucial in renal homeostasis and healing from injury. KRMs modulate the response to AKI, but the mechanism of their contribution remains unknown. Here, we will elucidate the molecular and cellular mechanisms that govern how KRMs maintain and restore renal function after injury. Our preliminary single-cell RNA sequencing data suggest that the KRM population consists of several undescribed subpopulations with distinct functions. Spatial transcriptomics shows that these subpopulations reside in distinct microenvironments and at least one appears to migrate to the proximal tubules in response to injury. We have also found that KRMs in both mice and humans express high levels of the complement protein and pattern recognition molecule C1q. Our central hypothesis is KRM subpopulations have a defined transcriptional response to renal injury and react to PTEC damage in a C1q-dependent manner. We will test this hypothesis through single-cell and spatial transcriptomics and a variety of in vitro and in vivo experiments, including the use of mice deficient in C1q expression in KRMs and a model of proximal tubule-specific injury. Understanding the involvement of the various KRM subpopulations and of C1q, one of the most abundant proteins produced by KRMs, will have a significant impact on our understanding of mechanisms that can be targeted for the treatment of AKI. The proposed training plan for the PI is sponsored by co-mentors Anupam Agarwal, MD, and James George, PhD. Included in the training plan are experiences that will help Matthew develop in three major areas: 1) rigorous immunological research in acute kidney injury, which includes developing familiarity with the existing literature, critical evaluation of data, and training in the responsible conduct of research; 2) rigorous training in advanced bioinformatics and next-generation sequencing analysis and 3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required for rigorous scientific research critical immunology and advanced bioinformatics skills necessary for the PI’s future career as a nephrology physician-scientist focused on precision medicine and immune-mediated kidney diseases.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY Exposure to early life stress (ELS) often is accompanied by adverse health outcomes earlier in adulthood and with more severity such as in the case of Systemic Lupus Erythamateous (SLE), an autoimmune disease. The risk for autoimmunity and cardiovascular disease (CVD) increases with ELS exposure and CVD is the predominant cause for early mortality in SLE patients. This project addresses the gap in knowledge of why coexistence with ELS is associated with higher prevalence and heart disease in SLE. In the case of SLE— despite reports linking worsened disease activity in patients with ELS—there have been no studies in preclinical rodent models of SLE in conjunction with ELS. Several investigations demonstrate that ELS is associated with a pro-inflammatory phenotype and vascular dysfunction. In our mouse model of ELS, maternal separation with early weaning (MSEW), we observed aortic endothelial dysfunction dependent on superoxide and increased numbers of F4/80+ macrophages, an innate immune cell, in the adventitia of the aorta. In addition, vessel dysfunction and aortic stiffness is exaggerated in MSEW mice subjected to pristane induction of SLE. We expect impairment in vascular function is due to proinflammatory macrophage presence in MSEW animals. Preliminary data shows mitochondrial dysfunction is present in MSEW mice indicating the superoxide impacting endothelial dysfunction may be mitochondrial derived. Thus, our overall hypothesis states that ELS accentuates the development and severity of aortic disease in a mouse model of SLE through mitochondrial-derived superoxide production and activated pro-inflammatory macrophages. This project is designed with two specific aims. First, we will determine if macrophages mediate development of aortic disease in ELS. We will use flow cytometry and RNA sequencing to determine immune activation differences between MSEW and control mice. We then will determine if absence of macrophages in vivo prevents MSEW vascular dysfunction compared to controls. Second, studies will address if ELS mediates enhanced development of aortic disease in SLE through mitochondrial superoxide production. The pristane-induced model of SLE will be used in conjunction with the MSEW protocol to determine if oxidative stress, previously linked to SLE-mediated hypertension, is accelerated by ELS. Experiments will examine markers for CVD in SLE using telemetry and vascular reactivity after ELS. We will also measure CVD and disease after blocking mitochondrial superoxide by MitoTEMPOL. We expect to see (i)elevated inflammatory macrophages that, when absent, reduce vascular dysfunction and (ii)a greater CVD burden in MSEW SLE mice reduced by MitoTEMPOL treatment. This project is critical to begin to understand the mechanistic relationship of ELS in SLE as well as crucial for studying immune driven diseases with CVD complications. ELS is associated with adverse health outcomes in a variety of diseases. Advances in the ELS field are essential to developing relevant and accessible intervention and prevention strategies for patients. Our studies provide two potentially complementary pathways for ELS-driven CVD.

NIH Research Projects · FY 2025 · 2022-08

Suicide is the 2nd leading cause of death in adolescents. Unfortunately, our ability to accurately predict suicidal ideation (SI) and suicide attempts (SA) among adolescents remains remarkably limited. Thus, there is an urgent need for biomarkers that can identify risk for SI and SA. There is also a need to identify novel molecular pathways that may underlie suicide risk. There is growing interest in microRNAs (miRNAs), a subclass of non-coding RNAs that regulate mRNA expression via post-transcriptional mechanisms, as potential mediators of disease pathologies and in the development of targeted novel therapeutics. Earlier, we reported that specific miRNAs were markedly altered in the brain of adults who died by suicide independent of psychiatric illnesses, suggesting that miRNAs can distinguish suicidality separately from psychopathology. Using a specific neural marker, we isolated neural-derived exosomes (NDEs) from blood plasma and found that these exosomes are highly enriched with miRNAs that are expressed in the brain. In preliminary studies, we also found remarkable resemblance in brain and NDE miRNA changes among adult and adolescent suicide populations. Differences in many miRNAs were common in adults and adolescents with SI or SA; however, a distinct set of miRNAs was associated exclusively with adolescent suicide. In addition, differentially expressed NDE miRNAs changed significantly in adults treated with ketamine. Our novel approach thus provides a unique opportunity to detect NDE miRNAs in plasma, which can be used as biomarkers for suicidality and treatment response. Based on our pilot data, we propose an overarching hypothesis that a subset of NDE miRNAs will be differentially expressed in adolescents with MDD and SI or SA compared with non-suicidal adolescents with MDD and healthy controls. There will be unique subsets of miRNAs specifically associated with MDD, SI, and SA. These miRNAs will have specific mRNA targets and biological pathways that may be associated with SI, SA, and MDD risk. To test these, we will examine genome-wide expression of NDE miRNAs and mRNAs in the following groups of adolescent subjects (11-19 y; n=240): 1) MDD with serious SI and a recent SA (MDD+SA), 2) MDD+SI without recent SA, 3) MDD without recent SI or SA (MDD-SI/SA), and 4) healthy controls without a history of mental disorder. We will also test if expression of NDE miRNAs will change across six weeks of antidepressant treatment (AD). With this, we will examine if: 1) specific subset(s) of NDE miRNAs are associated with SI and SA among adolescents, 2) specific miRNA/mRNA-regulatory pathway is associated with SI, SA, and MDD, and 3) response to AD treatment impacts differences in NDE miRNAs associated with MDD and SI/SA. Using our existing NDE miRNA datasets in 240 adults ages 20-65 y across the same groups proposed for this study, we will also examine if miRNA biosignatures are common in MDD and SI/SA groups for adolescents and adults, or if they differ by age. Altogether, our study will provide novel avenues to identify miRNAs as ‘‘molecular tools’’ for the development of a biomarker for suicidality across age group and eventually new molecular-based therapies to treat or prevent this disorder.

