University Of Alabama At Birmingham

NIH Research Projects · FY 2026 · 2025-03

Project Summary The overall goal of this proposal is to integrate advanced molecular imaging of HER2 expression and vascularity to assess treatment response to radiation following quantification of targeted HER2 bioavailability and heterogeneity in HER2+ breast-to-brain metastasis. HER2+ breast cancer has a higher incidence of brain metastases compared to other breast cancer subtypes. Patients with HER2+ breast cancer are 2-4 times more likely to develop metastases to the central nervous system compared to HER2-negative patients. Quantitative imaging provides the opportunity to evaluate intratumoral subregions of variable response and discordance of underlying biology between metastatic tumors. Furthermore, molecular imaging of HER2 with [89Zr]trastuzumab-position emission tomography (PET) with simultaneous quantification of vascular perfusion (Ktrans) from dynamic contrast enhanced (DCE)- magnetic resonance imaging (MRI) provides an opportunity be able to noninvasively quantify the spatial delivery of trastuzumab into brain lesions prior to radiation and systemic targeted therapy. New preliminary results reveal that trastuzumab can increase vascular delivery and decrease hypoxia in preclinical models of breast cancer, which can be longitudinally monitored by advanced imaging techniques and improve effects of radiation and chemotherapy. Furthermore, noninvasive imaging using [89Zr]trastuzumab-PET in HER2+ breast cancer has shown us that we can assess inter- and intra- tumoral heterogeneity in both preclinical and clinical cancer. In preclinical models of HER2+ primary disease, HER2 heterogeneity and expression correlate with response to cytotoxic therapies. The overarching hypothesis is that advanced imaging with PET/MRI can characterize underlying initial conditions in the tumor microenvironment on a personalized basis to provide biological evidence of intratumoral heterogeneity and delivery of systemic targeted therapies, providing surrogate information to predict treatment response to combination therapies in HER2+ breast-to-brain metastasis. To test this hypothesis, we’ve identified the following specific aims: 1) Quantify HER2+ expression and vasculature to assess bioavailability of trastuzumab in patients with HER2+ breast-to-brain metastasis and 2) Quantify intratumoral heterogeneity of brain lesions and discordance of HER2 heterogeneity in metastatic lesions in patients with HER2+ breast-to-brain metastasis. This translational approach to personalize, guide, and predict response to combination treatments in HER2+ breast- to-brain metastasis will provide an advanced, and noninvasive approach to improve patient outcomes in a patient population with dire need of improved treatment strategies.

NSF Awards · FY 2025 · 2025-03

The regional conference "Joint Alabama--Florida Conference on Differential Equations, Dynamical Systems and Applications (JAF DEDS)" organized by the departments of Mathematics at The University of Alabama at Birmingham (UAB), Auburn University Mathematics and Statistics Department, Florida International University (FIU) and Florida State University (FSU) Mathematics Departments will take place in Birmingham, AL, May 21-22, 2025. This meeting will be the third event in a sequence of annual JAF DEDS conferences moving between Auburn, UAB, FIU, FSU. The sizable growth of applied mathematicians specializing in partial differential equations and applied dynamical systems in the states of Alabama and Florida has led to new level of research activity in mathematical biology, fluid dynamics, medical imaging, mathematical physics, applied harmonic analysis and spectral theory. This regional conference series connects newly formed and existing research groups and provides opportunity for dissemination of recent results, especially to early career researchers without federal funding, facilitating interaction between an increasing number of regional graduate students and the internationally recognized experts in the field. The Third JAF DEDS Conference will be preceded by a graduate students day on May 20th, 2025, featuring two mini-courses by guest presenters and a professional development panel. Priority for financial support will be given to those with no other sources of support and special attention will be given to graduate students, postdoctoral fellows, and early career researchers. The tools and techniques from dynamical systems have been used to establish existence and investigate stability of special solutions (pulses, traveling waves, steady states, and fronts) for large variety of differential equations. These solution are often used to model complex physical phenomena across a range of applications, including evolution of surface water waves, coherent structures in optics, combustion phenomena, and plasma dynamics. Motivated by the recent progress, the scientific program of the conference will be centered around a variety of equations from the mathematical physics modeling optical systems, fluid motion and waves in novel materials. These systems are described by equations of Klein-Gordon or Nonlinear Schrodinger type and are either Hamiltonian or dissipative in nature. Understanding them will improve our theoretical knowledge and provide new insights into practical aspects of nonlinear optics, electronic transport in irregular media, new materials, and fluid dynamics. The goal of this conference is to connect researchers working in different aspects of PDE's and Dynamical Systems and to explore the deep connections between these fields, as well as to stimulate interactions among regional experts in these areas, graduate students and junior researchers. More information can be found on the website: https://www.uab.edu/cas/mathematics/events/conferences This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

Evaluating Social Brain Health in HIV: An RDoC-based Approach In our daily life, we frequently interact with others (e.g., friends, staff at grocery stores). While these interactions may appear effortless, actually they rely on a complex set of abilities, as we constantly need to recognize social cues (e.g., emotional expressions of faces or voices) from others, infer their internal mental states (e.g., intentions, emotions), and make appropriate responses. Difficulties in any of these abilities could substantially affect how one navigates social environment and harnesses social resources needed to manage a complex disease like HIV. A large body of work in social neuroscience has established that this set of abilities to process socially relevant information from oneself and others—referred to as social cognition—is crucial for efficient social functioning, is distinct from neurocognition (e.g., verbal memory), and is linked to a unique set of brain regions, including the temporo-parietal junction, amygdala, and dorsal medial prefrontal cortex. These brain areas are collectively known as social brain. The NIMH Research Domain Criteria (RDoC) project selected social cognition as one of the “fundamental aspects of human behavior” with well-established neurobiological mechanisms, and encouraged researchers to evaluate social cognition across multiple levels of assessments (e.g., neural, behavioral) to better understand mechanisms underlying poor social functioning and identify novel treatment targets. While there is urgency to examine the neurobiological processes and heterogeneity of neurocognitive impairments in people with HIV (PWH), much less attention has been given to research on social brain in PWH. This is unfortunate, as in-depth mechanistic investigation of social brain has led to successful evaluation of novel interventions using imaging-based biomarkers to improve social functioning in other populations. To address this knowledge gap, using an RDoC-based approach, this project aims to evaluate a hypothesis that social brain function is compromised in PWH, which can in turn lead to inefficient social functioning. This hypothesis was developed by synthesizing evidence across multiple lines of work, including our own. With well-validated paradigms and state-of-the-art fMRI tools, we will examine neural circuits and performance related to two core RDoC-recommended social cognitive constructs: Perceiving Social Cues (i.e., facial expression, prosody) and Understanding Others (i.e., belief, emotion). We will also examine the relationships between social cognition, neurocognition, and social functioning in PWH. By systematically evaluating this hypothesis using an RDoC-based approach, the findings of this project could offer mechanistic knowledge about HIV-associated CNS complications, insights into the heterogeneity of neurocognitive impairments in PWH, and novel treatment targets for improving brain health and quality of life of PWH, consistent with NIH Office of AIDS Research priority.

