Funding opportunities

Unraveling the Molecular Wiring that Controls Endothelial Cell Plasticity

Funding Type: 
Basic Biology V
Grant Number: 
Funds requested: 
$1 152 000
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Blood vessels, the pipes that serve as conduits for nutrients and oxygen, are critical for the repair and regeneration of any human tissue/organ. Our work focuses in developing novel technology to effectively grow the cells involved in the formation of new blood vessels. The findings generated thus far, and presented in this application as preliminary support, indicate that a specific subset of genes effectively regulates the metabolism of vessel-forming cells and drastically change their proliferative potential. The experiments outlined in this application will further explore these initial findings to improve upon this technology and understand the underlying reasons (mechanisms) that drive this change in proliferation potential. Findings from this application are likely to significantly improve our ability to generate blood vessels in a large number of tissues and thus, the present application has broad implications for regenerative medicine.
Statement of Benefit to California: 
Regenerative Biology is clearly the next frontier in Medicine. Research advances performed by investigators in California will result in patents benefiting the University and the State. Specifically within this application, the technology to be investigated has the potential to significantly improve our ability to give rise to cells that form blood vessels. These cells are critical to construct the pipes (blood vessels) that deliver nutrients and oxygen and that are essential in the regeneration of any tissue. In this manner, findings from the outlined experiments are likely to be incorporated in a large number of applications aiming at renewal, repair and /or de novo reconstruction of multiple tissue types, as blood vessels are an integral part of all human organs. In addition, the present proposal will offer employment and training to at least two individuals.
Review Summary: 
The goal of this Fundamental Mechanisms Award proposal is to investigate the role of cellular metabolism on the transition of mature endothelial cells (EC) to pluripotent “progenitor-like” cells. The hypothesis governing the proposed studies is that pluripotency in the endothelium is maintained by metabolic constraints that when altered can drive proliferation or differentiation of these cells. In order to assess this hypothesis the team has proposed three aims: (1) To explore the link between metabolic status and regulation of endothelial stem cellproliferation (2) To determine the effect of epigenetics and metabolic memory in the regulation of EC-stem cell pluripotency and (3) To investigate whether forced changes in metabolism triggers differentiation of EC-stem cells. Significance and Innovation - This project addresses important questions in stem cell and endothelial biology and the hypothesis proposed are highly innovative. - There are several technical concerns that reduce the potential significance of the project. - The project has a low focus on mechanism. There are few experiments proposed to investigate the mechanism by which metabolism influences pluripotency. - Although there appears to be a logical rationale a clear link between the two aims is missing and they almost appear as two independent projects. Feasibility and Experimental Design - There are significant concerns regarding the overall feasibility and experimental design of this project. - The proposal is poorly written with numerous errors, inconsistencies, and omissions. In addition, important terminology is used inappropriately. - The entire project is based on identification and characterization of a pluripotent, endothelial cell-derived progenitor cell, but the preliminary data do not adequately demonstrate that the applicant has defined or isolated such a cell. - The project is viewed as overly ambitious. It will generate an enormous amount of data, but it is not clear how these data will be analyzed. Principal Investigator (PI) and Research Team - The PI has an excellent track record in endothelial cell biology. - None of the team members have extensive stem cell expertise. Responsiveness to the RFA - The proposal is responsive to the RFA in that it utilizes human endothelial progenitors and reprogramming of ECs to pluripotent stem cells to study basic metabolic mechanisms of EC differentiation and function, however, the project has a low focus on mechanism.

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