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RN1-00527-1: Molecular mechanisms involved in adult neural stem cell maintenance
Recommendation: Recommended for funding
Scientific Score: 90
First Year Funds Requested: $470,916
Total Funds Requested: $2,348,520
Public Abstract (provided by applicant)
The adult brain contains a pool of stem cells, termed adult neural stem cells, that could be used for regenerative purposes in diseases that affect the nervous system. The goal of this proposal is to understand the mechanisms that promote the maintenance of adult neural stem cells as an organism ages. Understanding the factors that maintain the pool of adult neural stem cells should open new avenues to prevent age-dependent decline in brain functions and to use these cells for therapeutic purposes in neurological and neurodegenerative diseases, such as Alzheimer’s or Parkinson’s diseases.
Our general strategy is to use genes that play a central role in organismal aging as we have recently discovered that two of these genes, Foxo and Sirt1, have profound effects on the maintenance and self-renewal of adult neural stem cells. We propose to use these genes as a molecular handle to understand the mechanisms of maintenance of neural stem cells. Harnessing the regenerative power of stem cells by acting on genes that govern aging will provide a novel angle to identify stem cell therapeutics for neurological and neurodegenerative diseases, most of which are age-dependent.
Statement of Benefit to California (provided by applicant)
As the population of the State of California ages, neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease affect increasing numbers of patients. There are no efficient treatments of cures for these diseases. In addition to the devastating effects of neurodegenerative diseases on the patients and their relatives, the cost of caring for California’s Alzheimer patients—about $22.4 billion in 2000—has been estimated to triple by 2040 due to the aging of the baby-boomer’s generation.
Stem cells from the brain, or neural stem cells, hold the promise of treatments and cures for these neurodegenerative diseases. One therapeutic strategy will be to replace degenerating cells in patients with stem cells. Another approach would be to identify strategy to better maintain the pool of neural stem cell with age. Both approaches will only be possible when the mechanisms controlling the maintenance of these stem cells and their capacity to produce their functional progeny are better understood in young and old individuals.
We propose to study the mode of action in neural stem cells of two genes, Foxo and Sirt, that are known to play major roles to extend lifespan in a variety of species. These genes are major targets for the development of stem cell therapeutic strategies that will benefit a wide range of patients suffering from age-dependent neurodegenerative disorders.
The development of effective replacement therapies in neurodegenerative diseases will be a benefit for the rapidly aging population of California; it will also alleviate the financial burden that these age-related disorders create for the State of California.
Review
SYNOPSIS: The goal of this application is to define the role of two regulatory proteins in neural progenitors. The applicant hypothesizes that these proteins act to maintain the pool of functional neural stem cells (NSC) during aging by controlling a specific network of genes. The applicant reasons that depletion of NSC may contribute to cognitive changes associated with normal or pathological aging. Thus identifying ways to reactivate the molecular network under investigation in order to sustain the pool of NSC in the adult brain could have practical implications for human mental health. The PI’s study plan has three specific aims:
1) Assess the role of the two regulatory proteins in murine NSC as a function of age. Both gain of function and loss of function studies are proposed towards this end, using several strategies including small molecule inhibitors and activators that target one of the regulatory proteins.
2) Define the mechanisms of action of the two regulatory proteins (i.e. their genetic targets). In preliminary studies, the applicant has identified two potential targets, and, using more sophisticated methods, the PI hopes to identify additional targets, and thus describe the global program whereby these proteins moderate lifespan of adult NSC in mouse.
3) Explore the importance of the two regulatory proteins in human stem cells. The applicant speculates that quantitative differences in the lifespan of humans and rodents may translate into qualitative differences in the molecular mechanisms that sustain the lifespan of human adult stem cells. In collaboration with two investigators from his/her institution, s/he will derive human NSC lines from human embryonic stem (ES) cell cultures. Armed with these human NSC lines, s/he will basically repeat the in vitro studies on the function of the two regulatory factors described for specific aims one and two.
STRENGTHS AND WEAKNESSES OF THE RESEARCH PLAN: The proposal clearly addresses important facets of human aging and neurodegenerative disease. The idea that genes that regulate longevity may also regulate the long-term renewal potential of adult stem cells is a recent and very interesting concept, and the applicant has been a major contributor to this idea. Although depletion of neural progenitor cells is probably only one of the multiple underlying causes of age-related dementias and neurodegenerative disease states in humans, the research proposed here has the potential to impact mental health care. The idea is that identifying ways to reactivate the molecular network under investigation in aged NSC could maintain the pool of NSC for regenerative purposes. In this respect, the proposal is innovative and of high significance to CIRM.
