The Administrative Core will coordinate the activities of the three Projects and three Cores of this Program Project. The Specific Aims of the Administrative Core are: 1) to provide administrative assistance and fiscal oversight to all Projects and Cores B and C; 2) to facilitate communication both within the Program and between the Program members and other investigators, centers, programs and institutions; and 3) to establish and maintain an Executive Committee, an external Scientific Advisory Committee, and an Internal Advisory Committee. The services offered by the Core will include administrative and secretarial support (ordering of supplies, financial reports, assistance with budget management), organization of regular meetings and of the annual meeting with the Scientific Advisory Committee, and preparation of progress reports and other documents. The Director will oversee and coordinate all activities of the Core. He will meet regularly with the Administrator and with other Project Leaders/Core Directors to discuss administrative and managerial issues to insure that the Program is working effectively and efficiently. The Administrator and the Administrative Assistant will assist the investigators with financial matters, the organization of meetings and conferences, and general needs for the proper functioning of the Program.
The studies outlined in this proposal address fundamental issues of the biology of aging, specifically focused on the molecular characteristics, mechanisms and consequences of stem cell aging. Based on mutual interests and complementary areas of expertise, the three laboratories of this Program form a cohesive, collaborative team to address these basic questions. With expertise in stem cells in skeletal muscle (Rando laboratory, Project 1), epithelial stem cells (Artandi laboratory. Project 2), and neural stem cells (Brunet laboratory. Project 3), the Program has the following Specific Aims: 1) to understand the underlying molecular mechanisms that regulate stem cell function and that are responsible for declining stem cell function with age; 2) to characterize the transcriptional networks and epigenetic profiles in stem cells from different tissues; and 3) elucidate the age-related changes that are common among different stem cell populations and changes that are unique to stem cells in particular tissues. These Overall Aims are reflected in the Specific Aims of each Project, with emphases on the role of signaling pathways that regulate stem cell function. The major pathways to be explored in multiple Projects are the Wnt signaling pathway which has recently been shown to contribute to tissue aging by suppression of stem cell functionality, Telomerase and novel functions of the protein component (TERT) in regulating stem cell function and regulating Wnt signaling, and the Foxo transcription factors which regulate organismal aging. All of these will be examined in all three of the Projects, exploring mechanisms of co-regulation of genes that regulate stem cell function, and focusing on the causes and consequences of changes in transcriptional programs that determine age related changes in stem cell functionality. Of particular interest is the identification of mechanisms of stem cell aging that are shared among different stem cell populations. Within that context, all Projects will examine transcriptional networks and regulatory mechanisms, including epigenetic processes, that govern stem cell function and that drive changes with age. These broad goals will be supported by an Administrative Core and two Scientific Cores - a Mouse Aging Core and a Genomics and Ultra-High-Throughput Sequencing Core. The collaborative and coordinated efforts of the three laboratories participating in this Program are uniquely situated within the outstanding research environment of Stanford University to work at the interface between stem cell biology and the biology of aging to create a highly effective and synergistic research program focused on the molecular mechanisms of stem cell aging.
With age, there is gradual decline in muscle regenerative potential, resulting in incomplete regeneration and fibrosis. Studies from our laboratory have shown that the age-dependent decline in regenerative potential is due to a loss of functionality of the resident muscle stem cells known as "satellite cells" (SCs). The major goals of the studies of this proposal are to explore molecular pathways implicated in aging of SCs and to understand the mechanisms underiying the age-related decline in SC functionality. Our published and ongoing studies have focused on the role of Wnt signaling in the age-related suppression of SC function, at least in part by inducing a conversion of myogenic stem cells to a fibrogenic lineage. As such, the Specific Aims of this proposal are: 1) to analyze the mechanisms by which Wnt signaling and transcriptional readouts lead to age-related suppression of SC functionality; 2) to analyze how regulators of the Wnt pathway account for specific transcriptional responses and changes with age; and 3) to study the epigenetic profiles and determinants of young and old SC function. We will examine transcriptional programs and regulators in adult and aged SCs, testing for changes in cellular responses with age. A recent area of interest is the role of the co-activator of the Wnt pathway, BCL9, in SC aging and in determining the transcriptional response to Wnt by acting as a "histone decoder". Therefore, a major focus of these studies will be the characterization and regulation of the epigenetic status of adult and aged SCs and the regulation of both the Wnt pathway and the epigenetic state of aged SCs by BCL9. Using ultra-high-throughput sequencing, we will examine transcription factor targets in the Wnt/p-catenin pathway, interactions between this pathway and signaling via TERT (in collaboration with Project 2) and Foxo3 (in collaboration with Project 3), and global epigenetic profiles of adult and aged SCs. We will directly examine SC aging in cohorts of mice in which BCL9 is genetically deleted in the SC compartment. These studies will form the basis of a comprehensive analysis of the molecular basis of age-related functional changes of a stem cell population and how those changes both contribute to and are regulated by aging of the tissue and organism. RELEVANCE (See instructions): This Project will investigate basic mechanisms of aging of stem cells in skeletal muscle, a process which renders them less able to participate in muscle maintenance and repair after injury. Our research focuses on biochemical pathways that we believe can be modulated to enhance the functional properties of aged muscle stem cells, thereby reducing muscle atrophy and improving muscle repair after injury or disuse.
