Funding opportunities

Regulation of Adult Stem Cell Proliferation by RAS and Cell-Permeable Proteins

Funding Type: 
New Faculty II
Grant Number: 
RN2-00908
Principle Investigator: 
Funds requested: 
$3 056 649
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Our research focuses on developing new tools and models for the next generation of doctors and scientists in all specialties of regenerative medicine. The major obstacles in regenerative medicine are the limited number of pre-existing stem cells and the inability to regulate their proliferation. Our aim is to identify the mechanisms that regulate adult stem cell proliferation. We propose to use this knowledge to produce cell-permeable proteins to reactivate proliferation in these dormant stem cells. These engineered proteins could be used to stimulate regeneration in a variety of organs without the use of genetic vectors. As a model to study adult stem cell quiescence and activation, we study the hair follicle. The hair follicle is an organ that can regenerate itself many times during a lifetime. The mechanisms that regulate the cell cycle of the hair stem cells are likely to function in other adult stem cells. The products of this research will be cell-permeable proteins that mimic the activation of hair stem cells and could be applied to other organ systems to induce regeneration. These tools will be made available to the broader stem cell community to determine the efficacy of engineered cell-permeable proteins in different disease models. So while the immediate practical benefits of this research may to stimulate hair growth to cure hair loss, other medical diseases may benefit as well.
Statement of Benefit to California: 
A major goal of regenerative medicine is to replace organs and tissues lost from disease or injury using our own body’s cells. Our research focuses on approaches to induce pre-existing stem cells to divide and to develop models of human organ development to study regeneration. This research will greatly benefit the next generation of regenerative doctors and scientists and benefit the California economy now through the development of new tools and jobs. The major obstacles in regenerative medicine are the limited number of pre-existing stem cells and the inability to stimulate their growth for study or for wound repair. Our aims are to identify the mechanisms that regulate stem cell proliferation and that induce stem cell formation, using the hair follicle as a model. The hair follicle regenerated itself more than 10 times during a lifetime and its stem cells are readily accessible. We hope to translate our findings in the hair follicle into developing cell-permeable proteins to induce stem cells in other organs to divide. The products of this research will aid California by helping to speed recovery and to provide therapies for diseases once thought to cause permanent damage. These tools could reduce the suffering and long-term health consequences following organ damage, which should benefit all Californians. This approach should also benefit the health, biotechnology, and pharmaceutical industries of California and provide the next generation of California scientists and doctors with the frontline treatments for diseases in all organ types.
Review Summary: 
This is a proposal to study the regulation of adult stem cell proliferation in the mouse hair follicle. Specifically, the applicant is interested in understanding the signal transduction cascades that ultimately lead to cell cycle progression or arrest in the stem cells residing in the bulge of the hair follicle. The hair follicle has emerged as an interesting and accessible niche for adult stem cells, and repeated cycles of follicular regeneration offer an important model for studying the kinetics and regulation of stem cell cycling. Reviewers were enthusiastic about this superb proposal by an outstanding physician scientist with a stellar pedigree and training. They commented that the applicant is poised to make seminal discoveries on adult stem cell proliferation in adult hair stem cells, and has all of the essential prerequisite training to do so. The institution is a leader in stem cell research, and both the selected mentors and the institution are strongly supportive of the applicant, who was recruited to the institution to continue the kind of research proposed in the application. The research proposal is interesting, although reviewers were mixed regarding the potential impact and significance of the work because the stem cells could have been used more extensively for understanding developmental/regenerative issues common to all stem cells, rather than the intense focus only on cell cycling. The research plan was described as a good balance between small logical steps forward and a few high-risk, high-reward style experiments. There are some alternate approaches proposed for the riskiest experiments. The preliminary results are quite good and support the feasibility of the research plan. The proposal is illustrated beautifully, clearly written, and well supported by preliminary data and publications. The major cited weakness of the application was that the work may not be generally translatable to other stem cells, as the hair follicle compartment may be unique. Reviewers commented on the applicant’s very strong track record, and they were impressed that the applicant continued to produce solid research during medical training. They commented that the investigator has successfully tackled some tough developmental problems, and appears to be an up and coming young researcher. Four outstanding researchers have been recruited as mentors. The institution was described as excellent, including facilities, a stimulating and nourishing working environment, outstanding and dedicated mentors, and start up support from the department and institution. Overall, reviewers agreed that this applicant is a rising star at an excellent institution, and the research project proposed is interesting and solid.
Conflicts: 

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