NIH Research Projects · FY 2026 · 2025-03

Summary Rapid plasma membrane-to-nucleus relocalization of Signal Transducer and Activator of Transcription (STAT) family members upon cytokines stimulation is vital for signal transduction. Countless cell processes, including immune cell’s ability to fight pathogens, depend directly on STAT signaling. Extracellular signals typically result in STAT phosphorylation, triggering a conformational change that leads to importin recruitment and nuclear translocation. In the nucleus, STATs function as transcription factors, inducing the expression of a plethora of genes involved in native immunity, survival, cell growth, proliferation, and pathogen response. Gain-of-function (GOF) mutations in STAT1 and STAT3 are associated with various immunodeficiencies characterized by over- activated immune cells, autoimmunity, and increased risk of infections. This proposal focuses on STAT1 and STAT3. Leveraging the power of cryogenic electron microscopy and biochemical, biophysical, and cellular methodologies, we aim to illuminate what constitutes a knowledge gap at the center of innate antimicrobial protection in STAT signaling. Aim 1 will decipher the mechanisms activated STAT1 and STAT3 enter the cell nucleus under physiological conditions. STATs do not have a classical Nuclear Localization Signal (NLS) yet use importin α/β and the GTPase Ran for nuclear entry. The molecular mechanisms of STAT nuclear import have not been elucidated and appear to differ in different STAT family members. Understanding STAT’s quaternary structure is crucial in deciphering how the nuclear import machinery is recruited without a classical NLS. Aim 2 will catalog GOF mutations identified in STAT1 and STAT3 and examine their impact on STAT quaternary structure, NLS exposure, and nuclear signaling, establishing a causative relationship between GOF mutations and persistent nuclear activation of STAT1 and STAT3. Our integrative approach to molecularly characterize STAT1 and STAT3 GOF mutations based on genotype- phenotype correlations will generate a comprehensive atlas of all known mutations discovered thus far.

NIH Research Projects · FY 2026 · 2025-03

In Sub-Saharan Africa, 75% of women diagnosed with breast or cervical cancer are already in late-stage disease, a much more dire figure than women in high income countries. One reason for this is a lack of programs for cancer screening and early detection, which could be remedied by bundling breast and cervical cancer screening, an innovative approach that is known to improve access to preventative cancer care and yield an earlier cancer diagnosis, thereby decreasing its morbidity and mortality. Clinical Breast Exam (CBE) and the “screen-and-treat” approach for cervical cancer via visual inspection with acetic acid (VIA) are effective screening modalities and often the top choice in resource-limited settings. However, there is a critical gap in knowledge of how to effectively implement and optimize these bundled interventions. The Cameroon Baptist Convention Health Services (CBCHS) runs the largest and most comprehensive breast (CBE) and cervical cancer screening (VIA and HPV testing) program in Cameroon by bundling both screenings into a single service. Through a long-established collaboration between CBCHS and UAB researchers, there is now an opportunity to conduct implementation science-driven research to optimize the screening program, improve the screening to diagnosis to treatment cascade, and to effectively disseminate the program, thereby maximizing its public health impact. Guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) robust implementation science framework, the proposed career development award aims to 1) establish the reach and effectiveness of the bundled women’s cancer screening program and compare these metrics across stationary and mobile clinics, 2) identify the implementation outcomes of acceptability (patient level), appropriateness (provider level), and cost (organization level) along with barriers and facilitators to program maintenance (organization level), and 3) conduct implementation mapping via stakeholder (patients, providers, organizational leaders, Ministry of Health personnel) engagement to devise a patient-centered multi-level implementation strategy(s) to enhance and disseminate two bundled evidence-based cancer screening interventions into new clinic sites in the public health system in Cameroon. To successfully complete the project, the PI will receive mentorship from a team of experienced clinicians and researchers of health services, implementation science, and health economics. The PI will also gain focused training via a personalized dynamic learning plan in implementation science, mixed methods research, economic evaluation, and science of sustainability and scale. She will also participate in grant writing workshops over the award period in order to prepare follow-on grant proposals to further her work in the optimization of cancer control programs. Successful completion of the proposed research and training will position the PI as an independent, NIH-funded surgeon-scientist focused on enhancing global cancer control by implementing innovative, scalable, and evidence-based interventions.

NIH Research Projects · FY 2026 · 2025-02

Oncology financial navigation is an evidence-based intervention to combat cancer-related financial hardship by helping patients prepare for out-of-pocket treatment costs, optimizing health insurance, and accessing financial resources. Though research-based integration of oncology financial navigators has been proven beneficial for patients in controlled settings, little is known about how to implement oncology financial navigation into routinely-delivered oncologic care. To address this knowledge gap, we propose a pragmatic, hybrid effectiveness-implementation study to assess outcomes of oncology financial navigation delivered as routine cancer care at the University of Alabama at Birmingham. This study will build upon my existing skills in quantitative research methods, which has provided foundational work to better understand cancer-related financial hardship, and allow for the development of new skills in implementation science, pragmatic trials, and qualitative methods to address financial hardship. We hypothesize the proposed assessment will identify potential areas to improve implementation of oncology financial navigation, which will result in better financial and clinical outcomes for patients with cancer. Outcomes will be assessed using three specific aims. In Aim 1, we will track oncology financial navigation implementation strategies and their effect on implementation outcomes, including reach, adoption, implementation fidelity, and maintenance. In Aim 2, we will use routinely collected, patient-reported data to evaluate change in patient-reported measures of financial distress, financial difficulties, quality of life, and psychological distress for patients receiving oncology financial navigation compared to historical controls (“usual care”). In Aim 3, we will use qualitative interviews to assess how oncology financial navigation implementation strategies were leveraged to address implementation barriers identified from patient, provider, and health system perspectives. Through the evaluation of real-world oncology financial navigation implementation, this innovative project will create opportunities for immediate scalability and sustainability within value-based payment models. The proposed research is significant because it will provide foundational data on the utility of oncology financial navigation implementation strategies and their effect on implementation and patient outcomes in clinical settings serving a real-world pool of patients with cancer. Results from this study will inform a larger study testing implementation and integration of oncology financial navigators into routine cancer care delivery at multiple institutions nationally. Furthermore, it will provide the training and mentorship necessary to develop my independent research program and eventually achieve my ultimate career goal of developing and testing evidence-based interventions that target financial hardship in real-world settings to improve the accessibility of care for all patients with cancer.