NIH Research Projects · FY 2024 · 2022-08

Suicide is the 2nd leading cause of death in adolescents. Unfortunately, our ability to accurately predict suicidal ideation (SI) and suicide attempts (SA) among adolescents remains remarkably limited. Thus, there is an urgent need for biomarkers that can identify risk for SI and SA. There is also a need to identify novel molecular pathways that may underlie suicide risk. There is growing interest in microRNAs (miRNAs), a subclass of non-coding RNAs that regulate mRNA expression via post-transcriptional mechanisms, as potential mediators of disease pathologies and in the development of targeted novel therapeutics. Earlier, we reported that specific miRNAs were markedly altered in the brain of adults who died by suicide independent of psychiatric illnesses, suggesting that miRNAs can distinguish suicidality separately from psychopathology. Using a specific neural marker, we isolated neural-derived exosomes (NDEs) from blood plasma and found that these exosomes are highly enriched with miRNAs that are expressed in the brain. In preliminary studies, we also found remarkable resemblance in brain and NDE miRNA changes among adult and adolescent suicide populations. Differences in many miRNAs were common in adults and adolescents with SI or SA; however, a distinct set of miRNAs was associated exclusively with adolescent suicide. In addition, differentially expressed NDE miRNAs changed significantly in adults treated with ketamine. Our novel approach thus provides a unique opportunity to detect NDE miRNAs in plasma, which can be used as biomarkers for suicidality and treatment response. Based on our pilot data, we propose an overarching hypothesis that a subset of NDE miRNAs will be differentially expressed in adolescents with MDD and SI or SA compared with non-suicidal adolescents with MDD and healthy controls. There will be unique subsets of miRNAs specifically associated with MDD, SI, and SA. These miRNAs will have specific mRNA targets and biological pathways that may be associated with SI, SA, and MDD risk. To test these, we will examine genome-wide expression of NDE miRNAs and mRNAs in the following groups of adolescent subjects (11-19 y; n=240): 1) MDD with serious SI and a recent SA (MDD+SA), 2) MDD+SI without recent SA, 3) MDD without recent SI or SA (MDD-SI/SA), and 4) healthy controls without a history of mental disorder. We will also test if expression of NDE miRNAs will change across six weeks of antidepressant treatment (AD). With this, we will examine if: 1) specific subset(s) of NDE miRNAs are associated with SI and SA among adolescents, 2) specific miRNA/mRNA-regulatory pathway is associated with SI, SA, and MDD, and 3) response to AD treatment impacts differences in NDE miRNAs associated with MDD and SI/SA. Using our existing NDE miRNA datasets in 240 adults ages 20-65 y across the same groups proposed for this study, we will also examine if miRNA biosignatures are common in MDD and SI/SA groups for adolescents and adults, or if they differ by age. Altogether, our study will provide novel avenues to identify miRNAs as ‘‘molecular tools’’ for the development of a biomarker for suicidality across age group and eventually new molecular-based therapies to treat or prevent this disorder.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT One of the least-investigated areas of research in brain pathologies is glycosylation, which is a critical regulator of cell surface protein structure and function. ST6Gal1 is the primary enzyme that a2,6 sialylates N-glycosylated proteins destined for the plasma membrane or secretion. Sialylation adds a negatively-charged, sialic acid to the end of an oligosaccharide chain of a glycoprotein. Sialylation of distinct protein subsets has important effects on conformation, clustering and cell surface retention as has been found for some integrins, growth factor receptors and death receptors. Through this mechanism, ST6Gal1 regulates phenotypes including survival, invasion, and stem cell maintenance. However, there are critical gaps in our understanding of how ST6Gal1-mediated sialylation impacts brain tumor cell growth or differentiation state, and there are no studies identifying a2,6 sialylated proteins or ST6Gal1 regulated pathways in brain tumors. Our preliminary data demonstrate a novel, pro-tumorigenic role for a2,6 sialylation and ST6Gal1 in the deadly brain tumor glioblastoma. We seek to determine whether ST6Gal1- mediated a2,6 sialylation promotes brain tumor initiating cell maintenance and metabolic plasticity. In the short- term, our results will lead to an improved understanding of how ST6Gal1-mediated a2,6 sialylation regulates protein expression and function to impact brain tumor propagation. In the long-term, these studies may offer the potential for new mechanisms of therapeutic intervention for the treatment of brain tumors as ST6Gal1 inhibitors are under development.

NIH Research Projects · FY 2025 · 2022-08

The Recruitment and Engagement in Care to Impact Practice Enhancement (RECIPE) project has a goal to reduce the science-to-practice gap in sickle cell disease (SCD) by identifying individuals who are not receiving guideline based SCD care. Up to 50% of affected adults may not see SCD specialists, which limits the delivery of disease-specific screenings and treatment with disease modifying therapies. Issues are worsened for individuals living in rural regions or with socio-economic challenges known to accentuate health barriers. This team of investigators has been working to address this problem since the inception of the NHLBI-funded Sickle Cell Disease Implementation Consortium (SCDIC). In our previous studies, we identified a need to optimize research methodologies to engage individuals in evidence-based SCD care and established foundational terms through a Delphi consensus process, for “unaffiliated patients with SCD” and “SCD specialist”. The current project, RECIPE, will advance these efforts to identify and link unaffiliated patients to SCD specialists by applying implementation science research to adapt existing methods used in human immunodeficiency virus (HIV) care. Similar to SCD, individuals with HIV have faced significant healthcare scrutiny causing reciprocal misgivings about healthcare. In this project, we will adapt models for patient identification and engagement in HIV to SCD using a multi-staged, patient-oriented process. We embed this work in the Interactive Systems Framework for Dissemination and Implementation to ensure high quality implementation and evaluation in each stage of the affiliation process, with emphasis on the readiness of health systems to serve traditionally hard-to-reach populations and sustainability of this work in these areas.

