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.

Public Health Relevance

This Program Project Grant application will investigate basic mechanisms of aging of tissues, focusing on the stem cells in those tissues. This research holds promise for discovering mechanisms to help aged tissues heal more effectively by enhancing the ability of the stem cells to participate in tissue repair and regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG036695-03
Application #
8495840
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (03))
Program Officer
Kohanski, Ronald A
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$1,552,880
Indirect Cost
$479,174
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Rando, Thomas A (2017) Fleeting factors, turning back time. Nat Biotechnol 35:218-220
van Velthoven, Cindy T J; de Morree, Antoine; Egner, Ingrid M et al. (2017) Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo. Cell Rep 21:1994-2004
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Quarta, Marco; Cromie, Melinda; Chacon, Robert et al. (2017) Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss. Nat Commun 8:15613
Brunet, Anne; Rando, Thomas A (2017) Interaction between epigenetic and metabolism in aging stem cells. Curr Opin Cell Biol 45:1-7
Luo, Dan; de Morree, Antoine; Boutet, Stephane et al. (2017) Deltex2 represses MyoD expression and inhibits myogenic differentiation by acting as a negative regulator of Jmjd1c. Proc Natl Acad Sci U S A 114:E3071-E3080
Du, Hongqing; Shih, Chung-Hsuan; Wosczyna, Michael N et al. (2017) Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nat Commun 8:669

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