Muscle precursor cells (MFC) are tissue specific stem cells critical for muscle growth and regeneration. MPC are normally quiescent but in response to a growth stimulus are activated to proliferate and undergo differentiation/fusion. A portion of MPC must remain undifferentiated such that the MPC pool is restored and available to meet future growth requirements. The mechanisms that regulate MPC self-renewal vs. differentiation have been little studied. Stem cell antigen-1 (Sca-1, Ly-6A/E) is a member of the Ly-6 family of proteins that have been extensively studied in immune cells. The function of Sca-1 is largely unknown, but functions as diverse as cell signaling, cell adhesion and regulation of stem cell self-renewal have been proposed in immune cells. Based on our preliminary data, we postulate that Sca-1 plays a role in regulating the MPC pool during periods of growth. We show that Sca-lpos cells represent a pool of MPC that replicate slower and do not differentiate. We hypothesize that Sca-1 expression serves as a protective mechanism to maintain an adequate pool of MPC in muscle tissue after MPC activation. A set of 4 aims are proposed to analyze Sca-1 function in vitro (Aim 1) and in vivo (Aim 2) , regulation of its expression by cytokines and NFAT dependent signaling (Aim 3) and cloning of its ligand (Aim 4). A combination of cellular and molecular approaches will be utilized. Our proposed studies will define a novel pathway in muscle for regulating tissue specific stem cells. Studies of Sca-1 may lead to new strategies for manipulating myogenic stem cells in disease, repair and aging and define novel therapeutic targets for enhancing muscle growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR051372-02
Application #
7068550
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$295,821
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hall, Monica N; Griffin, Christine A; Simionescu, Adriana et al. (2011) Distinct roles for classical nuclear import receptors in the growth of multinucleated muscle cells. Dev Biol 357:248-58
Long, Kimberly K; Pavlath, Grace K; Montano, Monty (2011) Sca-1 influences the innate immune response during skeletal muscle regeneration. Am J Physiol Cell Physiol 300:C287-94
Simionescu, Adriana; Pavlath, Grace K (2011) Molecular mechanisms of myoblast fusion across species. Adv Exp Med Biol 713:113-35
Apponi, Luciano H; Corbett, Anita H; Pavlath, Grace K (2011) RNA-binding proteins and gene regulation in myogenesis. Trends Pharmacol Sci 32:652-8
Long, Kimberly K; Montano, Monty; Pavlath, Grace K (2011) Sca-1 is negatively regulated by TGF-beta1 in myogenic cells. FASEB J 25:1156-65
Hall, Monica N; Corbett, Anita H; Pavlath, Grace K (2011) Regulation of nucleocytoplasmic transport in skeletal muscle. Curr Top Dev Biol 96:273-302
Pavlath, Grace K (2010) A new function for odorant receptors: MOR23 is necessary for normal tissue repair in skeletal muscle. Cell Adh Migr 4:502-6
Griffin, Christine A; Apponi, Luciano H; Long, Kimberly K et al. (2010) Chemokine expression and control of muscle cell migration during myogenesis. J Cell Sci 123:3052-60
Pavlath, Grace K (2010) Spatial and functional restriction of regulatory molecules during mammalian myoblast fusion. Exp Cell Res 316:3067-72
Griffin, Christine A; Kafadar, Kimberly A; Pavlath, Grace K (2009) MOR23 promotes muscle regeneration and regulates cell adhesion and migration. Dev Cell 17:649-61

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