University Of Nebraska Medical Center

NIH Research Projects · FY 2025 · 2006-06

Abstract: Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular-mass metabolites between adjacent cells. They provide a pathway for propagating and/or amplifying the signal transduction cascades triggered by cytokines, growth factors, and other cell signaling molecules involved in growth regulation and development. Dysfunctional intercellular communication via gap junctions has been implicated in causing many human diseases. The objective of this project is to use a multi-disciplinary approach to identify the key intrinsic regulatory mechanisms that are responsible for Cx43 and Cx45 function. The central hypothesis is that unique intermolecular interactions within the divergent CT domain of connexins affect gap junction regulation. More specifically, we hypothesize that after myocardial infarction, differential regulation of Cx43 and Cx45 involves specific phosphorylations and protein interactions of their CT domain. The significance of this proposal is that discovery of how interactions mediated by the CT domain can be modulated would open the door to strategies to ameliorate pathological effects of altered connexin regulation in the failing heart. The following Specific Aims are proposed to investigate this concept: 1) What drives Cx43 away from gap junctions/intercalated discs in vitro and in a murine model of myocardial infarction? and 2) What promotes Cx45 gap junction/intercalated disc localization and is Cx45 expression in left ventricle hypertrophy after myocardial infarction an arrhythmogenic substrate? Upon completion of this project, we expect to describe novel mechanisms by which phosphorylation and protein partners regulate Cx43 and Cx45 function and strategies by which the pathological effects of Pyk2, Src, and Cx45 upregulation in failing hearts may be lessened.

NIH Research Projects · FY 2025 · 2001-09

Overall Component Project Summary The mission of the Nebraska IDeA Networks of Biomedical Research Excellence (NE-INBRE) is to stimulate and develop biomedical research capacity at institutions of higher education in Nebraska. The NE-INBRE is structured around two major components: primarily undergraduate institutions (PUIs) and PhD granting research institutions (RIs). Support for each PUI consists of: 1) campus research capacity development through support for faculty research and infrastructure enhancement, and 2) development of the undergraduate research pipeline of students through the NE-INBRE Scholars program. Expanding research capacity at the RIs includes providing significant support to multiuser core facilities in order to allow investigators from PUIs and RIs access to cutting- edge technology. The nine participating PUIs in the NE-INBRE research network include two publically supported State Colleges, three campuses of the University of Nebraska system, and four private institutions. The three participating RIs in the research network include two campuses of the University of Nebraska system and one privately supported medical center (Creighton University). Cutting-edge multiuser core facilities include cores in genomics, data science, and advanced microscopy. The three themes reflect the scientific foci of the NE-INBRE, infectious diseases, cancer biology, and cell signalling. These themes serve to link faculty and students at the separate institutions into productive networks based on their areas of expertise and interest. Throughout the tenure of the NE-INBRE, its primary objective at the undergraduate level has been to provide and expand research opportunities for students and create a pipeline of students to enter into biomedical research and other health professions. NE-INBRE investments in faculty research projects and infrastructure at the PUIs have created opportunities for both NE-INBRE Scholars and other undergraduate students to become involved in advanced biomedical research.

NIH Research Projects · FY 2025 · 1997-09

Project Summary This application is being submitted in response to the Administrative Supplements on Long-term Cancer Survivorship. Our proposed project aims to identify and re-engage adult survivors of childhood cancer who have transitioned from pediatric survivorship care to primary care but are no longer connected to structured survivorship follow-up. The project leverages and builds on institutional data revealing that over 59% of transitioned survivors are lost to follow-up at Nebraska Medicine and the Fred & Pamela Buffett Cancer Center (BCC).The project will use a mixed-methods approach, integrating retrospective EHR data, structured surveys, and qualitative interviews to understand disengagement patterns, evaluate adherence to Children’s Oncology Group (COG) Long-Term Follow-Up (LTFU) guidelines, and explore survivor-identified barriers and facilitators to care. A comparison group of engaged survivors within the adult survivorship clinic will be used to analyze predictors of continued care adherence. This supplement extends the BCC’s mission to promote innovative translational cancer research, excellence in cancer education and training, and outstanding patient-centered cancer care, and to reduce the burden of cancer and cancer health disparities across Nebraska and beyond. Aim 1: Identify and characterize adult survivors of childhood cancer at BCC who were transitioned to primary care and are no longer engaged in survivorship care, using electronic health record (EHR) data. We will use electronic health records (EHR) to identify two groups: (a) survivors who transitioned from pediatric to adult survivorship care and are currently followed in the adult survivorship clinic (control group, n ≈ 60), and (b) survivors who transitioned from pediatric care but are not currently followed in the adult survivorship clinic (experimental group, n ≈ 90). We will compare demographic, clinical, and geographic characteristics, with particular attention to rural and underserved populations. Aim 2: Assess adherence to COG LTFU screening guidelines and unmet needs among disengaged survivors compared to those retained in adult survivorship care. We will administer structured surveys and conduct chart audits to evaluate screening adherence, unmet psychosocial needs, and care navigation gaps for survivors in both groups. Analyses will focus on differences in adherence to recommended surveillance and prevalence of unmet health and psychosocial needs. Aim 3: Explore barriers/facilitators to long-term survivorship care not currently followed in the adult survivorship clinic. Qualitative interviews will be conducted with a purposive sample of survivors from the experimental group (expected n = 20) to identify key barriers to ongoing engagement in survivorship care to inform future re-engagement efforts. Findings will inform the design of future re-engagement strategies.

