Brent T. Harris, MD, PhD - US grants

The ability to move our arms and legs depends on the integrity of our upper and lower motor neurons, which relay electrical signals from our brain to our muscles. When motor neurons die, as occurs after injury or in a variety of degenerative diseases that affect primarily infants and children (spinal muscular atrophies) or adults (amyotrophic lateral sclerosis (ALS)), irreversible paralysis ensues. In order to develop better ways to treat these clinical conditions, I propose to investigate the signaling mechanisms that normally promote motor neuron survival and how these pathways may go awry in disease. The Barres lab has developed methods to purify and culture defined types of CNS neurons including spinal motor neurons (SMNs). Using these methods, they recently discovered that elevation of cAMP alone is sufficient to strongly promote the survival of SMNs, even in the absence of peptide trophic factors. I will investigate the signaling pathways that enable cAMP to promote survival, specifically focusing on the hypothesis that the newly described B-raf signaling pathway is involved. Second, I will test the hypothesis that spinal motor neurons survive after axotomy because their cAMP levels become elevated, allowing them to survive in the absence of their usual peptide trophic inputs from muscle and Schwann cells. I will also study whether elevation of cAMP levels will prevent SMNs from dying in a transgenic mouse model of ALS. Lastly, I will devise a novel technique utilizing adenoviral vectors and immunopanning to purify and culture upper motor neurons in order to investigate the signals that promote their survival in vitro. By defining the signaling mechanisms involved in upper and lower motor neuron survival in culture and in animal models my goal is to develop new strategies to treat patients with spinal cord injuries and motor neuron diseases.

ABSTRACT The Histopathology & Tissue Shared Resource (HTSR) is the Georgetown Lombardi Comprehensive Cancer Center (LCCC) resource for accessing human tissue for translational research and provides comprehensive, high-quality laboratory and interpretive pathology services. The HTSR collects and distributes fresh, frozen and formalin-fixed, paraffin-embedded tissues (10,773 patients consented to date) and supplies technical and pathology support for investigator-driven collection protocols, including the novel conditionally reprogrammed cells (CRCs) and zevatar projects. HTSR Codirector Brent Harris, MD, PhD, oversees the delivery of HTSR?s comprehensive pathology services related to human and animal tissues. Under the day-to-day management of Codirector Deborah Berry, PhD, the laboratory provides human tissue and liquid biospecimens for translational research projects and comprehensive histology services, including tissue processing, paraffin and frozen section microtomy, staining, immunohistochemistry (IHC), immunofluorescence, laser-capture microdissection and tissue microarray (TMA) construction, staining and interpretative analysis. The HTSR also offers expert bioinformatics technical support, pathology database search capabilities, consultation services and educational support and training for users. In response to user surveys, investigator feedback and Advisory Committee recommendations since the last review, the HTSR has expanded its services to include quantitative automated brightfield and immunofluorescence image analysis, immunophenotyping, microRNA (miRNA) in situ staining and TMA construction. The HTSR works cooperatively with the Genomics & Epigenomics Shared Resource (GESR) and the Proteomics & Metabolomics Shared Resource (PMSR) to prepare human and animal model tissues for downstream genomic, proteomic and metabolomic analysis. The HTSR works cooperatively with the Biostatistics & Bioinformatics Shared Resource (BBSR) to document clinical information and patient outcomes comprehensively for samples distributed from the HTSR, including specimens collected by the Survey, Recruitment & Biospecimen Collection Shared Resource (SRBSR) and Indivumed GmbH. Forty peer review? funded LCCC investigators representing all four LCCC Research Programs (Breast Cancer [BC], Cancer Prevention and Control [CPC], Experimental Therapeutics [ET], and Molecular Oncology [MO]) used the HTSR in 2017. The impact of the HTSR is demonstrated by the 70 peer-reviewed publications that have used HTSR resources in the current funding period.