NIH Research Projects · FY 2026 · 2022-08

The skeletal system provides crucial structural and functional support to the body. The long-term objective of this project is to uncover the pathogenesis of congenital skeletal disorders and develop strategies for skeletal regeneration by elucidating the key signaling mechanisms governing skeletal development. Early mouse genetic studies have uncovered a critical role of Wnt5a in limb skeletal development. Human mutations in WNT5A have also been implicated in Autosomal Dominant Robinow syndrome (ADRS), a disorder that manifests dwarfism and widespread skeletal dysplasia. Studies over the past 20 years have revealed that Wnt5a is a non-canonical Wnt ligand that signals through receptor Frizzled (Fz) and co-receptors Ror1/2 to activate the planar cell polarity (PCP) pathway for limb morphogenesis during skeletal formation. The objective of the current proposal is to characterize several fundamental properties of Wnt5a as a potent morphogen, such as its signaling potency and range, the structural foundation that governs these properties, and how human ADRS mutations alter its structure to modify WNT5A signaling. The objective will be achieved by specifically testing 1) how two Wnt5a isoforms that differ by 18aa residues at the N-terminus may function differently in PCP signaling to impact limb development; 2) how the Wnt5a isoforms and ADRS mutations may alter the mode through which Wnt5a clusters together Fz and Ror to trigger PCP signaling; and 3) how the ADRS mutations alter Wnt5a’s signaling potency and range during early limb development and endochondral bone formation. Building on our preliminary studies that mouse transgenes encoding different Wnt5a isoforms display remarkably different functional range in the limb, and that the two isoforms display different potency in activating PCP in the Xenopus model, we will first determine whether their function range is solely determined by the activity level difference, or additional factors such as dispersal ability during limb development. Secondly, we will use a set of biochemical and biophysical assays to test a structural biology based model, in which different N-terminal residues in Wnt5a isoforms and ADRS variants may alter the mode through which Wnt5a brings together Fz and Ror to form distinct type of ligand/receptor complexes with different activity levels. Thirdly, we will use a set of quantitative functional and molecular readout to determine how the ADRS variants may cause elevated PCP signaling activity in Xenopus, and how these variants impact Wnt5a- mediated skeletal development and endochondral bone formation in the mouse. These studies will elucidate mechanistically how the N-terminal region may regulate Wnt5a’s signaling activity in PCP, and how alterations in the N-terminus leads to skeletal defects in ADRS in humans.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Social experiences shape the health and longevity of humans and other social mammals. Social adversity in humans and in social nonhuman primates is associated with higher mortality and poorer health. One prevailing explanation is that chronic stress dysregulates the physiological response to stress, resulting in a chronic inflammatory phenotype that accelerates aging and is associated with chronic neurodegenerative diseases such as Alzheimer's disease. These inflammatory outcomes overlap with those influenced by diet. In comparisons of two prevailing diets that differ in nutritional composition—the Western and Mediterranean diets—Western diets are associated with not only poorer health and an increased risk of Alzheimer's disease and other dementias, but also a chronic inflammatory phenotype. These characteristics raise the question of how diet and social experiences interact to influence aging and health. The objective of the proposed study is to identify the molecular mechanisms that link social adversity and diet to the stress response and inflammation. If the inflammatory outcomes of social adversity and diet share some common molecular mechanisms, I hypothesize that the diet can mitigate age-accelerating phenotypes in the brain by modulating neuroinflammatory responses to social adversity. To test this hypothesis, I will leverage the advantages of studying female macaques, which are well-established animal models of human social behavior, aging, and chronic disease. I propose a two-pronged approach that combines studies of free-ranging macaques spanning the entire adult lifespan (Aim 1) with experimental manipulations of diet in a middle-aged macaque cohort (Aims 2 and 3), thus yielding insights into the relationships between stress, neuroinflammation, and aging in an integrated model. In both contexts, I will combine genome-wide gene expression measurements to characterize the genomic pathways associated with social adversity and diet. Insights gleaned from the free-ranging population (Aim 1) will be used to characterize how social adversity and diet interact to influence neurodegeneration and brain aging (Aims 2-3), and to understand the role of key cell types, including microglia (Aim 3). At its conclusion, this project will yield a detailed understanding of how social adversity and diet affect gene regulation and neuroinflammation in the aging brain, and how diet interventions can buffer against the health consequences of chronic social stress. Together, these results will advance our understanding of the mechanisms through which diet or social adversity impact cognitive and neurological resilience in the aging population. In addition, the proposed program of mentored training activities will allow me to develop a strong, independent research career in aging, focused on the nexus of aging, social behavior, neuroscience, and genomics.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT The primary objective of this proposal is to determine the conserved mechanism that underlies the development of different types of chronic pain and identify a tractable target with broad implications for therapy. Despite diverse pathological triggers and different upstream signaling pathways, nociceptive activity-induced functional and structural plasticity in the spinal dorsal horn serves as the common neural substrate for the different types of chronic pain. However, it remains unclear which molecular mechanisms orchestrate structural and functional plasticity in the spinal dorsal horn and whether these mechanisms are conserved across the different types of chronic pain. Rho GTPases (e.g., Rac1 and RhoA) play essential roles in dendritic spine morphogenesis and synaptic plasticity by controlling actin cytoskeleton organization. In particular, Rac1 promotes the formation, growth, and stabilization of spines and synapses. We previously identified Tiam1 as a critical regulator of Rac1- dependent spine morphogenesis in brain development. Tiam1 is activated by synaptic NMDARs and TrkB receptors and mediates their effects on actin and spine remodeling. During the pain processing, NMDARs and TrkB receptors-mediated central sensitization in the spinal dorsal horn are critically involved in chronic pain hypersensitivity, and Rac1-dependent increases in the size and density of dendritic spines account for the long- term nature of chronic pain. Our preliminary studies found that Tiam1 was activated in the spinal dorsal horn under neuropathic pain conditions and modulated synaptic remodeling by promoting peripheral nerve injury- induced actin polymerization and synaptic NMDAR stabilization. Moreover, Tiam1 deletion from excitatory neurons or spinal dorsal horn neurons prevented chronic pain development triggered by peripheral nerve injury, chemotherapy, diabetes, and inflammation. In this proposal, we will test our central hypothesis that Tiam1 links nociceptive activity-activated NMDARs and TrkB receptors to Rac1 signaling, orchestrating synaptic structural plasticity via actin cytoskeleton reorganization and functional plasticity via synaptic NMDAR stabilization in excitatory neuron populations in the spinal dorsal horn, which serves as a conserved mechanism underlying the development of different types of chronic pain and can be targeted for therapeutic chronic pain intervention. We will pursue the following three specific aims: 1) Identify Tiam1’s convergent function in different types of chronic pain; 2) Elucidate the mechanisms by which Tiam1 contributes to different types of chronic pain; 3) Validate spinal Tiam1 as a therapeutic target for the treatment of chronic pain. At the completion of this project, we will uncover a conserved mechanism that underlies the development of different types of chronic pain and identify a novel therapeutic target that could be translated into the clinic to treat chronic pain with broad implications.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY / ABSTRACT A major unresolved question in neurodegenerative disease is the mechanisms that drive selective cell vulnerability. Heparan sulfate proteoglycans (HSPGs) are glycoproteins that promote oligomerization of amyloid- β and prions in vitro and slow the clearance of amyloid-β in the brain of an Alzheimer’s disease mouse model. HSPGs interact with misfolded proteins through their HS chains and promote their internalization in immortalized neural cells. This protein aggregate uptake is profoundly impacted by the HS length and level of sulfation which, importantly, broadly differ between cell types. We and others have used highly sulfated HS-like glycopolymers to test the crucial role of HS in the interaction and in vitro replication of prions. However, the composition of endogenous HS and their specific roles in healthy aged and disease-affected brain are unknown. I found that mice expressing shorter HS chains showed prolonged survival and profoundly altered prion plaque distribution in brain when infected with a plaque-forming prion strain, but did not show any change in the prion disease phenotype caused by aggregate-forming prions. Here I will define the HS molecules that bind to physiological and misfolded prion protein in different neuronal populations. I hypothesize that the interaction of HS with misfolded prions is a major determinant underlying the selective cell vulnerability in prion disease. In Aim 1, I will determine the role of HS sulfation in the prion replication i) in vitro, using HS isolated from distinct neuronal populations, and ii) in vivo, by mouse models deficient in HS sulfation. I will measure how the variation in the HS sulfation impacts the PrP cell tropism and lesion targets in the brain, and how age affects HS composition. I will next manipulate the HS composition in different neuronal populations i) to measure the selective cell uptake of prions strains and their degree of dependence on HS (Aim 2), and ii) to test a new strategy to block prion progression based on using HSPG mimetics as vehicles to promote prion degradation in lysosomes (Aim 3). I expect to define the molecular mechanisms underlying selective cell vulnerability in prion disease and to discover new targets for the rational design of neuroprotective therapies for patients with prion disease. Due to the many commonalities between the pathogenesis of prion disease and Alzheimer’s disease, I plan to ultimately extend my research strategy to the study of cell targeting by amyloid-β. This K99/R00 application is an ideal pathway to independence that is supported by an outstanding group of mentors and advisors, extensive training in highly innovative techniques, a world-class scientific environment, and clear departmental commitment.