NIH Research Projects · FY 2025 · 1997-08

This application seeks continued support for a predoctoral Cancer Biology Training Program (CBTP) sponsored by the Eppley Institute, an academic unit of the University of Nebraska Medical Center (UNMC), with a sole focus on basic, translational and clinical cancer research. The Eppley Institute is a major component of the NCI- designated Fred & Pamela Buffett Cancer Center (FPBCC), which serves a large section of the West North Central Region, or “Heartland”, of the United States. Thus, the Eppley Institute and the CBTP play an important regional role in training future basic and clinical scientists for a career in cancer research. The continued success of the CBTP over the past four years reflects further expansion of the Cancer Center, with new leadership, an increase in state-of-the-art research space, a growing faculty, and a robust research base. Institutional commitment to the Program remains strong. The opening of an integrated cancer research and clinical facility (the FPBCC complex) in 2017 continues to challenge trainees to consider how their research may be translated into improvements in the diagnosis and treatment of cancer on a daily basis. This NCI T32 has been a major catalyst for state-of-the-art training in cancer research at UNMC, which attracts a large national pool of training grant- eligible predoctoral trainees each year. Thirty-three CBTP mentors have a wide variety of wxpertise in basic, translational and clinical cancer research and a strong track record of mentoring. Translational research by CBTP faculty in biomarker discovery and therapeutic development for pancreatic/gastrointestinal cancer is internationally recognized, and Rapid Autopsy/Organ Harvest Programs provide a unique collection of specimens for studies on pancreatic and prostate cancer. Research strength in hematological malignancies and hormone-driven cancers is also available to trainees. During the reporting period, a new administrative structure was introduced and major new initiatives were designed to keep pace with modern developments, enhance the distinctiveness of NRSA-supported training, and respond to feedback from trainees and advisory boards. The curriculum has been enhanced by the addition of training in Variability in Cancer Outcomes and Cancer Prevention, as well as T32-specific Hands-on Techniques Workshops in Mass Spectrometry & Proteomics and Spatial Transcriptomics. A trainee-organized annual mini-symposium will continue to provide opportunities for leadership. The success of the CBTP is reflected in the strong publication record of our trainees, low attrition rates (<6%), an improved time to graduation of 4.8 years, an increase in F awards and similar fellowships, and strong outcomes (with 96% of trainees continuing in research or related careers). Students who complete the CBTP have the life-long skills to contribute to the management of cancer in a meaningful way. Continued NRSA support is crucial to sustaining the advances in Program metrics, enabling further enrichment of the training experience, and ensuring the quality and diversity of CBTP trainees.

NIH Research Projects · FY 2026 · 1995-04

Abstract This competitive renewal for 5 R01 NS034239 now in its 27th year provides a research plan reflecting the National Institutes of Health strategic plan for HIV and HIV-related research. The plan lists neurologic complications as a primary study need. The current study seeks to investigate the interplay between aging, HIV-1 infection, and neurodegenerative diseases. The preliminary data now offered targets a significant need in biomedical research for neuroHIV. That need is the discovery and characterization of a viable animal models that would mimic the neuropathobiology of HIV-1 infection in the setting of Alzheimer’s disease (AD). It was previously not possible to study a dynamic interplay between viral infection of CD4+ T cell subsets, immunity, antiretroviral therapy (ART), and AD. We solved that problem as during the last grant cycle we created the needed model. Herein, we provide extensive data of its utility, have outlined viable experimental approaches, and affirm its significance to provide significant new insights into better understanding disease mechanisms and potential therapeutics that can be realized during the 28th to the 33rd year of the project. The proposed work rests on a sound research foundation by building on fundamental research findings made during the prior granting cycle. During that time we showed that amyloid β (Aβ)-specific helper T cell type-1 (Th1) and -17 (Th17) effector T cell (Teff) clones propel neurotoxic innate neuroinflammatory responses, proteinopathy, and neuronal dysfunction that were associated with cognitive impairment in amyloid precursor protein transgenic mice. Moreover, through parallel studies, we demonstrated that regulatory T cells (Treg) attenuate neuroinflammation and AD neuropathology, then restore cognitive function. With our novel AD humanized mice in hand, we now show that during HIV-1 infection we not simply see increases in neuroinflammation but that viral immune response can facilitates proteinopathy. We are now able to conduct studies of HIV-1 compartmentalization, virus-amyloid adaptive and innate immunity alterations, and consequences of immune-pathogenic and regulatory events. These can serve both to accelerate or ameliorate AD processes. The aims of the proposal will be to fully characterize the model at the cell, immune, tissue, and disease level by studies of innate macrophage-microglia and adaptive CD4+ Teffs pro-inflammatory factors known to affect the brain’s microenvironment. The second component will assess immune transformation by a spectrum of therapeutic agents that include antiretroviral therapy. We will now directly interrogate how T cell immunity drives the tempo of both HIV/AIDS in the setting of neurodegenerative disease. Finally, Tregs that are engineered to recognize Aβ by a transgenic T cell receptor (TCR) or a chimeric antigen receptor (CAR), will be employed as “future” therapeutic strategies to restore brain homeostasis, reduce plaque burden, and affect neuroprotective outcomes. Overall, we are, now in a position to investigate chronic HIV-1 infection in the setting of progressive AD and can study its relationship to immunity and ART with this new small animal models in hand.