Funding opportunities

Regulating diversity among neural cells generated by reprogramming.

Funding Type: 
Basic Biology V
Grant Number: 
Funds requested: 
$1 466 724
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Human neurological diseases such as autism, schizophrenia, Alzheimer's disease and Parkinson disease are highly prevalent and cause a large financial burden to affected families. Yet, these diseases suffer from extremely limited treatment options. One new set of methods to accelerate treatment of brain diseases is to generate patient-matched neurons resembling those impacted by disease, either by using pluripotent stem cells or generating them directly from skin cells. A barrier to using these cells is that it is presently difficult to produce the correct neuronal type without also generating unwanted types. Here we propose a series of experiments to identify the best methods to produce specific neuronal types from individuals for use in studying a broad range of brain diseases. These results are also likely to aid in producing neurons or neural stem cell that can be used to repair damaged brain or spinal cord regions arising from injury or stroke.
Statement of Benefit to California: 
The State of California has invested in stem cell research designed to produce valuable new disease models and to accelerate the path towards using patient matched cells for regenerative medicine. A major unsolved need in California is caused by the growing burden to State residents due to diseases that affect the brain such as autism and Alzheimer’s disease. This proposal aims to reduce that burden by developing new, efficient and cost effective methods to produce neurons of specific subtypes that match those impacted by various diseases, which is presently not possible. Success in this mission will broadly impact state-wide efforts to study disease and contribute to translational medicine aimed at diseases of the brain.
Review Summary: 
This Track 1, Fundamental Mechanisms Award application proposes to address the mechanistic basis of neuronal cell heterogeneity following reprogramming. The Principal Investigator (PI) proposes to: 1) make use of a multi-color lineage tracing system to identify differences in outcome among individual cells following differentiation of inducible pluripotent stem cells (iPSCs) into diverse neuronal lineages; 2) determine how altered transcription factor levels or ratios impact neuronal population outcomes and 3) determine the impact of other cell types on outcomes. If successful, the research could help drive a shift towards controlling/eliminating heterogeneity in neuronal cells derived from PSC or from direct reprogramming. Significance and Innovation - The heterogeneity of cell types derived from PSC or by direct reprogramming is a significant obstacle to effective stem cell therapy and to disease modeling. - The aims generally are descriptive and are not designed to generate mechanistic data. - Innovation is limited in this proposal and the proposed research is incremental. Feasibility and Experimental Design - Reviewers had major concerns with the experimental approach. For example, they noted that the markers chosen to identify specific cell types lack specificity, which could impact the accuracy of cell classification relevant to aims 1 and 3. They believed that the approach proposed for altering transcription factor levels would lead to uninterpretable results due to differing levels of expression. - The preliminary data supports the ability of the PI and team to conduct the research as proposed. - The research facilities and environment are excellent. Principal Investigator (PI) and Research Team - PI has an established track record with publications relevant to the conduct of this project. - The team has the requisite expertise to conduct the proposed research. Responsiveness to the RFA - Reviewers agree that the proposal is responsive to the RFA.

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