NIH Research Projects · FY 2025 · 2022-08

Project Summary: Alternative splicing processes over 95% of human mRNA and enables a single gene to encode distinct protein isoforms of different functions. Dysregulation of alternative splicing causes incorrect selection of exons and consequently various human diseases. Alternative exons are selected in early-stage spliceosome assembly. Due to our limited knowledge about early-stage spliceosome assembly, it is still challenging to develop therapies for diseases related to aberrant RNA splicing. Early-stage spliceosome assembly involves selection of exons and recruitment to the splicing sites of ribonucleoprotein complexes U1 and U2. These processes depend on the interplay of Ser/Arg-rich proteins (SR), U1-70K and U2AF-35. SR proteins are the key factors that coordinate all these events. The SR family consists of 12 members and shares Arg-Ser repetitive regions (RS) that are subjected to phosphorylation. In this proposal, we have selected the prototype of the family, SRSF1, as a model to investigate the central roles of SR proteins in spliceosome assembly. Mounting cellular studies have shown that SRSF1 promotes inclusion of exons by binding to exonic splicing enhancer RNA motifs, and phosphorylation of SRSF1 regulates not only the overall splicing pattern, but also the spliceosome assembly. Despite the progress in cellular studies, elucidating the mechanisms by which phosphorylation of SRSF1 regulates exon selection and spliceosome assembly is challenging due to low solubility of SR proteins, U1-70K and U2AF-35. Our lab has obtained all three of these proteins in the soluble full-length form. With this success, we have found that the SRSF1 RS region (a) displays RNA-binding preference and its phosphorylation inhibits RNA binding; (b) is essential for interaction with U1-70K and U2AF-35, which are responsible for recruitment of U1 and U2 complexes, respectively; (c) mediates phase separation, which is consistent with its role in organizing nuclear speckles. This proposal will (1) use the high- throughput method RNA Bind-n-Seq to systematically investigate how phosphorylation regulates RNA-binding specificity of SRSF1; (2) use a combination of NMR, molecular dynamic simulations and other biophysical methods to elucidate the structural mechanism by which SRSF1 interacts with U1-70K and U2AF-35; (3) investigate how the RS region balance its roles in modulating RNA-binding affinity, mediating protein interactions, and organizing phase separation in the phase-separated state. In summary, our proposal will advance our knowledge of exon selection and splicing factor interaction during early-stage spliceosome assembly.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY Osteoarthritis of the knee is one of the most common causes of chronic pain in the US, and a common reason that patients take long-term opioids for pain. Total knee arthroplasty is often used to treat advanced knee osteoarthritis, with nearly a million patients undergoing total knee arthroplasty in the US each year. Many patients who undergo total knee arthroplasty are taking opioids preoperatively. However, preoperative opioid use is associated with worse postoperative pain, higher complication rates, and higher postoperative opioid use. Even low dose opioids can induce dependence and hyperalgesia, so postoperative pain can be harder to control in patients who have been taking chronic opioids, which can then lead to more difficult rehabilitation after surgery. Tapering opioids preoperatively holds potential to improve outcomes in total knee arthroplasty by counteracting these negative effects of opioids. However, the existing literature on preoperative opioid taper is limited. Several small retrospective studies have suggested a benefit, but detailed preoperative taper protocols have not been published, and high quality prospective studies have not been conducted. This proposal looks to advance the field of preoperative opioid tapering. Aim 1 will develop and refine a preoperative opioid taper protocol for patients undergoing total knee arthroplasty. Aim 2 will assess the feasibility of preoperative opioid taper intervention in a pilot randomized trial. At the completion of the pilot trial in Aim 2, the intervention will be ready to be tested for efficacy in a multicenter randomized control trial as the next step in this research. The overall goal of this 4-year Mentored Patient-Oriented Research Career Development Award (K23) proposal is to support Kevin Riggs, MD, MPH to become an independent investigator in the field of improving arthroplasty outcomes, with a focus on pain and opioid use. This award will provide comprehensive mentoring, training, and research experience to facilitate Dr. Riggs’s progression toward becoming an independent investigator. Specifically, Dr. Riggs will gain expertise in developing interventions, clinical trial design, and evaluation of functional status and other patient-reported outcome measures. This will position Dr. Riggs to become a leader in improving surgical outcomes for patients undergoing arthroplasty.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY This application is for the “Trauma Resuscitation with Group O Whole Blood Or Products” (TROOP) trial, a pragmatic, multicenter, phase III randomized clinical trial to evaluate the clinical effectiveness and safety of whole blood, compared with component blood therapy, in trauma patients predicted to require large volume blood transfusions. Trauma is one of the leading causes of death in the United States, and disproportionately affects the young, killing those who might otherwise have lived long and productive lives. Injuries account for more years of potential life lost before 75 than any other cause. Hemorrhage remains the most common cause of preventable death after injury, and blood transfusion is an essential part of treatment. Modern blood banking practices separate donated whole blood into components. The current standard of care in trauma transfusion is the balanced administration of equal numbers of units of blood components (packed red blood cells, plasma, and platelets), effectively attempting to reconstitute whole blood. A renewed approach to blood transfusion therapy in trauma is to use whole blood from the outset, which has not been separated. Compared with component therapy, whole blood offers several potential advantages, but there are only a small number of, mostly observational, studies comparing whole blood and component therapy, and they are very heterogeneous. TROOP will randomly assign eligible patients to either whole blood resuscitation or component therapy (the current standard of care). The trial uses a highly innovative, Bayesian, group-sequential, combined non-inferiority/superiority design. The trial has been designed in collaboration with NHLBI’s Innovative Clinical Trials Resource, funded by a U34 Planning Grant (U34HL148472). In keeping with recent expert recommendations, the primary outcome will be 6-hour mortality. TROOP will enroll 1,100 patients, over 36 months, at 12 level I trauma centers. The trial will have 85% power to determine non-inferiority, and 80% power to determine superiority. We have assembled a highly experienced team of investigators with significant and complementary expertise in this type of research. The Clinical Coordinating Center is based in the Center for Injury Science at the University of Alabama at Birmingham, and the Data Coordinating Center is based in the School of Public Health, at the University of Texas Health Science Center at Houston. The knowledge gained from this clinical trial will transform the way in which massively bleeding trauma patients are transfused. TROOP is exceedingly well positioned to improve mortality from trauma, and reduce the number of preventable deaths resulting from hemorrhagic shock.