NIH Research Projects · FY 2025 · 2025-02

Converging evidence suggests that major depressive disorder (MDD) involves maladaptive processes impairing the ability of individuals to appropriately interface with the environment leading to compromised structural and synaptic plasticity in the cortico-limbic brain areas. So far, no coherent hypothesis fully explains this phenomenon. Fine-tuning of transcriptional regulation by gene x environment interaction is central to MDD etiology. In this regard, long-non-coding RNAs (lncRNAs), a class of regulatory RNAs, are gaining traction for their role in key brain functions and behavior, including MDD. How lncRNAs participate in MDD pathogenesis is not clearly understood; however, their potential engagement in epigenomic reprogramming and subsequent fine- tuning of the transcriptome at the genome-wide level is being considered a paradigm shift in understanding the refinement of cellular processes. Remarkably, a majority of lncRNAs are selectively expressed in the brain in a cell and tissue-specific manner. More importantly, lncRNAs have access to chromatin due to their permanent presence in the nucleus, where they can participate in the programmed arrangement of linear chromatin structure to conformational compactness, a process pivotal to epigenetic reprogramming. Specifically, nuclear lncRNAs may cause a facultative progression of a heterochromatin state following a higher-order chromatin structure formation in 3-dimensional (3D) space, which can initiate genome-wide silencing of transcriptional activity. This can possibly be achieved through nuclear lncRNA-mediated recruitment of chromatin modifier PRC2 in conjunction with methyltransferases EZH2 and SUZ12, thereby facilitating the placement of H3K27me3 repressive histone marks on chromatin. Interestingly, both lncRNAs and chromatin conformational changes are highly sensitive to environmental cues. Using a multitude of innovative approaches, the proposed study seeks to mechanistically examine nuclear lncRNA regulation of 3D chromatin organization and its functional significance in MDD. We propose an overarching hypothesis that a dynamic shift in the expression of a unique pool of nuclear lncRNAs, their interactions with specific RNA binding chromatin modifiers, and consequent repatterning of global gene expression via a facultative progression of 3D heterochromatin state in a cell type- specific manner will be central to MDD pathogenesis. To test this, in the prefrontal cortex and hippocampus from MDD and well-matched controls, we propose to examine: 1) global shift in nuclear lncRNA transcriptome and its correlatedness within an expression framework in a cell type-specific manner; 2) cell type-specific 3D chromatin conformation changes mediated via a specific repertoire of nuclear lncRNAs following genome-wide analysis of higher-order chromatin organization; 3) role of chromatin modifier PRC2 complex and its interaction with nuclear lncRNAs in reshaping 3D heterochromatin organization; and 4) impact of nuclear lncRNA-mediated 3D heterochromatinization on global gene expression and consequent functional responses in a cell type-specific manner. If proven, the study will provide novel avenues to develop lncRNA-based therapeutic interventions.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT Urologic chronic pelvic pain syndrome (UCPPS) is a condition characterized by persistent pelvic pain and lower urinary tract symptoms (LUTS) and has an incompletely understood etiology. The symptomology of UCPPS is often differentially attributed to the urinary bladder in females and the prostate in males. Two important factors that have been associated with both the development of UCPPS and symptom flares in patients are chronic stress and dysregulation of extracellular heme homeostasis. The objective of this application is to examine the role of hemopexin (Hpx) in pelvic and visceral pain associated with UCPPS. Hpx is a glycoprotein with anti- inflammatory effects due, in part, to scavenging of heme, a hemoglobin precursor located in red blood cells (RBCs). Liberation of heme from damaged RBCs has previously been associated with stress exposure, and cell- free heme has deleterious effects including production of reactive oxygen species and promotion of inflammation and pain. AIM 1 will examine the relationship between chronic stress exposure, cell-free heme concentration, and development of pelvic/bladder hypersensitivity in the context of Hpx depletion. AIM 2 will assess whether chronic stress exposure alters nociceptive processing in spinal dorsal horn neurons in Hpx KO and WT mice. AIM 3 will use small animal fMRI to compare brain activity before and after stress exposure in Hpx KO and WT animals. Identification of a mechanistic role of Hpx and/or regulation of heme homeostasis in pain associated with UCPPS will reveal a novel avenue for the therapeutic development. The proposed research will be completed under the mentorship of Dr. DeBerry (Sponsor) and Dr. Bolding (Co-sponsor) and is one component of the fellowship training plan that will enhance the applicant’s expertise in 1) biostatistics, 2) neuroimaging analysis, 3) neuroimmunology in chronic pain, and 4) scientific writing and leadership skills. The proposed research and training will be carried out at the University of Alabama at Birmingham (UAB) Heersink School of Medicine with support from the UAB Graduate School, Behavioral Neuroscience (BN) Doctoral Program, and UAB Small Animal Imaging Shared Facility.

NIH Research Projects · FY 2026 · 2025-02

During postnatal development when the eye is still growing, an “emmetropization mechanism” uses the eye's refractive error to regulate the growth of the scleral shell to match the axial length of the eye to the focal plane. Despite this, in over 40% of Americans and up to 96% of groups in East Asia, the eye becomes too long for its own optics and is thus myopic. Even low amounts of myopia raise the risk of developing blinding conditions and refractive surgery does not change this. Thus, effective strategies to slow eye growth and reduce the prevalence of myopia are needed. One possible factor in the increasing incidence of myopia is the difference in the visual environment - the "image statistics" - between natural and man-made worlds, but to date there has been no good way to test this. This project will use a novel experimental technique and tree shrews, small diurnal mammals closely related to primates, to answer this question. Specific Aim 1. Determine the anti-myopia effectiveness of a range of real-world visual scenes. We will explore whether different visual scenes do or do not significantly affect emmetropization. Specific Aim 2: Develop an improved Repeated Low-level Red Light (RLRL) anti-myopia therapy. Recent results of `low level' red light therapy have shown impressive anti-myopia results, but these therapies are not low level but exceed established laser safety standards. Of the existing animal models only tree shrews and non-human primates have myopia reduced by red light; we will here attempt to develop more effective and safer short-time-exposure anti-myopia red light therapies. Specific Aim 3: Develop objective recommendations for lighting spectra. It is increasingly apparent that the spectrum of ambient light has powerful effects on refractive development, and common lighting sources vary widely in their spectrum. We will attempt to determine if different lighting spectra could be a risk factor for myopia.

