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The molecular basis underlying adult neurogenesis during regeneration and tissue renewal

Funding Type: 
New Faculty II
Grant Number: 
RN2-00940
Principle Investigator: 
Funds requested: 
$1 725 830
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Regeneration of lost body parts has long fascinated humans, yet regeneration remains one of the great mysteries in biology. Forty years ago, studies on the mammalian brain provided evidence that new neurons are generated throughout life. It is now widely accepted that neurons are born (neurogenesis) in a wide range of animals, including humans, from neural stem cells maintained in the adult brain. Neural stem cells, however, do not readily compensate for lost neurons after injury or due to diseases of the nervous system, such as Parkinson’s or Alzheimer’s disease. The existence of neural stem cells has raised hopes that in the future we may be able to manipulate or promote stem cells in living organisms to divide, acquire the fate of specific cell types, migrate to the proper location and replenish lost neurons. Alternatively, another source of stem cells for tissue replacement could be stem cells derived from adult, embryonic, or cells re-programmed to acquire a stem cell-like state. All of these prospects will require that we fully understand how stem cells can be signaled to divide, acquire the desired cell fate and integrate into a functional nervous system. Our understanding of how repair of the nervous system can be achieved could benefit from studies of organisms that, in contrast to humans, are capable of regenerating the nervous system. For more than a century, scientists have been intrigued by freshwater planarians (flatworms); these animals, when cut into small pieces, have the remarkable ability to regenerate complete organisms from small body pieces. This ability to regenerate missing parts originates from a population of adult stem cells planarians maintain throughout life. Thus planarians are an excellent system in which to examine how stem cells are signaled to divide and to become all the different cell types during regeneration. It is now possible to apply advanced scientific methods to study planarians; we can visualize the stem cells, label the different organ types and inhibit the expression of specific genes. One of the truly amazing properties of planarians is their capability for rapid repair and regeneration of the central nervous system, a capacity that is limited in most animal models currently studied. In this study, we will use planarians to identify and analyze the function of genes implicated in neurogenesis during regeneration and normal cell turnover. Successful identification of novel genes would help to fill gaps in our knowledge of conserved biological mechanisms that stimulate proliferation and differentiation of stem cells in the central nervous system. This information has the potential to contribute to our ability to induce human embryonic or adult stem cells to divide and acquire neuronal fates, which would be valuable for transplantation therapies to treat nervous system injuries or neurodegenerative disorders.
Statement of Benefit to California: 
The inability to recover from loss of neuronal function afflicts a large number of people: in the U.S. alone, 4 million people have been diagnosed with Alzheimer’s disease, 1.5 million have Parkinson’s disease, and 0.25 million suffer from spinal cord injuries. The aim of this proposal is to establish a model of regeneration to study how stem cells can be directed to replace lost neurons after injury. Invertebrate organisms have provided powerful venues to investigate biological conserved mechanisms, and their study has led to discoveries of biomedical relevance. Our research on planarian stem cells and neural regeneration has the potential to make contributions to our knowledge of genetic pathways that control neuronal determination of stem cells or, if disrupted, could lead to neurological disorders. These studies provide a unique opportunity to examine how regeneration of the nervous system can be achieved at the molecular and cellular levels and have implications for the development of neural stem cells in regenerative medicine.
Review Summary: 
This is a proposal to identify factors that induce neuronal differentiation of stem cells, using planarians as a model organism of regeneration, tissue homeostasis and stem cell biology. Planarian flatworms maintain a population of pluripotent stem cells throughout life that are capable of replacing the central nervous system (CNS). The investigator plans to generate antibodies that recognize planarian neural proteins that are conserved in humans, and proposes to use these antibodies to monitor the differentiation of stem cells into mature neurons during regeneration. S/he will then use microarray platforms to differentially analyze genes expressed at various stages of differentiation, followed by high throughput whole mount in situ hybridization analysis screens for tissue-specific expression of target genes. Finally, the applicant will use inhibitory RNA to knock down the expression of conserved genes, in order to assess the effect of these genes on neurogenesis. Reviewers were very supportive of this new principal investigator with a novel and unusual proposal. Employing stem cells to replace lost tissue in human CNS disease and injury will require a careful understanding of the signaling factors required for neuronal differentiation of stem cells, and a great deal of exciting information might be gleaned from this creative proposal utilizing an intriguing and surprisingly under-explored model organism. The major potential limitation to the work is the extent to which specific molecular targets from the flatworms will be applicable to humans. This is always a risk when working with lower species, but reviewers commented that the phenomenon of limb and CNS regeneration is biologically remarkable and worthwhile of in-depth study. The research proposal was judged as logical, carefully thought-out, and impeccably written. The applicant provides extensive preliminary data of excellent quality, and considerable attention is given to controls, potential pitfalls, and alternative approaches. Reviewers noted that planarian worms are a good model system for these screening experiments: they are easy to manipulate genetically and they can be maintained in high numbers at relatively low cost. As an example of the power of the approach, reviewers noted that the applicant estimates that his group could screen 1000 genes within 3-6 months of each microarray screen. The applicant is a promising new investigator with good training and a high-quality publication record, and seems well-placed to be able to achieve the goals outlined in the proposal. S/he has extensive expertise in all facets of this work, particularly in the planarian flatworm model and in developing tools for gene analysis and regeneration. The proposal includes a general career development plan and identifies two prominent mentors. Reviewers also supported the applicant’s plans to reach out to other academic institutions for collaborations and mentorship. The institution has a strong biology program and was enthusiastic in support of the applicant. The institution has provided an adequate start-up package consisting of research funding, laboratory space, and one year of protected time from teaching responsibilities. Overall, reviewers felt that this was an intriguing and creative proposal from a promising new investigator. They commented that project is high-risk, but one that is worth an investment.
Conflicts: 

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