NIH Research Projects · FY 2025 · 2022-08

Enter the text here that is the new abstract information for your application. For the United States to continue to be the leader in biomedical research, it must develop a workforce that is well trained and eager to join the rapidly expanding enterprise. However, many students lack early engagement and opportunities to develop skills and content knowledge to interest them in these research careers, and thus the students often fail to complete a Bachelor of Science degree (BS) and be interested in biomedical research and careers. For over 10 years Jefferson State Community College (JSCC) and the University of Alabama at Birmingham (UAB) have partnered to develop a dynamic program to bridge JSCC students into undergraduate and graduate biomedical and behavioral education and research careers. Our original Bridges to Biomedical Careers grants (BBC) predicted that 75% of students would gain a BS in 5 years or less, 35% would enter a biomedical graduate education program and 35% would enter biomedical careers. Of the 95 students in BBC, 98% have successfully completed or are currently completing a BS in biomedical/behavioral sciences in 5 years or less and 75% are in (or applying for) biomedical and behavioral graduate programs. The remaining 25% are pursuing research careers with a BS. One of the greatest challenges for students in BBC has been their need to work during the school year to pay for their tuition, thus decreasing the time they could devote to their research. The new NIGMS B2B program addresses this challenge by funding students to carry out research throughout two entire years, starting with a summer research internship in their rising sophomore year at JSCC. Bridges-UAB takes advantage of this greater student funding to enhance student success even further. It will include a very rigorous recruitment of freshman students at JSCC, including a research workshop and an introduction to research course and develop other JSCC and UAB partnership biomedical courses. Bridges-UAB will promote closer interactions between JSCC and UAB in research and education and provide students at JSCC and UAB with educational opportunities, internships and mentoring that will immerse them in biomedical and behavioral research and prepare them for research careers. Bridges-UAB will provide scholarships to cover the sophomore and junior years, and UAB plans to cover most senior year costs, thus paving the way for the students to focus on immersing themselves in cutting-edge research. Upper-level students will be encouraged to be peer mentors to newer students, and top Bridges-UAB students will return to present their research at JSCC in the workshop and other courses, encouraging the JSCC students to consider research careers. The Broader Impact will be to expand the biomedical research workforce. The Intellectual Merit will be to identify methods that engage and prepare all students for careers in biomedical research.

NIH Research Projects · FY 2024 · 2022-08

PROJECT SUMMARY Conventional models of Parkinson’s disease (PD) dysfunction do not account for sensory feedback, which is both clearly represented in the basal ganglia and clearly impaired in PD. Despite the critical importance of this feedback to normal movement, the contribution of impaired sensory processing to PD pathophysiology is unknown. Our long-term goal is to clarify the role of sensory feedback in the production of pathological motor commands in PD. This research could help reveal the neural basis of both PD pathology and its treatment, leading to more efficient clinical practices, driving the development of novel therapeutic technologies, and helping to alleviate the enormous burdens of PD on patients and providers. In healthy people, the motor system will automatically ignore sensory feedback that is not directly relevant to the current behavioral goal. In this proposal, we seek to determine whether the basal ganglia participate in this goal-directed sensory filtering, and whether this process is impaired in PD. This phenomenon could potentially provide a framework to explain PD motor symptoms with a single underlying cause: normal sensory feedback is not filtered appropriately, which reduces the ability of the motor system to produce normal commands. Underdamped sensory feedback could produce excessive transcortical reflexes in rigidity, corrupt the brain’s internal models and interfere with movement planning in bradykinesia, and even produce tremor via stochastic resonance (a phenomenon common in nonlinear neural systems in which a sub-threshold oscillation is amplified by noise). Whether or not our specific hypotheses are supported, the experimental paradigms of this study will generate unparalleled data and insights into sensorimotor integration in the human brain. If our hypotheses are correct, however, we will further provide a framework for an unprecedented mechanistic model of PD symptom generation and a roadmap towards improved treatment.

NIH Research Projects · FY 2025 · 2022-08

Project Summary Epilepsy is a common neurological disorder, with a worldwide prevalence of over 65 million. There is general agreement that epilepsy is caused by hyperexcitable neuronal networks and most therapeutic strategies have focused on decreasing excitation by targeting neuronal synaptic proteins. Even with the available antiepileptic drugs, there is still no cure and 30% of patients are resistant to treatment. Historically, epilepsy has been viewed as driven solely by defects in brain processes; however, this brain-centric perspective neglects the fact that the function of the nervous system is affected by the metabolic state of the body. Current research recognizes that microorganisms influence the brain by modifying metabolic factors in the gut, the “gut-brain axis.” Most of the evidence thus far is correlative showing that changes in the gut microbiota can affect seizure outcomes. However, there is a gap in knowledge regarding specific mechanisms by which gut microbes contribute to seizure development that may offer novel approaches to treat epilepsy. Viral infection-induced epilepsy is the most common cause of epilepsy worldwide and is often difficult to model in rodents due to high mortality rates. However, the Theiler's murine encephalomyelitis virus (TMEV) is a low-mortality viral-induced model of temporal lobe epilepsy. Intracranial TMEV injection leads to hippocampal neuronal dysfunction, widespread cortical astrogliosis, and seizure-genesis peaking at 6 days post infection in ~50% of adult C57BL/6 mice. While central nervous system inflammation has been posited as a potential modulator of seizure phenotype development in TMEV infection, the molecular mechanism is unclear. Data obtained from this model surprisingly indicated that the majority of taxonomies underrepresented in TMEV-infected mice with seizure phenotypes contained genera associated with the production of the bacterial metabolite S-equol. These bacteria convert dietary daidzein into S-equol, which has been shown to activate large conductance Ca2+- and voltage-activated K+ (BK) channels. Activation of BK channels play an important role in controlling neuronal excitability and therefore represents a novel target for the treatment of epilepsy. This proposal will determine if depletion of the microbial-derived metabolite, S-equol, increase seizure occurrence in TMEV-injected mice. It further tests the hypothesis that S- equol-producing microbial species confer neuroprotection against seizure susceptibility and neuronal hyperexcitability following TMEV injection via activation of BK channels. This hypothesis will be tested using a combination of EEG and electrophysiology recordings, mass spectrometry and 16S RNA sequencing. To determine whether these findings are broadly applicable to other types of epilepsy we will examine three models of epilepsy, TMEV, kainic acid and a genetic epilepsy model. This work takes a critical step causally linking specific microbial shifts to neuronal excitability, seizures and epilepsy and will identify microbial metabolites that can be targeted for therapeutic intervention.

