Funding opportunities

Mechanism and Utility of Direct Neuronal Conversion with a MicroRNA-Chromatin Switch

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05886
Principle Investigator: 
Institution: 
Funds requested: 
$1 392 426
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Many human diseases and injuries that affect the brain and nervous system could potentially be treated by either introducing healthy neurons or persuading the cells that normally provide supporting functions to become functioning neurons. A number of barriers must be traversed to bring these goals to practical therapies. Recently our laboratory and others have found ways of converting different human cell types to functioning neurons. Surprisingly, two routes for the production of neurons have been discovered. Our preliminary evidence indicates that these two routes are likely to work together and therefore more effective ways of producing neurons can likely be provided by understanding these two routes, which is one aim of this application. Another barrier to effective treatment of human neurologic diseases has been the inability to develop good models of human neurologic disease due to inability to sample tissues from patients with these diseases. Hence we will understand ways of making neurons from blood cells and other cells, which can be easily obtained from patients with little or no risk. Our third goal will be to understand how different types of neurons can be produced from patient cells. We would also like to understand the barriers and check points that keep one type of cell from becoming another another type of cell. Understanding these mysterious processes could help provide new sources of human cells for replacement therapies and disease models.
Statement of Benefit to California: 
The state of California and its citizens are likely to benefit from the work described in this proposal by the development of more accurate models for the testing of drugs and new means of treatment of human neurologic diseases. Presently these diseases are among the most common afflicting Californians, as well as others and will become more common in an aging population. Common and devastating diseases such as Alzheimer’s, Schizophrenia, Parkinson's Disease, and others lack facile cell culture models that allow one to probe the basis of the disease and to test therapies safely and without risk to the patient. Our work is already providing these models, but we hope to make even better ones by understanding the fundamental processes that allow one cell type (such as a skin cell or blood cell) to be converted to human neurons, where the disease process can be investigated. In the past the inability to make neurons from patients with specific diseases has been a major roadblock to treatment. In the future the studies described here might be able to provide healthy neurons to replace ones loss through disease or injury.
Review Summary: 
This proposal seeks to uncover molecular mechanisms involved in the direct conversion of human fibroblasts to neurons. The first specific aim will investigate different ways to convert fibroblasts into neurons through the use of microRNAs and neurogenic transcription factors. The second specific aim will examine whether the microRNA/chromatin switch can be altered to guide the neurons into different subtypes. The third aim will focus on delineating epigenetic pathways that prevent neuronal dedifferentiation. The fourth aim will examine possible approaches to convert astrocytes or lymphocytes into neurons. Significance and Innovation - Reviewers unanimously agreed and were impressed that this project addresses multiple unsolved problems in use of reprogramming human cells for regenerative medicine. - Reviewers agreed that a more in depth understanding of transdifferentiation and the microRNA switch for direct neuronal conversion is extremely significant and highly innovative. - Reviewers viewed this proposal as creative and logical, and highlighted the importance of the proposed study in understanding mechanisms linking transcriptional control to the determination of a specific cell type. Feasibility and Experimental Design - Reviewers were highly impressed by the preliminary results, and based on these results, expressed great confidence that the proposed experiments in all four aims are entirely feasible. - Experimental design was simple yet powerful, well thought out and clearly defined. Appropriate technology will be employed. - Reviewers predicted successful completion of all specific aims. - In addition to detailed experimental methodology, reviewers were also impressed by proposed alternative approaches. Principal Investigator (PI) and Research Team - The PI is an outstanding and highly productive researcher with an excellent publication record directly relevant to this proposal. - The PI and research team have appropriate and sufficient expertise to successfully complete the proposed project. Responsiveness to the RFA - The proposal was viewed as responsive to this RFA.
Conflicts: 

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