NSF Awards · FY 2025 · 2025-02

Understanding how electrons, the particles carrying negative electric charge, move through materials is crucial for developing next-generation technologies. At the microscopic level, where electrons exhibit behaviors vastly different from those in everyday macroscopic objects, we encounter what are known as quantum effects. These effects are foundational to advances in modern physics and have led to innovations, such as superconductors, solar cells, and light-emitting diodes. By studying and harnessing these quantum effects, we can better understand the behaviors and dynamics of electrons in materials, which is essential for developing advanced devices. Moreover, recent advances in machine learning techniques offer new opportunities for creating powerful and efficient computational tools. This NSF EPSCoR Research Fellows project aims to develop new computational methods to simulate the fundamental behaviors and dynamics of electrons at the quantum level by incorporating cutting-edge machine-learning techniques. These simulations, based on an interdisciplinary approach, can push the boundaries of scientific knowledge and have the potential to deliver broad societal benefits through technological innovation. This EPSCoR Research Infrastructure Improvement: EPSCoR Research Fellows project aims to provide a fellowship to an Assistant Professor and training for a graduate student at the University of Alabama at Birmingham (UAB). Unveiling the underlying mechanisms of quantum effects requires accurate simulations, with density functional theory (DFT) calculations serving as a powerful tool. However, as the system size increases, the computational cost of DFT calculations rises dramatically, making simulations increasingly expensive. Machine learning techniques show promising potential in addressing this challenge. By collaborating with an expert in quantum materials and method development at the host institute, the University of Texas at Austin, this project aims to develop a machine-learning-based, multifunctional computational method capable of simulating quantum effects in large-scale systems. This method will then be applied to investigate scientifically important systems, such as twisted 2D systems and 2D heterostructures. The research will involve methods of DFT, Wannier functions, and the state-of-the-art deep learning techniques. This proposed research not only broadens the research scope of the Principal Investigator (PI) to transform the PI's career trajectory, but also initiates multiple collaborations both within and between institutes. Furthermore, the research will result in open-source packages that will benefit the theoretical condensed matter physics community. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-01

Abstract Deep South states Alabama, Arkansas, and Mississippi see some of the poorest health outcomes in the nation. Further, health outcome gaps associated with limited access to care and lower household income are seen in higher chronic disease prevalence and poorer lifestyle behaviors. Limited resources in primary care clinics exacerbate these challenges and hinder research efforts. Primary Care HEART-NET (Health Enhancement through Access and Research in Transformative Networks) aims to establish primary care research infrastructure in the Deep South to improve access to research and support chronic disease prevention and treatment in medically underserved populations. HEART-NET unites three institutions (University of Alabama at Birmingham, University of Arkansas for Medical Sciences, and University of Mississippi Medical Center) that include two CTSA awardees, two practice-based research networks, an IDeA-CTR awardee, and PCORNet involvement, along with 45+ primary care clinics serving a population that is 57.8% rural, to accelerate research in primary care settings and strengthen research infrastructure in primary care. HEART-NET aims to 1) work with primary care providers to seamlessly integrate research into clinics workflows; 2) apply a collaborative framework involving patients, clinicians, and communities to develop research processes with local input; 3) use innovative technologies to increase patient access to primary care research and reduce research burden; and 4) collaborate with NIH infrastructure to amplify nationwide research impacts. The significant health challenges in the Deep South, HEART-NET’s strong primary care research experience, and the potential to engage communities to improve access to studies in a variety of clinical settings make HEART-NET ideally suited to help communities prevent and manage long-term chronic disease, promoting better health for all.

NIH Research Projects · FY 2026 · 2025-01

Cancer is the leading cause of disease-related death among US children, making high quality end-of-life (EOL) care a critical component of cancer care. However, not everyone receives high quality EOL care and little is known about what drives variation in quality of EOL care. A recently developed framework for systematically examining differences in quality of palliative care in pediatric oncology posits that access to care, patient/ family interactions with the healthcare system, and stress all impact care quality. Further, we recently established quality measures for EOL care for children with cancer, including measures related to (i) location of death (e.g., death in preferred location), (ii) medically-intense EOL care (e.g., no mechanical ventilation in the last 14d), and (iii) supportive care services (e.g., palliative care in the last 30d). The new framework for examining variation in quality of EOL care and new quality measures allow us to examine the role of access to care, patient/family interactions with the healthcare system, and stress in explaining variation in quality of EOL care among children with cancer. We will leverage Children’s Oncology Group (COG) resources. COG’s largest registry study (Project:EveryChild) enrolls children diagnosed with cancer at ≥200 participating sites. We will gather data about quality of EOL care via electronic health record (EHR) abstraction and bereaved parent surveys. Variables related access to care will include psychosocial support, household material hardship, and area information, and receive care; patient-healthcare interaction will include language, medical literacy, and area characteristics, and stress will include resilience and area characteristics. These variables will be collected via EHR abstraction at COG sites, bereaved parent surveys, and residential address linkages to information about the area they live, work, and receive care. We will use these data to examine the role of access to care, patient/family interactions with the healthcare system, and stress in variation in quality of EOL care. Lastly, we will deepen our understanding of how those domains affect quality of EOL care and potential interventions through semi-structured interviews with bereaved parents with high- and low-quality care. Using a mixed methods approach, we will address the following Aims: Aim 1: Examine the role of access to care, patient/family healthcare interactions, and stress in variation in quality of EOL care. Aim 2: Develop and validate a prediction model to identify children at high risk of receiving poor quality EOL care. Aim 3: Explore how access to care, patient/family healthcare interactions, and stress influence quality of care and potential interventions to overcome these barriers. Upon completion of this proposal, we will have critical data about the role of access to care, patient/family interactions with the healthcare system, and stress in explaining variations in quality of EOL care, a model to identify those at risk of low quality EOL care, and recommendations for potential interventions. This work will inform development of risk-based interventions to ensure all children with cancer have high quality EOL care.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Neurodevelopmental disorders are common, debilitating disorders including autism, intellectual disability, and perhaps even schizophrenia. Recent genetic findings have identified mutations in multiple genes in various cellular pathways as genetic causes of rare neurodevelopmental disorders including autism spectrum disorders, intellectual disability, and others. This proposal will characterize a genetic mouse model, already generated and breeding in our laboratory, to delineate its function in the brain for the first time. Specifically, the proposal will be on a gene implicated in a well-defined neurodevelopmental disorder, as well as in autism and schizophrenia. Because this gene encodes a protein that is known to alter gene expression and chromatin modifications in non-neuronal cells, we will obtain multiome single nucleus RNA-sequencing and snATAC-seq data and analyze and correlate these two data sets while examining in parallel chromatin state. These data will span 3 critical time points during development and two key brain regions. We will also examine morphological changes in brain subregions using structural MRI as well as the morphology of neurons in the brain of these mice. A broad behavioral profile including learning/memory, social domain, and repetitive domains will be obtained to provide outcome measures for future studies. Finally, we will examine synaptic and neuronal function in two select brain regions using slice electrophysiology approaches. These unbiased, experiments will identify novel downstream targets in mammalian brain, elucidate behavioral outcome measures for future studies, and generate new hypotheses anticipated to lead to future potential therapeutic strategies.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Motor proteins harness the energy of nucleotide binding and hydrolysis to power replication, transcription, translation, protein turnover, and much more. To fully understand molecular motors there is a need, not only for the atomic detail of the structure, but also a knowledge of the energetics and kinetics of the reactions catalyzed. Our research seeks to quantify the mechanisms of the reactions catalyzed by motor proteins in transcription and protein homeostasis. Advanced human aging results in a decline of protein homeostasis networks. This decline leads to misfolded and aggregated proteins that result in many human diseases including some cancers, type II diabetes, and neurodegenerative diseases. Protein homeostasis networks are underpinned by motor proteins from the AAA+ superfamily (ATPases Associated with various cellular Activities). We are undertaking quantitative studies of the mechanisms of enzyme catalyzed protein unfolding and translocation of three representative Class 1 AAA+ molecular motors, S. cerevisiae Hsp104, E. coli ClpB, and E. coli ClpA. Recently, there has been a substantial increase in the number of structures of AAA+ motors. However, there remains a gap between our knowledge of the three-dimensional static structure and functional mechanistic studies of these motors. Using transient state kinetics and single molecule approaches, we will fill this gap by quantitatively defining the elementary rate limiting steps for enzyme-catalyzed protein unfolding by the protein disaggregating machines, Hsp104, and ClpB, compared to ClpA, the motor component of an ATP dependent protease. This will include an interrogation of the coupling of ATP to protein unfolding and translocation as well as the impact of substrate stability on the mechanisms of unfolding. We seek to answer the long-standing question of how the kinetic mechanisms are modulated by co-chaperones? In contrast to Archaea and Bacteria that employ a single DNA- Dependent RNA polymerase (RNAP) to transcribe all genes, in Eukarya, different RNA polymerases specialize in transcription of subsets of the cellular transcriptome. All eukaryotic cells express at least three nuclear RNA polymerases: Pol I synthesizes most ribosomal RNA (rRNA); Pol II synthesizes messenger RNA (mRNA) and most regulatory RNAs; and Pol III, synthesizes transfer RNA (tRNA) and the 5S rRNA. This “division of labor” between the Pols has been known for many years, yet the functional divergence between the three eukaryotic polymerases remains poorly understood. We have embarked on a quantitative mechanistic examination and comparison of the three eukaryotic polymerases with the objective of answering the following questions: What are the unique mechanistic differences between the three Pols that make them specialists? What is the intrinsic fidelity for the three Pols? Does nuclease activity quantifiably increase fidelity and, thereby, provide proofreading activity? Does pyrophosphorolysis quantifiably increase fidelity through kinetic proofreading?

