Non-random template DNA strand segregation in muscle progenitor cells

描述(由申请人提供)：本提案描述了一项为期六年的基础生物医学研究和临床医学培训计划，最终申请者将获得斯坦福大学医学院的医学博士学位。申请者以前在获得生物化学学士学位的同时完成了多学科研究，现在将接受发育和细胞生物学方面的广泛培训。该培训计划将使申请者获得干细胞生物学领域的专业知识，重点是与年龄相关的干细胞功能损害的机制。托马斯·兰多，医学博士，博士将指导申请人的研究培训。兰多博士是干细胞和衰老生物学领域的知名领导者。他是神经学和神经科学教授，帕洛阿尔托退伍军人事务医院神经科主任兼老年研究、教育和临床中心主任，斯坦福长寿中心副主任。此外，一个由斯坦福大学医学院发育生物学系教职员工组成的咨询委员会将提供科学和专业指导。这项拟议的研究将集中在肌肉干细胞的不对称细胞分裂上。最近的研究证实，不对称干细胞分裂涉及非随机模板DNA链和中心体分离到两个子细胞中的一个。拟议中的实验将检验这种不对称性背后的机制。具体目标包括：1)建立基于非随机中心体分离的非随机模板链分离机制；2)研究中心体有丝分裂激酶Aurora-A在建立细胞不对称性中的作用；3)研究不对称模板链分离与干细胞功能随年龄下降的相关性。为实现这些目标而提出的研究主要涉及从小鼠来源的骨骼肌干细胞的分离和分子操作。公共卫生相关性：不对称细胞分裂是最终负责各种组织的发展、维持和再生的基本过程。这项拟议的研究将研究控制细胞生长的分子机制，这些细胞既能形成成熟的肌肉，又直接与年龄相关的肌肉萎缩和纤维化有关。对这些机制的深入了解将有助于深入了解衰老的分子和细胞基础，并将确定和探索改善与年龄相关的组织功能障碍和疾病的新的治疗策略。

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.