Funding opportunities

Mechanism of Direct Lineage Conversion into Induced Motor Neurons

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07512
Funds requested: 
$1 111 800
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
No
Public Abstract: 
The goal of our proposed study is to determine at the molecular level how a few select genes can convert human skin cells from patients into motor neurons, the nerve cells that are lost in diseases such as Lou Gehrig's disease. This approach has the potential to greatly accelerate our learning of why neurons die in these diseases because they can be generated from any individual with the disease and therefore allow personalized disease studies. This is critically important because many brain diseases have unidentified genetic causes, which makes the construction of animal models impossible. In addition, this procedure can be implemented for many patients in parallel, which greatly expedites research progress. The key to harnessing the power of this technology is to understand the precise nature of the nerve cells that it makes and learn how to modify the process to optimize the resulting neurons. By developing a deep understanding of how the conversion process works, we will help to deliver the benefits of this promising approach.
Statement of Benefit to California: 
Neurologic disorders are among those that most commonly afflict Californians. Unfortunately, many of these diseases have been difficult to study because the genetic mutations that cause them are mostly unknown, making the construction of animal models impossible. Lineage reprogramming offers the ability to take skin cells from an individual with any heritable nervous system disorder and convert them into nerve cells in unlimited supply for laboratory studies. Critically, this allows the interrogation and testing of nerve cells that at least to some extent recapitulate the diseased state of the individual from which they were derived. Therefore, this approach could exponentially increase the types of nervous system diseases that can be studied by scientists. The key to harnessing the power of this system is to understand in great detail the molecular character of the nerve cells that are made and how to optimize the technique to improve them. Our proposal aims to do exactly this with the ultimate goal of bringing the full potential of this approach into clinical reality.
Review Summary: 
This fundamental track proposal aims to characterize the mechanisms underlying direct conversion of fibroblasts to induced motor neurons (iMNs). Genome wide analysis of gene expression and DNA methylation will be used to compare iMNs to primary motor neurons isolated post-mortem and induced motor neurons that were derived from induced pluripotent stem cells (iPSCs). Mechanistic studies are described that aim to elucidate the sequence of events and also the transcriptional networks that underlie direct reprogramming of fibroblasts to iMNs. Significance and Innovation - The basic hypothesis is not novel, however this is mitigated by the timeliness and urgency of the issues addressed in the proposal. - Reviewers agreed that a thorough characterization of iMNs and a mechanistic understanding of the phenomenon is timely and necessary for development of better disease models as well as for therapeutic applications of stem cells. - Addresses an important and challenging issue for the therapeutic potential of stem cells. Feasibility and Experimental Design - Substantial concerns were noted regarding the low efficiency of direct reprogramming that would likely lead to high levels of cellular heterogeneity, which will complicate interpretation of data. - Reviewers found the proposal overambitious and were doubtful that the proposed plan can be completed in the funding period. - Some reviewers were not convinced that there would be enough cells to carry out the ChIP-Seq in human iMNs in Aim 3, and reviewers’ enthusiasm was further reduced by the lack of any proposed controls. Principal Investigator (PI) and Research Team - Talented and productive PI with significant expertise in iMN derivation and appropriate team. Responsiveness to the RFA - All reviewers were in agreement that the proposal was responsive to the RFA.
Conflicts: 
  • Alexander Meissner

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