Funding opportunities

Molecular regulation of stem cell potency

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07422
Principle Investigator: 
Funds requested: 
$966 510
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
The field of stem cell biology as it applies to regenerative medicine requires a detailed understanding of what controls stem cell function. Our fundamental interest is in the molecular pathways that control how potent as a stem is in terms of its ability to make new tissues in response to injury and disease. We have focused on a population of stem cells in skeletal muscle that are responsible for the healing of muscle after injury. These cells normally exist in a dormant state and it is in that state that they are most potent. However, when these cells are stimulated to divide, and especially when the cells are grown in the laboratory, they very quickly lose their potency, as they do gradually during aging. The main focus of our proposal is to understand what controls that potency and to determine if we might be able experimentally to enhance the potency of muscle stem cells. These findings will lead to a more fundamental understanding of stem cell biology and also have the potentially to enhance greatly our ability to use these cells for therapeutic purposes such as healing traumatic injuries, treating degenerative diseases such as muscular dystrophies, and slowing age-related muscle loss.
Statement of Benefit to California: 
A major benefit to California of our studies will be to bring hope to patients across the state with diseases and disorders of muscle for which there is no cure and limited treatment options. This would include veterans with traumatic limb injuries associated with substantial muscle loss and thousands of patients with muscular dystrophies. Due to the growing field of regenerative medicine from the investment of the citizens of California in CIRM, this state has become the world leader in the development of stem cell therapeutics. Our research would contribute substantially to this enterprise by increasing our understanding of the control of the potency of stem cells to repair muscle and by developing methods to enhance that potency. Our ongoing studies have revealed ways to increase the potency of muscle stem cells experimentally, and we will directly test these in studies of muscle repair. In addition, we will explore the processes that determine and control muscle stem cell potency, and we will test directly for the actions of specific genes that may be important determinants of stem cell potency. The successful completion of these studies would put California at the forefront of stem cell therapeutics for muscle loss and degenerative muscle diseases.
Review Summary: 
The objective of this proposal is to examine the molecular and functional properties of human muscle stem cells (MuSCs). The overall goals of this proposal are to assess stem cell potency using transplantation assays, and to characterize the transcriptional and epigenetic profiles and the regulatory mechanisms that determine that potency. In Aim 1, human MuSC populations of high (quiescent) and low (proliferating) potency will be compared using transplantation assays in vivo in mice. Aim 2 will correlate the potencies of these populations with transcriptional and epigenetic profiles. The effects of altering chromatin modifying enzymes on the potency of MuSC populations will also be investigated. These studies aim to explore a fundamental property of stem cell biology and thereby provide new knowledge to enhance stem cell potency for therapeutic applications. Significance and Innovation - The identification of factors that can modulate the ability of a stem cell population to turn into a given cell type would be a significant contribution to the field. -The use of an AV-GFP virus to follow the fate of treated cells in the mouse in vivo system is innovative. - A similar series of studies as those proposed have already been done previously by the PI using mouse cells, so the novelty is lacking Feasibility and Experimental Design -Preliminary data is presented to support the technical feasibility of most of the proposed experimental plans and support the hypotheses. -The PI proposes to use novel mechanisms to expand MuSC in vitro, which is difficult otherwise. -In Aim 1, MuSC will be treated in vitro to develop high or low potency. Their effect on muscle formation will be examined in vivo after transplantation in mice. The reviewers were concerned that the effect of p38 inhibitor on MuSC potency was not clearly demonstrated. -In Aim 2, the transcriptional and epigenetic profiles of MuSCs under different culture conditions will be compared to quiescent cells. The reviewers expressed concerns that targets identified using mouse cells should be screened in human cells before additional profiling of human cells, such as in the approach used for Aim 2b. - Detailed description of the bioinformatics approach and interpretation of results, especially for Aim 2, are missing. -Principal Investigator (PI) and Research Team - The expertise and track record of the PI were regarded a major strength of the application. - The required collaborations to obtain human MuSC are in place. Responsiveness to the RFA - The application is very responsive to aspect 1 of RFA: 1) understanding basic cellular or molecular mechanisms pertinent to human stem cells (or reprogrammed cells) and their related biology.
Conflicts: 

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