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 i nclude: 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.
| Liu, Ling; Charville, Gregory W; Cheung, Tom H et al. (2018) Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells. Cell Stem Cell 23:544-556.e4 |
| Paulk, Nicole K; Pekrun, Katja; Charville, Gregory W et al. (2018) Bioengineered Viral Platform for Intramuscular Passive Vaccine Delivery to Human Skeletal Muscle. Mol Ther Methods Clin Dev 10:144-155 |
| Charville, Gregory W; Cheung, Tom H; Yoo, Bryan et al. (2015) Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells. Stem Cell Reports 5:621-32 |
| Rodgers, Joseph T; King, Katherine Y; Brett, Jamie O et al. (2014) mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature 510:393-6 |
| Charville, Gregory W; Rando, Thomas A (2013) A sexy spin on nonrandom chromosome segregation. Cell Stem Cell 12:641-3 |
| Charville, Gregory W; Rando, Thomas A (2013) The mortal strand hypothesis: non-random chromosome inheritance and the biased segregation of damaged DNA. Semin Cell Dev Biol 24:653-60 |
| Liu, Ling; Cheung, Tom H; Charville, Gregory W et al. (2013) Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep 4:189-204 |
| Cheung, Tom H; Quach, Navaline L; Charville, Gregory W et al. (2012) Maintenance of muscle stem-cell quiescence by microRNA-489. Nature 482:524-8 |
| Charville, Gregory W; Rando, Thomas A (2011) Stem cell ageing and non-random chromosome segregation. Philos Trans R Soc Lond B Biol Sci 366:85-93 |
