Pluripotent embryonic stem cells (ESCs) have the remarkable capacity to differentiate into any specialized cell type in the human body and are therefore of potential therapeutic value for neurodegenerative diseases, spinal cord injury, diabetes, heart disease, and numerous other degenerative diseases. Moreover, several of these same stem cell pathways are hyperactivated in tumorinitiating/ cancer stem cells. Therefore identifying novel gene regulatory pathways required for both the growth of these unique cells, as well as their differentiation into specialized cell types is key to developing novel therapeutic approaches for the treatment of degenerative disease and cancer. Our goal is to further develop a specialized, high-impact research program focused on understanding the mechanisms of gene regulation in pluripotent stem cells. With this information, we will design and develop assays to identify new drugs that regulate the differentiation of stem cells into specialized cell types and that suppress tumor growth by eradicating tumor-initiating/cancer stem cells. Our comprehensive and integrated research program will maximize the likelihood of realizing our goal of identifying chemical compounds that can specifically control cellular fates for therapeutic use.
To fully benefit from the potential of regenerative medicine to treat injury and degenerative diseases we need to be able to effectively control and manipulate cellular fates on demand. This will require the successful translation of basic knowledge gained from understanding the molecular mechanisms controlling stem cell differentiation into specific cell fates, such as specialized cells of organs (e.g. insulin producing pancreatic beta cells) or specific types of neurons.
In order to more effectively accomplish this, it will be necessary to understand the molecular circuitry that operates in stem cells and bestows these remarkable cells with their unique ability to become any cell type. My laboratory has been successful in identifying novel stem cell pathways that regulate this fundamental capacity of stem cells and that can be targeted therapeutically. In the short term, the benefit to California will be the relocation of my specialized research program to the state, and, with the support of CIRM, the further development of this world-class, high-impact research program, which will perfectly complement the existing research strengths in genomics, RNA biology, and stem cells at the University. In the longer term, the
citizens of California will benefit from my laboratory’s efforts aimed at the identification of new drugs that will target these crucial, stem cell pathways and stimulate the body's own repair mechanisms. We anticipate that these new drugs will heal diseased tissues and organs previously considered irreparable. Moreover, our research has the potential of identifying new chemotherapeutic agents that target cancer stem cells, a recently identified cell that is likely to be responsible for incidences of tumor recurrence following treatment. The State of California will benefit by being at the heart of these clinical advances and the resulting economic impact as they translate to the market.
The candidate principal investigator (PI) is an early- to mid-career scientist whose research focuses on the role of microRNAs (miRNA) in stem cells, developmental processes and disease. The PI has already made major contributions to the field by identifying and characterizing a number of key regulators of miRNA function. The planned research program will focus on understanding mechanisms underlying the pluripotency and differentiation of embryonic stem cells (ESC) by finding novel miRNA regulators and characterizing their molecular and cellular roles. The PI will further identify small molecule modulators of miRNA dynamics and explore their use in manipulating ESC regulatory pathways and their potential for therapeutic approaches involving alteration of stem cell fate.
Research Vision and Plans
-The proposed research program addresses an important but poorly studied topic: the translational control of pluripotency.
-The proposed work is likely to have high significant impact with implications for both ESC biology and cancer biology.
-The approach is innovative and relies on state-of-the-art techniques.
-A concern was expressed that the research program is too reductionist and narrowly focused and might lack adequate relevance to human ESC differentiation. A differing view was also expressed that the work could be transformative.
PI Accomplishments and Potential
-Reviewers considered the candidate’s accomplishments and overall potential as outstanding.
-The PI has made seminal contributions to an understanding of miRNA regulation.
-The PI has been extremely productive, publishing a number of important articles in high impact journals including Cell, Nature and Science.
-The candidate is well funded with research grants from National Institute of Health and the American Cancer Society.
-The PI has demonstrated leadership by service on editorial boards and grant review committees, participation in scientific organizations and directing a major graduate core course.
-The PI is a recognized leader in the field of stem cell research and has received a number of honors and awards.
-Letters of recommendation were generally outstanding, including a particularly strong one from a Nobel laureate, although one letter seemed rather tepid.
Institutional Commitment and Environment
-The institutional commitment is substantial and appears to be conducive to a successful and productive career for the PI.
- The candidate’s research fits well with the established programs at the applicant institution.
-The PI’s projected leadership role should be a boost for stem cell research at the applicant institution.
- A motion was made to move this application into Tier 1, Recommended for Funding. The motion carried. Because more than 35% of GWG members opposed the motion, opponents have exercised their right to have that position reported to the ICOC.
- Key points of the minority report are:
- -uncertainty as to whether the proposed project, while having recognized merit, would be transformative or particularly relevant for the stem cell biology field.
- -concern that some of the proposed approach was too reductionist in scope.