NIH Research Projects · FY 2026 · 2025-01

Project Summary Multiple myeloma patients often develop bone lesions, resulting in poor prognosis and skeletal-related events (SREs, including hypercalcemia, spinal cord compression, vertebral collapse, pathologic fractures and bone pain). Bone lesions in multiple myeloma patients are caused by increases in osteoclast formation activity. Hence, antiresorptive drugs such as denosumab and bisphosphonates are presently used to treat bone lesions in multiple myeloma. Nevertheless, both drugs cause osteonecrosis of the jaw by suppressing the immune system. Denosumab is a human monoclonal antibody against RANKL, which is a critical regulator of osteoclast formation. Moreover, denosumab increases risk of serious infections, which is due to the inhibitory effect of denosumab on the immune system since RANKL also regulates immune cell development and survival. RANKL exerts these diverse functions by activating its receptor RANK. Furthermore, as a biological agent, the cost of denosumab is high and the method of delivery (injection) is not ideal. Thus, a better targeting strategy would be to use small molecules to target RANK signaling pathways that are involved in osteoclastogenesis and multiple myeloma- associated SREs but not in the immune system function. Our group previously discovered two motifs in the RANK cytoplasmic domain that regulate osteoclast formation in vitro. To study the role of the two RANK motifs in osteoclast formation in vivo, we have generated and characterized knockin (KI) mice bearing inactivating mutations in the two motifs. Osteoclast formation is dramatically impaired in the KI mice, confirming the role of these two motifs in osteoclast formation in vivo. Importantly, inactivation of these two motifs does not affect the ability of RANK to mediate immune cell development and survival. Therefore, we hypothesize that specifically targeting these two RANK motifs has the potential to serve as effective and selective therapeutic targets for bone lesions in multiple myeloma. Our long-term goal is to develop efficacious and safe small molecule drugs targeting the two RANK motifs for preventing bone lesions in multiple myeloma. We have developed cell-based assays for identifying compounds targeting the two RANK motifs. From a high throughput screen of 200,000 compounds with the cell-based assay systems followed by counter screen assays, numerous compounds were identified that potently inhibited osteoclast formation. Medicinal chemistry efforts on two of these hit compounds has led to the development of one compound that possesses improved potency and drug-like properties that are suitable for proof-of-concept mouse model studies as well as back-up compounds. The objective of this R21 proposal seeks to carry out important translational exploratory and developmental studies to evaluate the conceptual and technical feasibilities of this novel therapeutic targeting strategy for bone lesions in multiple myeloma. Positive outcomes of the proposed work will lay the solid foundation for applying for R01 funding to support future development of efficacious and safe drugs for preventing and treating bone lesions in multiple myeloma patients.