NIH Research Projects · FY 2024 · 2022-08

Abstract Hypoxia is one of the key microenvironmental factors that impinges upon tumor progression and metastasis of solid tumors such as breast cancer. While evaluating the impact of hypoxia, our group made an unanticipated but striking observation that in chronic hypoxia, mammary tumors display a remarkable increase in the number of nucleoli per cell. We found that this increase is concomitant with upregulated activity of the nucleolus. In the nucleolus, RNA Pol I transcribes rDNA (contains the sequences of 18S, 5.8S and 28S rRNAs) to drive ribosome biogenesis. We contend that this increased ribosome biogenesis is essential for hypoxic cell survival and subsequent disease progression. In response to hypoxia, nucleolar ERK signaling activity is increased. Increased ERK directly impinges upon the activity of UBF, a nucleolus-specific transcription activator, which activates RNA Pol I. We contend that this increased nucleolar activity is a vulnerability of hypoxic tumor cells. Our objective is to test an approach to exploit the dependence of hypoxic breast cancer cells on ERK activation. We contend that debilitating the rRNA biogenesis following nucleolar ERK activation following hypoxic stress will remarkably restrict the tumor growth and metastatic spread of breast cancer cells. To test this, we will adopt carefully designed cellular and animal experimental approaches to test the effect of antagonizing ERK and RNA Pol I activity on metastatic progression. Additionally, we will identify mechanistic details of nucleolar ERK functions. Overall, our work will reveal novel aspects of nucleolar ERK response of tumor cells that support their survival and metastatic ability under hypoxia.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT Dr. Rachel G. Sinkey is a maternal-fetal medicine subspecialist who seeks to become an independently funded clinician-scientist focused on hypertension and cardiovascular (CVD) disease in pregnancy and the postpartum period. She seeks a K23 Mentored Research Award to realize this goal and has assembled a team of world- renowned experts to provide mentorship as she completes a tailored, five-year career development and mentored research plan. In the comprehensive career development plan the candidate will: 1) obtain skills to independently design and conduct clinical trials; 2) complete a Master of Science in Public Health degree; 3) attain contemporary hypertension knowledge, and 4) obtain career skills in strategic grant planning and writing. The customized career development plan will be accompanied by a mentored randomized clinical trial focused on preeclampsia. Preeclampsia (PE) is a hypertensive disorder that occurs in the second half of pregnancy, complicating up to one in twelve pregnancies. Delivery immediately following PE diagnosis carries the least maternal risk; however, when possible, delivery is delayed if the gestation is preterm (<37 weeks) to decrease major effects of prematurity. Despite this, maternal or fetal health factors may lead to delivery of a preterm patient with PE including: 1) maternal end-organ damage or uncontrolled severe hypertension (known as severe PE), and 2) fetal abnormalities (involving amniotic fluid, fetal testing and/or uterine artery Dopplers). The American College of Cardiology/American Heart Association Hypertension Guideline defers pregnancy hypertension management to the American College of Obstetricians and Gynecologists (ACOG). ACOG recommends antihypertensive treatment for severe hypertension (BP ≥160/110 mmHg), to avoid acute cardiovascular complications. On the other hand, treatment of non-severe hypertension in women with PE is controversial, due to concerns that lowering arterial perfusion to the fetus may lead to impaired fetal growth. There is also concern that anti-hypertensive therapy may mask severe PE, leading to maternal harm. Evidence supporting these concerns is limited, and it is unknown whether antihypertensive treatment safely prolongs pregnancy, a prerequisite for neonatal benefit. Given these critical gaps in knowledge, we propose “The ACHIEVE Trial”, a phase II, open-label RCT (N=132) of antihypertensive treatment in preterm patients with non-severe PE. Participants will be randomized 1:1 to: 1) intervention – anti-hypertensive therapy for BP goal <140/90 mmHg, or 2) usual care – antihypertensive therapy only if BP ≥160/110 mmHg. In Aim 1 we will determine if treatment to achieve a BP goal <140/90 mmHg prolongs mean time to delivery. In Aim 2 we will examine whether the intervention reduces perinatal and maternal morbidity. We will also collect and store blood for future studies investigating CVD biomarkers and endothelial dysfunction. This research study, accompanied by a comprehensive career development plan, will provide a strong foundation for a productive independent career in clinical research focused on hypertension and cardiovascular disease in pregnancy and the postpartum period.

NIH Research Projects · FY 2026 · 2022-07

The fine-tuning of transcriptional regulation by gene x environment interaction is central to maladaptive processes associated with major depressive disorder (MDD). Research over the past decade has provided strong support for the importance of epigenetic mechanisms in MDD pathogenesis. microRNAs (miRNAs), a class of small noncoding RNAs, are generating enormous interest not only as epigenetic mega-regulators of gene expression, but also for their role in disease pathophysiology and treatment targets. We and other investigators have shown differential regulation of miRNAs in the brain of MDD individuals. It is generally agreed that miRNAs mediate post-transcriptional gene silencing in the cytoplasm through seed sequence of miRNAs and complementary sequences in the 3′-untranslated regions (UTR) of target mRNAs via Argonaute (Ago)- based-RNA-induced silencing complex (miRISC). Recently, a paradigm-shifting phenomenon has been put forth with the concept of “nuclear localization” of select mature miRNAs. These miRNAs, containing unique set(s) of nuclear signals in the 3’ terminus, can shuttle back to nucleus from cytoplasm where they can regulate the expression of select nuclear pool of coding and non-coding RNA transcripts post-transcriptionally, but more remarkably, transcriptionally. At the transcription level, there is evidence of putative binding sites of mature miRNAs in the gene promoter regions with partial or perfect sequence complementarity, which enables nuclear miRNAs to regulate gene transcription, including primary(pri-)-miRNAs. Post-transcriptionally, nuclear miRNAs in conjunction with endonuclease Drosha, can target pri-miRNAs or can bind to 3’UTR region of nuclear coding transcripts via miRISC. The newly discovered mechanism poses an interesting possibility that within the nucleus, miRNAs may have the distinct capability of repatterning the gene transcription dynamics dramatically where they can not only regulate their own expression at pri- and precursor(pre)-miRNA levels, but also at the nuclear coding transcript level. This could be highly relevant in MDD-associated maladaptation processes. We propose an overarching hypothesis that a dynamic shift and nuclear enrichment of mature miRNAs driven by specific nuclear signals and their regulation of key pri-, pre-, and mature miRNAs, and coding genes within the nucleus, and consequent functional attributes, will be central to MDD pathogenesis. Using highly innovative approaches and well characterized and matched brain samples from MDD and non-psychiatric control subjects, we aim to determine: 1) the nuclear enrichment of miRNAs, cytosolic to nuclear shift, and their functional relevance; 2) possible mechanism(s) of miRNA translocation; 3) the unique transcriptional regulatory role of nuclear miRNAs in changing the promoter dynamics of target genes as a function of Ago1 complex; and 4) the unique role of nuclear miRNAs in modifying the processing of pri-miRNAs as a function of Drosha microprocessor complex. Our study is highly innovative and has the potential to uncover the unique role of nuclear miRNAs in redefining transcriptome as a mechanism in MDD etiology and identifying novel targets for therapeutic intervention.

