Abstract

Mammalian aging is associated with functional defects in numerous tissues that require replenishment of lost or damaged cells during life. Many observations in the literature provide evidence that stem cells and progenitor cells are altered with advancing age. However, the specific gene pathways that govern stem cell aging and the precise changes that occur in tissue progenitor cells during aging remain to be defined. We will use genetically engineered mice to study specific gene pathways implicated in stem cell aging. These include the Wnt pathway (Projects 1, 2 and 3), the telomerase pathway (Project 2) and the Insulin/Foxo pathway (Project 3). We will investigate stem cell function in several tissues with well defined stem cell populations, including muscle stem cells (Project 1), skin and intestinal stem cells (Project 2) and neural stem cells (Project 3). The Core will support the state-of-the-art mouse genetic approaches which focus on sophisticated loss-of-function studies in vivo using Cre-lox technologies.
The Aims of the Core are:
Specific Aim 1. To generate all the genetically engineered mouse cohorts and controls for analysis of stem cell biology and aging for sharing among the three laboratories of the Program Project.
Specific Aim 2. To provide histology services to support each project including tissue harvesting, fixation and tissue section preparation for analysis among the three laboratories of the Program Project.
Specific Aim 3. To procure and house wild-type mice from the NIA's Aging Mouse Colony for analysis of aging wild-type mice by the three laboratories of the Program Project.

Public Health Relevance

Emerging evidence indicates that altered stem cell function can contribute to human aging. However, the precise changes that occur in stem cells with advancing age and the pathways that govern these changes remain obscure. Investigating the function of three pathways - Wnts, telomerase and Foxo3 - in stem cell biology and aging will greatly enhance our ability to intervene in the aging process..

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG036695-03
Application #
8495854
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$227,618
Indirect Cost
$79,862

  Institution

Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305

  Publications

Nakayama, Karina H; Alcazar, Cynthia; Yang, Guang et al. (2018) Rehabilitative exercise and spatially patterned nanofibrillar scaffolds enhance vascularization and innervation following volumetric muscle loss. NPJ Regen Med 3:16
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
Jeong, Mira; Park, Hyun Jung; Celik, Hamza et al. (2018) Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo. Cell Rep 23:1-10
Quarta, Marco; Cromie Lear, Melinda J; Blonigan, Justin et al. (2018) Biomechanics show stem cell necessity for effective treatment of volumetric muscle loss using bioengineered constructs. NPJ Regen Med 3:18
Tabula Muris Consortium; Overall coordination; Logistical coordination et al. (2018) Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562:367-372
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
Wosczyna, Michael N; Rando, Thomas A (2018) A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration. Dev Cell 46:135-143
Dulken, Ben W; Brunet, Anne (2018) Same path, different beginnings. Nat Neurosci 21:159-160
Leeman, Dena S; Hebestreit, Katja; Ruetz, Tyson et al. (2018) Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359:1277-1283
Judson, Robert N; Quarta, Marco; Oudhoff, Menno J et al. (2018) Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential. Cell Stem Cell 22:177-190.e7

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