Funding opportunities

Genetic manipulation of human embryonic stem cells and its application in studying CNS development and repair

Funding Type: 
SEED Grant
Grant Number: 
RS1-00333
Principle Investigator: 
Funds requested: 
$642 361
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
Yes
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
SYNOPSIS: This proposal is focused on studies to address directed differention of hESC to motor neurons, specifically spinal motor neurons, to address feasibility of using hESC derivatives in CNS development and repair. The focus is on fezl, a zinc finger transcription factor, that has been recently identified in overexpression studies as a master regulator in corticospinal tract (CST) development and cortical spinal motor neuron (CSMN) fate determination in mice. The applicant proposes to: 1) genetically manipulate hESC including making, by homolous recombination, fezl homozygous mutant hESC and also constructing BAC transgene with or without a fezl overexpression cassette; 2)looking at CST development and the role of fezl by transplantation studies of genetically marked hESC into embryonic mice CNS and 3)transplanting genetically modified hESC differentiated into neural precursors into normal and spinal cord injury models to assess potential for integration into mature CNS. SIGNIFICANCE AND INNOVATION: The applicant will apply novel and highly innovative techniques to the study of gene expression in the development and repair of axons in the CNS. Fezl biology likely to be important in understanding biology of corticospinal development and potentially has applicability in repair and/or regeneration in ALS and spinal cord injury. Potential nearer term clinical applicability. STRENGTHS: • Exciting proposal by an extremely well trained, young applicant • Excellent academic environment with top-flight collaborators at UCSD • Has the potential to provide insights leading to clinical application. WEAKNESSES: Potential downside to the fezl knockout/ overexpression strategy is that fezl by itself unlikely to be sufficient (for normal development/regenertion)- ie is not a single gene that acts alone but rather works with other genes. Also the project seems rather ambitious for the two year time span. DISCUSSION: Fez-like is a master gene for development of the corticospinal tract. In KO mice, the whole tract is absent. Overexpression results in an entire extra corticospinal tract. Identification of this master gene now creates an opportunity to study upper motor neurons which are also lost in some forms of neurodegenerative disease. However, no single gene acts alone. So it is a little naive to think that other related genes are not involved in fate switching. In general, the proposal is very exciting and innovative. This is a productive, young investigator who has established a strong collaboration with the Gage laboratory at the Salk nearby. The PI acknowledges the difficulties in homologous recombination and of doing straight transgenesis. PROGRAMMATIC DISCUSSION: During programmatic review, there was an agreement to recommend this applicant for special consideration if funding became available based on: 1) this is a new investigator; 2) scientific merit of proposal 3) applicability of this research to ALS and spinal injury
Conflicts: 

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