NIH Research Projects · FY 2025 · 2022-07

The U.S. initiative of Ending the HIV Epidemic (EHE) has fallen short of its goals, and geographic differences in HIV care outcomes have only widened in the last decade. For example, here are significant differences in HIV care outcomes, such as viral suppression and hospitalization rates, among people living with HIV (PLWH) between the Western and Southern regions of the U.S., as well as among urban centers and rural areas. These geographic differences are also observed in other chronic diseases, yet, PLWH appear to be at higher risk of poorer health outcomes than persons not living with HIV (PNLWH), especially in rural areas. These geographic differences are likely largely driven by underlying factors in our health systems, such as access to healthcare, providers, and specialized care centers in rural areas—an understanding of these pathways that elucidate these differences is urgently needed to develop the next generation of HIV interventions operating at the health systems levels, and ever more now in the context of compounding chronic diseases affecting PLWH. The National Clinical Cohort Collaborative (N3C) leverages real-world, national data and presents an unprecedented opportunity to inform the NIH priority aims to understand the factors that affect both HIV and other chronic conditions. N3C is the largest electronic health record (EHR) repository in U.S. history (>20M patients), contains both unparalleled individual-level granular clinical and historical data, and represents the largest U.S. cohort of PLWH with their HIV and other chronic conditions outcomes data (>120K), allowing us to evaluate the bi-directional impact of existing HIV infection and other chronic diseases outcomes. Furthermore, individual-level data in the N3C are uniquely positioned to merge publicly available datasets that measure area-level health systems factors. Our central hypothesis is that the observed geographic differences in HIV and other chronic diseases occur in a larger context of individuals embedded in health systems with very significant differences across the U.S., between urban areas as well as between urban and nearby rural areas. Understanding these forces, allows us to determine the next generation of HIV interventions. Our three aims respond to the NIH call using data science, rigorous and reproducible machine and statistical learning, and multi-level mediation and epidemic modeling. The goal of Aim 1 (HIV outcomes) is to identify multilevel, geographic and health systems differences in HIV outcomes (e.g., viral suppression and hospitalization) over the recent years. The goal of Aim 2 (chronic diseases outcomes) is to understand the independent and aggregated impact of geographic differences and clinical characteristics on health outcomes (2a) and quantify the differential impact of HIV on other chronic diseases outcomes at the U.S. population level by geography (2b). The goal of Aim 3 (HIV epidemic modeling) is to quantify the impact of other chronic diseases on HIV care and prevention outcomes by geography at the population-level for the national EHE initiative’s priority jurisdictions.

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY / ABSTRACT Sickle cell disease (SCD) is the most common genetic red blood cell disorder in the African American (AA) population. Prior to 1970, only half of the children with SCD survived to adulthood. With universal newborn screening and medical advances (antibiotic prophylaxis, transfusions, hydroxyurea, stem cell transplantation and gene therapy), survival rates have improved. In patients with SCD, transition from pediatric to adult medical care is a high-risk period for death. Preventing premature death requires that patients with SCD engage in self-care as they transition into adulthood. However, cognitive impairment is a pervasive debilitating feature of SCD across the lifespan, and influences ability to engage in effective decision-making needed for self-care. Additionally, cognitive impairment is compounded by specific challenges faced by transition-aged youth with SCD due to health-related disparities and poor social determinants of health. As such, there is an unmet need for patients with SCD to adopt and assimilate decision-making skills to enhance self-care and self-advocacy, which could result in improvement in transition of care and independence in adulthood, thus preventing life-threatening complications and premature death. This study aims to utilize a cognitive remediation program (CRP) delivered via telehealth to improve decision-making skills necessary for successful transition of care. Scientific Aim 1 will determine if a 4-week CRP improves transition readiness skills in youth with SCD (10-18y). Persistence of improvement across time will also be evaluated. Scientific Aim 2 will assess brain-related changes pre- to post- CRP, in order to identify neurobiological markers related to cognitive changes in youth with SCD after intervention. Additionally, two exploratory aims will be investigated in order to 1) identify demographic and clinical characteristics associated with improvement in transition readiness skills post-CRP, and 2) to test the feasibility and preliminary efficacy of a 1-year post-CRP booster session in order to continue to maintain transition readiness skills. Overall, this study will promote my long-term career goal of improving quality of life for patients with SCD and will provide opportunities for additional training and career development. The career development plan includes formal training in research methodology specific to conducting clinical trials, engagement of minority populations in research, and neuroimaging methodology and analyses. The scientific and training plans are supported by a team of experienced mentors and advisors who are committed to the success of this project and my development as a patient-oriented scientist. The primary mentor is an expert in neurocognitive outcomes among blood disorders, an experienced mentor of young investigators, and the director of the UAB Institute for Cancer Outcomes and Survivorship. The results of this proposal will be utilized to form the foundation of a future clinical trial designed to test the refined CRP among those who are most likely to benefit from the intervention. This project will strengthen my skills as a clinical researcher, establish an independent research platform, and make a true contribution towards improving long-term health outcomes in patients with SCD.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY Opioid use disorder (OUD) is characterized by persistent drug seeking often accompanied by a loss of interest in natural rewards. Current FDA-approved treatments for OUD target the endogenous opioid system directly, either as substitution therapies (e.g. buprenorphine, methadone) or antagonists that oppose opioid effects (e.g. naltrexone, naloxone). Although these therapies have helped reduce overall harm, they are rarely a cure for OUD. As the seat of executive function, the PFC plays an integral role in decision-making, impulse control, and the cognitive regulation of drug craving and relapse. Thus, novel compounds capable of promoting neural plasticity to augment or restore PFC function possess enormous therapeutic potential for treating substance use disorders (SUDs). Structural plasticity in the PFC could produce long-lasting protective effects against relapse, and would reduce the need for chronic medication. Plasticity-promoting, psychoplastogenic compounds may also have broad-spread restorative effects on downstream neural circuits, and may normalize aberrant plasticity and neural activity across addiction networks. Psychedelic compounds including 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) and ibogaine potently induce spine growth in the PFC in a serotonin 5-HT2A receptor-dependent manner. This class of drugs also elicits long-lasting anti-addictive properties across a wide variety of SUDs, but their side effects including hallucinations and cardiotoxicity limit their therapeutic potential. To overcome these barriers to therapeutic application, we engineered a safer psychoplastogenic 5-HT2A receptor ligand called tabernanthalog (TBG), which chemically resembles ibogaine and 5-MeO-DMT, yet lacks hallucinogenic effects and cardiotoxicity and does not bind to opioid receptors. We demonstrated that TBG decreases both alcohol and heroin consumption and reduces relapse rates long-term in a heroin self- administration model after a single treatment. However, the pharmacological and brain-specific mechanisms that mediate these anti-addictive effects are currently unknown. The overarching objectives of this project are to determine the in vivo receptor targets mediating the anti-addictive effects of TBG, and whether TBG’s psychoplastogenic effects within addiction neural circuitry is a mechanism of action for TBG therapy. Establishing the anti-addictive mechanism of TBG will aid continued drug discovery of more potent and selective compounds for treating addiction and may help identify patient populations that are likely to respond to treatment. In addition to identifying the role of serotonin receptors and structural plasticity in the effect of TBG, this proposal will also screen the therapeutic potential of TBG in a polydrug (opioid and alcohol) use model and determine the specificity of TBG therapy for opioids versus natural rewards. Information gained from this project will provide insight into TBG’s potential as an anti-OUD therapeutic and its mechanism of action, thus allowing us to further optimize TBG and related compounds for translation to the clinic.