The experiments proposed play off of a now well-established conceptual paradigm that the two regulatory proteins under investigation, and other family members, are master regulators of cellular aging. However, the use of NSC in this context is novel, and the proposal to investigate certain regulatory pathways is significant. The study plan exploits state of the art technologies and bioassays but there are no novel approaches at work. Critical reagents, technologies and collaborators are in place for all the studies proposed.
The experiments in Aims 1 and 2 (analysis of the function of the two regulatory proteins in NSC in vitro and in vivo using mouse models) are logical and straightforward, whereas the ones in Aim 3 (analysis of their function in vitro in human NSC, derived from human ES cells) are hard to judge. For example, it is not clear what cells will be used. Nevertheless, a study of human NSC is of importance and provides stronger relevance to the mission of CIRM. The preliminary data supports the central premise of the studies that the two regulatory proteins may enhance the lifespan of NSC. Although the work on the genetic targets of these proteins in rodent and human NSC seems unlikely to go beyond the descriptive level in the five-year time frame of this grant, this was not considered a major concern.
The applicant acknowledges potential pitfalls in the work proposed and where possible describes alternative approaches. For example, functional redundancy of one the regulatory proteins with other members of the protein family it belongs to is a potential problem. To address this issue, the applicant has recently produced mice with a null allele of another family member that is highly expressed in brain.
Several recommendations were made with regard to prioritizing or improving certain experiments. For instance, the applicant’s proposal to examine NSC maintenance in mice in which the genes that encode the two regulatory factors are conditionally deleted in adult NSC is listed as a long-term goal. However, one reviewer felt that these are critical experiments that should be performed earlier rather than later. Another reviewer suggested a few specific improvements to experimental protocols.
QUALIFICATIONS AND POTENTIAL OF THE PRINCIPAL INVESTIGATOR: The applicant is clearly a very talented scientist, and his/her potential to become a leader in the stem cell field and make seminal contributions is outstanding. The PI has been productive at every stage of his/her career development to this point. S/he generated a number of first author research publications at both the predoctoral and postdoctoral levels, and these papers appeared in top-tier scientific journals. The applicant has expertise in research related to this proposal, as evidenced by the subject matter addressed in his/her papers.
The applicant was appointed to the faculty at his/her institution in 2004, and the first publications as an independent investigator are already appearing in high-quality journals. S/he has already secured R01 grant support from the National Institutes of Health, together with several smaller grants from private foundations.
The applicant has also presented a carefully considered plan for career development. Several official mentors, including a well known scientist at the applicant institution, and collaborators have been listed. S/he will meet with these individuals and with the department chair at least once a year to discuss progress and plans. The scientific environment at the applicant institution is outstanding.
INSTITUTIONAL COMMITMENT TO PRINCIPAL INVESTIGATOR: An enthusiastic letter from the applicant’s Department Chair details a generous commitment of space and resources. It has also assigned an official mentor to guide and advise him/her through the early years of his/her career development. The institutional track record of the applicant institution for developing the careers of its junior faculty is outstanding, and the institution has made a major commitment to increase stem cell research and biomedical engineering.
DISCUSSION: Overall, there was great enthusiasm for this proposal, since the applicant is outstanding, and so is the institutional environment. One reviewer stated that this application was one of the three best proposals in his/her pile. The application itself was considered a great proposal with a great research plan, and with all critical elements in place. However, the innovation level of this proposal was considered a little low. Aim 1 was described as being conventional. Aim 2 is mechanistic, and utilizes elegant technology. Aim 3 was described as less well thought out (derive human NSC from human ES cells and repeat aims 1 and 2), but also as the most interesting aim, since it intends to test the hypothesis that depletion of NSC may contribute to neurological changes associated with aging. This aim is based on the general idea that humans live longer than mice due to molecular differences, and consequently differences in lifespan, in their adult stem cells. It was acknowledged that it is challenging to study aging. One suggestion for improvement of Aim 3 was to include in the analysis NSC derived from mouse ES cells to compare to those derived from human ES cells. It was also mentioned that the function of one of the regulatory proteins under investigation has already been well studied in HSC. Notwithstanding these minor suggestions and comments, overall the reviewers agreed that this is a great application from an excellent candidate with a stellar track record and great collaborators.
The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:
- Wagers, Professor Amy