NIH Research Projects · FY 2026 · 2025-01

Mutations disrupting cilia function (Pkd1 or Pkd2) cause renal cyst formation. The relationship between cilia, the Pkd proteins (polycystins) and cytogenesis is poorly understood. Induction of Pkd1 and Pkd2 gene loss in adult mice causes focal cyst initiation, despite the genes being efficiently deleted from nearly all the cells in the kidney. It was proposed that an additional insult may be required for cystogenesis to occur. Multiple groups have now reported that the number of cysts and the cyst expansion rate is accelerated by renal injury. This led to the hypothesis that polycystins regulate an injury and repair process. In the absence of polycystins, cells that experience an injury are unable to repair adequately leading to maladaptive repair conditions. We predict these maladaptive-repair cells contribute to the focal cysts in adult mutants and to the rapidly forming, widespread cysts induced by injury. This is further supported by gene expression analyses revealing that a subpopulation of epithelial cells in pre-cystic mutants have elevated expression of genes induced by renal injury. One gene we found to be aberrantly expressed prior to cyst initiation in the Pkd1 and Pkd2 mutants and following injury is CDKN1A (p21), a protein involved in cell cycle inhibition and maintenance of epithelia cell differentiation. In normal kidney epithelia, p21 is not readily detectable, but is induced rapidly by injury to prevent injured cells from proliferating until repair is complete. p21 down regulation then allows the cell to progress through the cell cycle to complete tissue repair. Unexpectedly, the number of p21 expressing cells was greatly increased in Pkd2 mutants , despite cystic kidney disease being considered a proliferative disorder. Our data are in direct contrast to findings from nearly 20 years ago showing that Pkd1 and Pkd2 function through the Jak/Stat pathway to induce p21 expression. One goal of this project is to directly address this controversy by defining the relationship between p21 expression and cyst development and severity in Pkd1 and Pkd2 mutants. We will determine whether is abnormally regulated as part of an altered injury response in the mutants. Our studies will determine whether cells expressing p21 display cellular characteristics and transcriptional changes linked to cyst development. We will trace the fate of cells that express or had expressed p21 to determine if they contribute to cysts. Finally, using innovative mouse models where we can sustain or repress p21 expression at defined stages of cystogenesis, we will directly test the importance of p21 in cyst initiation and expansion. Collectively, our data will provide a detailed understanding of p21’s role in cystic disease. As such, the data will pave the way for innovative strategies to manage PKD more effectively, potentially leading to improved treatment options and better outcomes for PKD patients.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Post-transcriptional mRNA modifications are central to establishing proteomic and functional diversity in mammalian cells. These post-transcriptional mRNA modifications and their functional consequences are controlled by RNA-binding proteins (RBPs). However, our understanding of these alterations and the role of RBPs in melanoma metastasis is limited. Therefore, to identify RBPs that promote melanoma metastasis, we performed a large-scale in vivo short-hairpin RNA screen by targeting 1500 human RBPs. Our in vivo screen identified that YTHDF1, a reader of m6A modified RNA, is necessary for metastatic melanoma. The genetic inhibition of YTHDF1 resulted in increased anoikis induction and enhanced NK cell-mediated metastatic melanoma eradication. Additionally, an unbiased Photoactivable Ribonucleoside-Enhanced Crosslinking (PAR- CLIP) analysis and follow-up studies identified IMPDH1, an enzyme of the de novo guanosine synthesis pathway, and TrkB/BDNF that regulates Neurotrophin signaling pathway as potential downstream mediators of YTHDF1-function in metastatic melanoma. IMPDH1 promoted anoikis resistance, while the TrkB/BDNF pathway was necessary for suppressing NK cell-mediated cytotoxicity against melanoma cells. Our overall objective is to determine the role of cell-intrinsic (anoikis resistance) and cell-extrinsic (NK cell-mediated anti-tumor immunity) pathways in YTHDF1-driven melanoma metastasis and to establish pharmacological targeting of IMPDH1 and TrkB/BDNF pathways as an approach for melanoma therapy. Aim 1 studies will determine the role of YTHDF1- mediated anoikis resistance in driving melanoma metastasis and the role of IMPDH1 and the de novo guanosine synthesis pathway in this process. Aim 2 studies will ascertain the role of YTHDF1-driven suppression of NK cell-mediated anti-tumor immunity in promoting melanoma metastasis. We will also determine the role of TrkB/BDNF pathway and its ability to inhibit the NKG2D activating ligand ULBP6 in suppressing NK-cell function downstream of YTHDF1. Aim 3 studies will evaluate the therapeutic efficacy of TrkB/BDNF and IMPDH1 inhibitors either alone or in conjunction with other US FDA-approved metastatic melanoma therapies. Aims 1-3 studies will utilize complementary cell culture models based on established melanoma cell lines, short-term patient-derived melanoma cultures and patient-derived xenografts (PDXs) of naïve and drug resistance metastatic melanoma. The in vivo models for the proposed studies will include syngeneic, genetically engineered mouse models of metastatic melanoma, spontaneous human melanoma metastasis model, and a highly innovative immunocompetent humanized NSG-Tg(Hu-IL15) mice. These mice develop human NK cells in addition to other immune cells after human hematopoietic stem cells transplant, which will allow us to perform studies in the context of human NK cells. Collectively, these studies will uncover a novel YTHDF1-driven melanoma metastasis pathway that can be targeted for treating naïve and drug-resistant metastatic melanoma.

