Funding opportunities

The role of neural stem cells in cerebellar development, regeneration and tumorigenesis

Funding Type: 
Research Leadership 1
Grant Number: 
LA1-01747
Principle Investigator: 
Funds requested: 
$5 919 616
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Stem cells have the remarkable ability to renew themselves and to generate multiple different cell types. This allows them to generate normal tissues during development and to repair tissues following injury, but at the same time, renders them highly susceptible to mutations that can result in cancer. Only by understanding the signals that control growth and differentiation of stem cells can we learn to harness their regenerative capacity and restrain their malignant potential. The research described in this proposal is aimed at elucidating the role of neural stem cells in development, regeneration and tumor formation in the cerebellum. Our previous studies identified a population of neural stem cells in the developing cerebellum. We now propose to use genetic approaches to mark these cells and identify the cell types that they generate during normal development. In addition, we plan to examine the capacity of these cells to regenerate the cerebellum following radiation. Finally, we propose to study the ability of these cells to give rise to brain tumors, and use the models that result from these studies to develop and test novel approaches to therapy. These studies will pave the way towards use of stem cells for repair of neurological damage and help develop more effective treatments for patients with brain tumors.
Statement of Benefit to California: 
We have previously identified a novel population of neural stem cells in the cerebellum. This proposal is focused on understanding the role of these cells in normal development, regeneration and tumor formation. It has the potential to benefit California in a number of important ways. 1. Treatment of Brain Damage: Radiation is the most commonly used treatment for brain tumors, and children who receive this treatment often suffer severe side effects, including a progressive loss of intellectual function. By studying the ability of cerebellar stem cells to repair brain tissue, we will advance the treatment of patients suffering from brain damage due to radiation therapy. The knowledge we gain may also be more broadly applicable, advancing the use of stem cells to repair damage due to congenital brain disorders, trauma and stroke. 2. Treatment of Brain Tumors: Medulloblastoma and astrocytoma are the most common brain tumors in children. By examining the role of stem cells in development of these tumors, we will deepen our understanding of how brain tumors form, and develop novel approaches to treating them. Moreover, we will create new model systems that can be used to test these therapies, with the hope of moving the most effective ones forward towards trials in patients. 3. Technology: Our research will culminate in the invention and generation of new drugs and approaches to therapy that will be made available for licensing by the academic institutions in California, such as {REDACTED} and its collaborators, and developed by pharmaceutical companies based in the State. 4. Collaboration: Our work is multidisciplinary and translational in nature. As such, it will require collaboration with other investigators, including stem cell biologists, neurobiologists, cancer biologists and chemists involved in experimental therapeutics. Once discoveries are made that may be of benefit to patients, we will also work with clinicians to move these discoveries towards the clinic. Californians will be the likely first beneficiaries of these therapies because the clinical trials will be conducted here and we will make an effort to make sure that Californians have immediate access to these therapies when they become standard. By bringing together investigators from various fields and focusing their attention on clinically relevant problems, our studies will advance the translational potential of stem cell research in California.
Review Summary: 
The candidate principal investigator (PI) is an early-to-mid career scientist who leads a robust research program at an academic institution. The PI’s research focuses on the role of neural stem cells in development, regeneration, and tumorigenesis in a key brain region, the cerebellum. Building on the PI’s earlier identification of a stem cell population in the developing cerebellum and influential work on signaling pathways critical to cerebellar development, the planned research will track the fate of these cells in normal development, assess their capacity to contribute to cerebellar regeneration, and investigate their role in the generation of brain tumors. These studies should provide critical, new insights into neuronal development and advance novel therapeutic approaches for repair of neurological damage and the treatment of brain cancers. Reviewers characterized the PI’s proposed research as having extremely high significance and excellent potential for illuminating novel aspects of neuronal development. The PI’s scientific accomplishments in the area of cerebellar development and his/her ongoing studies using state-of-the-art genetic and lineage-tracing approaches have already had a major impact on an understanding of regulatory networks in the developing brain. Although reviewers expressed some concern that the candidate has yet to make major contributions in the area of neuronal regeneration and that proposed cerebellar regeneration models are rather preliminary, planned investigations of tumorigenesis in the brain, particularly in the context of pediatric brain tumors, were viewed as exciting, important, and likely to provide novel insights into links between stem cells and cancer. Moreover, the tumorigenesis research should benefit greatly from supportive and complementary research and chemical-biology resources at the applicant institution. Reviewers generally viewed the PI as a scientific leader because of the seminal contributions he/she has made to the field of cerebellar development. Additionally, he/she is rapidly emerging as a top researcher in the cancer stem cell field. The PI has been highly productive as an independent researcher, with publication of numerous important papers in high-impact journals. His/her achievements are further reflected in invitations to present seminars at influential meetings and prestigious institutions and the successful acquisition of very substantial research support from the NIH and private foundations. Reviewers noted, however, that the candidate has not yet demonstrated leadership roles in other capacities such as in stem cell peer-review groups or scientific societies/organizations. The PI was lauded in letters from top leaders in the fields of cancer biology and neuroscience who stressed the candidate’s stellar contributions to developmental biology, systematic and thoughtful approach to research, and tremendous potential as an emerging leader in the cancer stem cell field. The institutional commitment to the PI was viewed by reviewers as outstanding. This included an extremely generous commitment of laboratory space, matching funds for equipment, additional support for relocation and research, and access to excellent core facilities. Additionally, an active community of stem cell researchers, many with complementary research interests, will provide a strong intellectual and collaborative environment. Reviewers also noted that the applicant institution has committed to recruiting the candidate’s spouse, who is an independent stem cell scientist; this represents a particularly beneficial leveraging of award funds. In summary, this is an extremely strong application from an emerging leader in neurodevelopment and the study of neural stem cells and their role in tumorigenesis. Major strengths include the PI’s significant research on cerebellar development, highly productive and ambitious research program, very strong letters from experts in the field, and outstanding commitment by the applicant institution.
Conflicts: 

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