NIH Research Projects · FY 2025 · 2022-07

Program Director/Principal Investigator (Last, First, Middle): Lungu, Claudiu T. Project Summary The Deep South Center for Occupational Health and Safety (DSC) is a consortium of two major universities in Alabama, University of Alabama at Birmingham (UAB) and Auburn University (AU) established in 1982 as an Education and Research Center (ERC) funded by the National Institute for Occupational Safety and Health (NIOSH). The mission of the DSC is to Train and develop professionals who protect and promote the health and safety of workers through interdisciplinary education, training, research and outreach. The DSC offers high quality interdisciplinary graduate training in three OSH academic programs: Industrial Hygiene (UAB), Occupational Health Nursing (UAB), Occupational Safety and Ergonomics (AU) and one allied discipline, Occupational Injury Prevention (AU). The DSC has a long tradition of training OSH professionals in our region through the Continuing Education program and has provided training resources, information and consulting to businesses and organizations through the Outreach program. The Center is also providing research training to investigators and students through the Pilot Project Research Training program. Recognizing the OSH burden that affects disproportionally racial and ethnic minority groups as well as disadvantaged communities and individuals, the DSC will focus on minimizing this burden while striving to eliminate disparities showing our commitment to DEI. The mission of the DSC will be achieved through the following specific aims: Specific Aim 1: Maintain and enhance our excellence in interdisciplinary academic education. The DSC will continue to offer high quality academic programs at the level of master’s, doctoral and certification in Industrial Hygiene (IH), Occupational Health Nursing (OHN) and Occupational Safety and Ergonomics (OSE) with the allied Occupational Injury Prevention Research Training (OIP) program. Specific Aim 2: Continue to be the main training and outreach resource of OSH for business and organizations in the region. The DSC will continue to offer our Continuing Education (CE) core courses to a broad spectrum of OSH professionals including offering to military personnel on US military bases and health care professionals (HCPs). Specific Aim 3: Collaborate with other academic and research institutions, businesses, non-profit and professional organizations, other ERCs and TPGs to find the best mechanisms and tools to protect the life, health and wellbeing of broad categories of workers. The DSC will continue to be an active participant and support state and regional organizations and conferences. Specific Aim 4: Conduct high quality fundamental and applied research related to the NIOSH NORA agenda to advance the field of OSH. One of the main goals of the DSC faculty is to develop new knowledge investigating the causes of occupational diseases and injuries, and proposing new solutions for prevention. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

NIH Research Projects · FY 2025 · 2022-07

Abstract This proposal describes a 5-year research plan to adapt and evaluate implementation of three evidence-based interventions to achieve the goals of Ending the HIV Epidemic (EHE) in Alabama (AL). This combination intervention will (1) use novel big data approaches to inform precision public health efforts to increase testing in priority populations, (2) decrease time to linkage to care, and (3) decrease time to viral suppression (VS) among persons newly diagnosed with HIV in AL, a priority state in the national EHE Initiative. The proposal leverages a dynamic and innovative collaboration of experienced investigators from the University of Alabama at Birmingham (UAB) Center for AIDS Research (CFAR) and the HIV Divisions of the state health department in AL (ADPH) and the Mobile County Health Department (MCHD). The MCHD serves six predominantly rural counties in the southwestern region of AL with low testing coverage, high incidence, and suboptimal times to linkage and VS for newly diagnosed cases of HIV. We propose a type 2 hybrid implementation-effectiveness study guided by the Consolidated Framework for Implementation Research (CFIR) and Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) frameworks to adapt, implement, and evaluate three Centers for Disease Control (CDC) evidence-based interventions: (1) a data-driven approach to direct Community-based HIV testing in areas with low testing coverage, (2) Project Connect, to expedite linkage at time of diagnosis and (3) a Rapid ART start program at MCHD community clinics in Alabama (“COAST-AL”). In Aim 1, we will use qualitative methods to adapt COAST-AL combination intervention to the local context. In Aim 2, we will deploy the adapted intervention across MCHD services areas over 36 months. Our primary effectiveness outcome is days to VS after HIV diagnosis using state-level surveillance data from ADPH. Our primary implementation outcome is proportion of zip code tabulation areas with at least 15% of the adult population tested by 36 months compared to baseline using surveillance and commercial HIV testing data sets. We will evaluate intervention acceptability, feasibility, appropriateness from clients through in-depth interviews and with providers through surveys. In Aim 3 we will conduct interviews with key stakeholders and work collaboratively with local and state health department stakeholders to identify and prioritize implementation strategies that can be deployed to sustain COAST-AL and facilitate its implementation in other public health jurisdictions across AL and other rural EHE-prioritized states. Results of this research will lay the groundwork for a larger implementation trial that will include rigorous evaluation of implementation strategies to integrate COAST-AL into clinical and public health systems to meet EHE targets.

NIH Research Projects · FY 2026 · 2022-07

Project Summary/Abstract Most senior design courses in Biomedical Engineering (BME) challenge students with the task of creating engineered solutions to unsolved clinical problems. This experience, however, is often the first time in the curriculum that students are exposed to needs finding, communicating with clinicians, following an engineering process to generate innovative solutions, and incorporating user feedback. Through the proposed activities, we will introduce clinical innovation experiences earlier in the curriculum so that BME students enter their capstone year as experienced innovators. We will capitalize on existing partnerships between medicine, engineering and business in design, innovation, and entrepreneurship to form an early interdisciplinary BME education that fosters more experienced and creative biomedical engineers well into the 21st century. Three specific opportunities for strategic enhancement of the BME undergraduate experience at UAB have been identified. First, there is a need to create a cohesive experience for BME underclassmen, as student exposure to BME faculty and content is limited in the first two years. Secondly, there is a large gap in time between the early design courses and the senior capstone, during which exposure to clinical problems is sparse, and design/innovation are not emphasized. Thirdly, there is a need for higher level engineering design activities in the capstone experience. The objective of the present proposal will be met through three aims. The first aim is to introduce to clinical innovation and design thinking to freshmen and sophomores by providing needs finding opportunities in a clinical setting and guiding them toward development of solutions to clinical problems in a classroom setting. In the second aim, ten rising BME juniors will take part in a 10-week summer clinical immersion in which they will perform needs finding and customer discovery surrounding medical/assistive devices or processes, develop a preliminary design/prototype, and create a business model. A faculty team will screen their output for use in the upcoming senior design course. The third aim is to enhancement the senior capstone experience by accelerating the project selection process and teaching best design practices during the first semester. In the second semester, new online modules covering business topics will free up valuable class time for advanced engineering topics and design activities that will improve student learning outcomes and increase the potential for novel, patentable designs. In addition, we will launch a new effort with the UAB Office of Disability Support Services (DSS) to recruit students with disabilities into our undergraduate program. People with disabilities represent a powerful stakeholder and given our record of accomplishment for product development in this space, this activity will serve to improve overall success and involve an underserved constituent in engineering.