NIH Research Projects · FY 2025 · 2024-12

Project Summary: Automated continuous vital signs bedside monitoring is used to detect the physiologic deterioration associated with a clinically meaningful event in high-income countries (HIC); yet, many low-and middle-income countries (LMIC) still rely on manual intermittent vital sign monitoring systems. As a result, the current usual care monitoring system often misses opportunities to detect clinically meaningful events in a timely manner, and results in high in-hospital complications and mortality rates. Consumer wearable devices (CWD) offer an outstanding opportunity to address these challenges and provide a wireless vital signs monitoring system. CWDs, e.g., Fitbit and Xiaomi band, provide vital signs data comparable to clinical grade bedside monitors in both children and adults for temperature, heart rate (HR), pulse oximetry (SPO2), and respiratory rate (RR). In this application, we propose to develop (R21 phase) and scale up (R33 phase) a CONsumer-grade wearable monitoring System to improve Outcomes in Low resource settings (CONSOL) in Ghana to enhance the triage of pediatric patients who present for trauma evaluation in the emergency department (ED), and to enhance the postoperative vital signs monitoring processes of children who undergo surgery for appendicitis by the clinical care team. CONSOL is a CWD-based platform that collects CWD data and displays them, in near-real time, on an IPad to clinicians in the hospital, and simultaneously on the smartphone to surgeons remotely, and shows HR, skin temperature, RR, and SPO2 trends transmitted to the monitoring clinicians in near-real time. We hypothesize that CONSOL data will correlate well with usual care vital signs data and will be equivalent to or better than usual care hospital monitoring in detecting physiologic deterioration associated with clinically meaningful events. Trauma and postoperative appendectomy children suffer physiologic deterioration associated with clinically meaningful events and are less communicative about their condition than adults, and thus would greatly benefit from continuous vital signs monitoring. The R21 specific aims are to: Aim 1: Replicate our previous methodology to validate CONSOL VS data in pediatric trauma and postoperative appendicitis patients to detect abnormal VSs indicative of clinically meaningful events at the Korle-Bu Teaching Hospital (KBTH) in Ghana; Aim 2: Prospectively deploy CONSOL in the ED and surgery unit at KBTH to provide near real-time vital sign information to clinical and nursing teams; and improve CONSOL usability by (1) conducting focus groups/interviews and observations to elucidate failures in detecting clinically meaningful events; and (2) modifying the clinician user interface. The R33 specific aims are to: Aim 3: Prepare for the implementation process by identifying moderators, mediators, and mechanisms of action of CONSOL in Ghana hospitals, and Aim 4: Implement the enhanced CONSOL in near real time at the 37 Military Hospital and Greater Accra Regional Hospital, and evaluate the effectiveness of CONSOL in capturing clinically meaningful events.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a severe and progressive neuromuscular disease that affects 1:5000 live male births, making it the most common form of muscular dystrophy. DMD is caused by the disruption of the DYSTROPHIN gene that results in the production of a non-functional or absent dystrophin protein. Lack of dystrophin in muscle results in myofiber death and fibrosis that can result in fatal cardiac arrhythmia and/or respiratory failure in end-stage DMD patients. Interestingly, many DMD patients report sleep disruption, nighttime sleep/wake disruptions, nocturnal blood pressure dipping, and other symptoms independent of diaphragm respiratory muscle weakness. These symptoms are strongly influenced by the circadian system, which suggests that DMD patients exhibit dysregulated circadian rhythmicity of which root molecular cause has not been directly identified. While the loss of dystrophin is the primary cause of DMD, it is evident that the circadian clock has the ability to influence many of the same muscle health parameters, such as muscle function and metabolism, and may represent a novel pathological factor influencing DMD patient outcomes. This proposal will investigate the contribution of circadian rhythm disruption to DMD disease pathology and the mechanism of action to induce disease-associated pathophysiologies through the use of a novel conditional dystrophin loss-of-function mouse model. This proposal will evaluate the contribution of Dystrophin expression in the skeletal muscle and suprachiasmatic nucleus (SCN)/brain towards the regulation of circadian rhythm, and define its role in muscular health and disease pathogenesis.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Targeted radiotherapeutics are an emerging class of highly effective treatments that leverage the potent therapeutic properties of radiation in a biologically focused manner to provide systemic killing of cells of interest with reduced non-target toxicity. These therapies have been utilized in cancer, inflammatory, degenerative and hyperproliferative diseases with great clinical efficacy. There are currently, however, two main limitations of targeted radiotherapeutics. The first is that the choice of targeting molecules is limited to a select number of peptides and small molecules. This is driven in large part by the second limitation, which is that a targeting molecule must have specific pharmacokinetic and pharmacodynamic properties that are not provided by traditional antibody targeting moieties. A targeted radiotherapeutic must combine high affinity and specificity for its target with rapid binding and blood clearance in order to minimize the radiation delivered to the bone marrow and clearance organs. A new class of antibodies, termed nanobodies, offers a combination of high affinity binding in a low molecular weight vector that endows rapid blood clearance by renal filtration. Nanobodies are growing in clinical use, however to date most have been derived from the immunization of dromedaries. Immunization- generated nanobodies have been demonstrated to have high retention in the kidneys, which is thought to be driven by a large number of positively charged amino acids in their framework that lead to endocytosis in the proximal tubules of kidneys. The inherent dependency of the tertiary structure of a nanobody on its primary sequence poses significant challenges to modifying the positively charged amino acids in existing nanobodies. Given these limitations, we have developed a novel nanobody framework that has greater than 90% reduction in kidney retention. This framework will serve as the basis of our proposal, in which we will test the hypothesis that reduced kidney retention can improve the therapeutic index of targeted radiotherapy. Additionally, we will explore whether previously isolated nanobodies from immunizations can have their complementarity determining regions engrafted into this framework. Nanobodies will also be designed to incorporate a sortase tag that allows for rapid and facile site-specific conjugation to bifunctional chelators for both imaging and therapeutic radionuclide incorporation. The radiolabeled nanobodies will be assessed in vitro for affinity, specificity and stability prior to in vivo PET imaging and radiotherapy studies. Overall, this proposal has the potential to generate a novel method for generating nanobodies with ideal pharmacokinetics for radiotherapy against virtually any target.

NIH Research Projects · FY 2026 · 2024-12

The study investigates the association between growth hormone deficiency and longevity in mouse models. We discovered that GHRH-KO mice with extended lifespans have different circulating lipid profiles, with ceramides being the most significantly altered lipid class. Ceramides have been implicated in several pathways related to aging, including insulin resistance, mitochondrial dysfunction, inflammation, apoptosis, and cellular senescence. The study aims to determine the role of ceramides in regulating healthspan and lifespan in mice, and to investigate the impact of genetic and pharmacological interventions that lower ceramide levels. The research approach involves integrating the understanding of GH action and ceramide signaling from the cellular and tissue levels to whole-animal outcomes. The results of this proposal will provide new insights into the differential mechanisms of action and offer the possibility of developing translational interventions. The proposed project is novel and has the potential to revolutionize our understanding of mammalian aging and longevity.

NIH Research Projects · FY 2026 · 2024-11

Project Summary: This proposal will answer two key questions. 1. Does IL-4 act through the aryl hydrocarbon receptor (AhR) pathway to inhibit the development of double negative 2 (DN2) B cells? 2. How does IL-4 induce endogenous ligands of AhR to suppress T-bet+ B cells? We recently showed that in SLE, down-regulation of IL- 4R and defective maintenance of resting naïve (rNAV) B cells were associated with increased development of Tbet+CD11c+ activated naïve (aNAV) B cells and DN2 B cells. Co-culture of SLE B cells with IL-4 promoted the maintenance of rNAV B cells and blocked both type I and type II interferon (IFN)-promoted development of aNAV and DN2 B cells. Single-cell transcriptomics of lupus mouse B cell stimulated in vivo with IL-4 revealed up- regulation of IL-4-induced1 (IL4i1). As an L-amino acid oxidase, IL4i1 can catalyze the synthesis of indole-pyruvic acid (IPyA) derivative endogenous AhR ligands leading to upregulation of AhR response genes. Metabolome analysis revealed that IL-4 induced AhR agonistic metabolites in B cells, including kynurenine (Kyn) and indole- 3 metabolites. In the absence of IL-4, AhR agonists 6-Formylindolo[3,2-b]carbazole (FICZ) and Kyn significantly suppressed IFNβ and TLR7-induced T-bet+CD11c+ IgD− B-cell development. We hypothesize that IL-4 activates AhR through a combined effect of IL4i1 and IDO1 to promote the formation of endogenous AhR ligands in B cells. In Aim 1, we will determine if AhR is required to inhibit T-bet+ B cell development in mice and what pathways and metabolites are involved. This will be tested using conditional AhR-deficient mice under chronic TLR7 stimulation conditions (Aim 1a). The pathway for the production of AhR ligands, including indole-3 metabolites and Kyn, will be determined using Il4i1−/− mice and Ido1−/− mice (Aim 1b). The ability of AhR agonistic metabolites to regulate T-bet+ B cell development in vivo will also be tested (Aim 1c). In Aim 2, we will use B cells derived from SLE patients to determine if AhR is required for IL-4 to suppress DN2 B cell development (Aim 2a). We will further determine if modulation of IL4I1, IDO1, and their downstream metabolites can alter the development of DN2 B cells (Aim 2b). Significance. A primary focus in SLE research has been studies of elevated pro-inflammatory factors that drive pathogenic autoimmune responses. We propose that therapies designed to promote long-term homeostasis in otherwise abnormally stimulated immune cells could be more efficacious and less toxic. Identifying small molecular metabolites that act directly in B cells to induce homeostasis may lead to the development of orally active druggable targets that are efficacious in treating SLE. Innovation. The proposed project is novel as B-cell endogenous metabolic ligands that can maintain B-cell homeostasis and suppress T-bet+ B-cell development are unknown. Team and Environment. Drs. Mountz, Rubio, and Hsu have a history of collaboration to study cytokine-mediated B cell single cell transcriptomics and pathogenesis in SLE. Dr. Barnes, Director of the UAB Targeted Metabolomics and Proteomics Laboratory (TMPL), will provide expertise in metabolomics analysis.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY The Streptococcus genus contains many human pathogens of medical significance. S. pneumoniae is one of the most important human respiratory pathogens worldwide, and the increased incidence of multidrug resistance in streptococci is a significant public health concern. Unfortunately, antibiotic discovery and development has slowed down in recent years, and there is an urgent need for novel antibiotics against streptococci and other pathogens. The eubacterial ribosome is an essential organelle, and a target for numerous antibiotics. The ribosome consists of three RNAs and 56 proteins. One of these proteins, L27, product of the rpmA gene, is a component of the ribosomal large subunit that does not have an equivalent in eukaryotes and archaea. In Firmicutes and related bacteria, L27 has an additional 9–12 amino acid N-terminal extension compared to their counterparts in Gram-negative bacteria like Escherichia coli. We previously described a novel cysteine protease, named Prp, that cleaves the N-terminal extension of L27, and showed that this cleavage step was essential for cell viability in Staphylococcus aureus. Here, we show that, in S. pneumoniae, L27 cleavage by Prp plays a role in ribosome activation. The overall objective of this exploratory/developmental project is to understand the roles of Prp and L27 cleavage in S. pneumoniae. Why do S. pneumoniae, S. aureus and related bacteria employ this additional Prp-mediated L27 cleavage step? Our hypothesis is that cleavage of L27 by Prp serves as a checkpoint required for full activation of the ribosome and may be associated with dormancy, persistence and survival under certain conditions. In this project, we will explore the role of Prp and L27 cleavage using a combination of genetics, functional assays, quantitative mass spectrometry and cryo- electron microscopy. Our specific aims are: Aim 1: Define the role of Prp and L27 cleavage in ribosome function; Aim 2: Examine the structural consequences of L27 cleavage. Our project addresses a gap in knowledge about streptococcal ribosomal structure, assembly and regulation and targets a hitherto undescribed step in ribosomal assembly—processing of ribosomal protein L27 by the Prp protease—that appears to be unique to Firmicutes and related bacteria. The role of L27 in translation is controversial and the role of Prp in ribosomal assembly and function is still unknown. A better understanding of these processes may lead to more effective therapeutics against S. pneumoniae and other Gram-positive pathogens that target these mechanisms.

