Non-random template DNA strand segregation in muscle progenitor cells

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DESCRIPTION (provided by applicant): This proposal describes a six-year training program in basic biomedical research and clinical medicine that will culminate in the applicant's receipt of M.D. and Ph.D. degrees from Stanford University School of Medicine. The applicant has previously completed multidisciplinary studies while earning a bachelor's degree in biochemistry and will now receive extensive training in developmental and cellular biology. This training program will allow the applicant to gain expertise in the realm of stem cell biology with a focus on the mechanisms of age-associated impairment of stem cell function. Thomas A. Rando, M.D., Ph.D., will mentor the applicant's research training. Dr. Rando is a renowned leader in the fields of stem cell and aging biology. He is Professor of Neurology and Neurological Sciences, Chief of the Neurology Service and Director of the Geriatric Research, Education, and Clinical Center at the Palo Alto Veterans Affairs Hospital, and Deputy Director of the Stanford Center on Longevity. In addition, an advisory committee comprised of faculty from the Department of Developmental Biology at Stanford University School of Medicine will provide scientific and professional guidance. The proposed research will focus on asymmetric cell division in muscle stem cells. Recent work has confirmed that asymmetric stem cell division involves non-random template DNA strand and centrosome segregation to one of two daughter cells. The proposed experiments will examine the mechanisms underlying such asymmetries. The specific aims include: 1) establishing a mechansim of non-random template strand segregation based on non-random centrosome segregation, 2) investigating the role of the mitotic kinase Aurora-A at the centrosome in establishing cellular asymmetry, and 3) studying the relevance of asymmetric template strand segregation to the decline of stem cell function with age. The studies proposed to achieve these aims primarily involve the isolation and molecular manipulation of skeletal muscle stem cells derived from mice. Public Health Relevance: Asymmetric cell division is a fundamental process that is ultimately responsible for the development, maintenance, and regeneration of various tissues. The proposed studies will examine the molecular mechanisms that control the growth of cells that both give rise to mature muscle and have been directly implicated in age-associated muscle atrophy and fibrosis. An enhanced understanding of these mechanisms will provide insight into the molecular and cellular basis of aging and will identify and explore novel therapeutic strategies for ameliorating age-related tissue dysfunction and disease.