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

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

Funding Type: 
New Faculty II
Grant Number: 
RN2-00908
Award Value: 
$3,017,978
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Active
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.
Progress Report: 

Year 1

Our research proposal focuses on understanding the global regulation of adult stem cells, both in the setting of normal growth and in disease. Under certain conditions, adult stem cells become refractory to stimulation and growth. The mechanisms of this refractory growth are unknown but may contribute to the inadequate regeneration. As a model to study mechanisms of adult stem cell growth and disease, we are studying the hair follicle, which regenerates itself several times during our lifetime. A rare disease in humans causes the hair cycle to stop so that no new hair is regenerated. We have uncovered two molecular pathways that are defective in this disease that might explain the inability of the hair to regenerate. In addition, we have made progress in developing cell-based models to study the regulatory pathways that normally control these molecular pathways. This latter model will be used to perform drug-based screens to identify compounds that can interact with these pathways and could be used to treat refractory stem cell diseases.

Year 2

The overall goals of our investigations are to better understand the links between stem cell proliferation, differentiation, and ultimately regeneration. Using the hair follicle and embryonic stem cells, the regulation of organ-specific and non-organ-specific stem cells can be studied. In the past year, we have published our working, characterizing a model of hair stem cell defects. This model has been the basis for our ongoing studies to identify mechanisms to mobilize refractory stem cells. In addition, we have identified different mechanisms for how stem cells potentially forecast growth by preparing proteins and RNAs that they require before they differentiate. Future work in this area is necessary to attempt to stimulate organ regeneration in tissues that are refractory for self-healing.

Year 3

The primary goals of our CIRM-funded research are to investigate the mechanisms of stem cell proliferation and refractoriness in adult and embryonic stem cells. Our focus has been on pathways that are functionally important to stem cell proliferation that are targetable by small molecules or by approaches that are unlikely to cause DNA damage. The outcome of such research may be the identification of targetable pathways in activating or suppressing stem cell proliferation during organ regeneration.

Year 4

The primary goals of our CIRM-funded research are to investigate the mechanisms of stem cell proliferation and refractoriness in adult and embryonic stem cells. Our focus has been on pathways that are functionally important to stem cell proliferation that are targetable by small molecules or by approaches that are unlikely to cause DNA damage. The outcome of such research may be the identification of targetable pathways in activating or suppressing stem cell proliferation during organ regeneration.

Year 5

Tissue regeneration requires the activation and mobilization of specialized cells called stem cells. These cells are responsible for producing new cells to replace a tissue or organ during injury. In many tissues, these cells stay dormant until they are stimulated to grow. These stem cells are important not only for their role in tissue regeneration but in many diseases are the point of origin for cancer. Thus understanding what regulates the growth of stem cells is important for many areas of human health. The signals that stimulate stem cell growth are not well known. My lab studies how progenitors grow using the hair follicle and embryonic stem cells as models of tissue and organ development. With funding from the California Institute of Regenerative Medicine, our lab has developed new methods and discovered new properties for stem cell growth. First, we discovered that abnormalities outside of the stem cell compartment can interfere with stem cell growth (Mukhopadhyay 2011). Second, we discovered about different levels of the same signal can control an important growth factor called Sonic Hedgehog in hair follicle growth (Mukhopadhyay 2012). Third, we are learning about how basic units of a stem cell are regulated during their growth. These units, called ribosomes and histones, regulate the synthesis of new proteins or control genes, respectively, and have unique characteristics in stem cells. By studying these areas, we hope to understand unique targets to regulate stem cell growth.

© 2013 California Institute for Regenerative Medicine