NIH Research Projects · FY 2025 · 2024-10

PROJECT SUMMARY This application is for an NIDDK K23 award for Dr. Gabriela E. Halder, a Female Pelvic Medicine and Reconstructive Surgeon (FPMRS) at the University of Texas Medical Branch. Dr. Halder has shown promise as an early investigator in patient-centered research but needs further training to achieve her goal of becoming a leader in the use of Human Centered Design (HCD) and Dissemination and Implementation (D&I) methods to address disparities in access to treatments for urogynecologic conditions. This award will provide protected, mentored support to obtain the following career goals: 1] acquire proficiency in HCD methods to systematically design intervention procedures and materials; 2] obtain advanced skills in applying appropriate D&I frameworks, measures, design methods, and implementation strategies for behavioral interventions; 3] develop expertise in health systems research methods and outcome measures; 4] develop and strengthen research leadership, management, and grantsmanship skills. Her mentors for this K23 are Dr. Heidi Brown (Primary), an NIH NIDDK funded FPMRS and leader in D&I; Dr. Elizabeth Lyons (Co-mentor), an NIH funded expert in HCD; and Dr. Rebecca Rogers (Co-mentor), an NIH funded FPMRS and leader in patient-centered research. Dr. Halder also has 4 advisors with expertise in health systems research, clinical research, and academic leadership. Latinas suffer more perioperative complications that their non-Hispanic peers when undergoing urogynecologic surgery, in part, because of lower surgical preparedness. We previously developed Telehealth Intervention to Increase Patient Preparedness for Surgery (TIPPS) which is one of the few interventions proven to successfully increase surgical preparedness for patients undergoing urogynecologic surgery. Unfortunately, our intervention studied mostly White women, excluded non-English speakers, and was not cost-effective nor practical. Therefore, there is a gap in knowledge on culturally appropriate, language-sensitive, and sustainable interventions that increases Latina surgical preparedness for urogynecologic surgery. Dr. Halder’s proposed research will use HCD and D&I methods to center stakeholder input to develop TIPPS-Latina – a usable and sustainable intervention that considers the cultural and societal needs of Latina patients and their clinical environments, an approach not used thus far in development and testing of other surgical preparedness interventions. Aim 1 will identify factors associated with surgical preparedness using a participatory action research framework. Aim 2 will use the HCD framework of Discover, Design/Build to develop TIPPS-Latina. Aim 3 will pilot test TIPPS-Latina using a mixed methods approach that determines feasibility and implementation outcomes. The expected outcome of this mentored research is to provide a foundation for a larger randomized clinical trial that assess the effectiveness of the developed intervention and a successful transition to research independence for Dr. Halder.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Chronic exposure to psychostimulants leads to maladaptive long-lasting molecular and functional changes in the brain of vulnerable individuals that may contribute to susceptibility to Substance Use Disorder (SUD). Despite significant advances in understanding genetic and epigenetic factors that may underlie SUD, few effective treatment options exist. In order to advance our knowledge to therapeutic avenues, we need to overcome some of the existing technical and practical limitations of existing models, including the inability to characterize drug-induced changes nervous-system- wide with cellular resolution and the lack of in vivo high-throughput screening platforms for putative regulators and therapeutic compounds. The nematode Caenorhabditis elegans is a simple and well-characterized model organism that has led to many fundamental discoveries in conserved biological mechanisms. The genetic amenability and the compact nervous system allow us to conduct high-throughput screens and to analyze the entire nervous system with single neuron resolution, respectively. Combining advanced genetic, genomics, microscopy, and behavioral approaches, we will generate comprehensive molecular (transcriptome and chromatin landscape), behavioral, and neuronal activity atlases in response to acute vs. chronic exposure to cocaine. Leveraging these atlases, we will use high-throughput screening approaches in C. elegans to identify genetic regulators that underlie nervous-system-wide molecular and functional changes as a result of drug exposure. Finally, the genetic amenability of the C. elegans model allows us to causally examine the mechanistic roles of these regulators in drug-induced plasticity with unprecedented locus and cellular specificity. By establishing these approaches and platforms in the C. elegans model with cocaine, we can investigate other classes of drugs in the future, and open up new avenues for disease mechanism investigation and therapeutic identification for SUD.