Funding opportunities

The Role of Higher-Order Chromosome Structure in Pluripotency and Reprogramming

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-05816
Funds requested: 
$1 333 080
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
The development of methods to "reprogram" cells of adults such as skin cells to cells resembling embryonic stem (ES) cells is a major breakthrough in stem cell biology. ES cells have the potential to develop into any type of tissue. This means that skin cells taken from a patient could be induced to become ES-like cells and then used to replace virtually any diseased or damaged tissue in that same individual. However, reprogramming is still an inefficient process, which limits its potential application in cell transplantation therapy and studies of disease. Genes reside on chromosomes in the cell nucleus, and the manner in which chromosomes are packaged and positioned in the nucleus—the nuclear architecture—is now recognized to be important in regulating gene expression and cell identity. The nuclear architecture is different between somatic cells and stem cells. Understanding how the nuclear architecture change during reprogramming, and how interactions among chromosomes regulate pluripotency is very important for understanding the mechanisms of reprogramming. In this study we will undertake biochemical, computational, molecular investigations to understand the role and mechanisms of changes in nuclear architecture in reprogramming to pluripotent cells. These studies should help us to develop novel strategies to make reprogramming more efficient so that cells can be generated on a large scale for use in regenerative medicine, individualized medicine and drug discovery.
Statement of Benefit to California: 
California is the most populous state in the nation. Each year numerous patients in California suffer from diseases, such as Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, multiple sclerosis, diabetes and cancer, without a cure. Since many of these diseases are chronic and require life-time treatment, the medical costs incurred are a huge burden for patients’ families and for the society. Stem cell treatments offer hope for many patients suffering from currently incurable diseases. The development of technology to reprogram patient-specific skin cells into induced pluripotent stem (iPS) cells moves us one step closer to developing stem cells suitable for cell replacement therapy and drug screening. Stem cells generated from a patient could potentially be used to replace that individual’s diseased or damaged tissues while avoiding an immune response. Patient-specific iPS cell lines can also be used for drug discovery and toxicology studies. Since the mechanisms of reprogramming are largely unclear, being able to define the mechanisms underlying iPS cell induction will be important before iPS cells can be used effectively for therapy to address some of the most devastating healthcare issues in our state. California is a leader in stem biology research, and significant economic benefits, including job creation and revenue associated with application of stem cell technologies and drug discoveries, could accrue to the State of California and its citizens.
Review Summary: 
This proposal aims to understand the architecture of the cell nucleus and chromosome structure in pluripotent stem cells and how these properties change during reprogramming. The proposed studies focus on a pluripotency gene and its interaction with other chromosomal regions. The applicant argues that this research may lead to a better understanding of the reprogramming process to inform strategies that will improve the efficiency of generating pluripotent stem cells. Significance and Innovation - While studying the chromosome architecture characteristic of pluripotency is useful, reviewers were not convinced that the proposed studies would have a major impact on understanding pluripotency. - Reviewers were unclear of the significance that the proposed studies would have on developing improved methods of reprogramming, especially given that the efficiency of generating induced pluripotent stem cell lines is already improving with integration-free methods. - The research plan was not viewed as highly innovative. Feasibility and Experimental Design - Preliminary data provided are sound; however the pluripotency readouts are not adequate, as they do not include an analysis of differentiation potential. The same criticism applies to the proposed pluripotency assays. - The proposed specific aims were largely descriptive. Reviewers felt that Aim 3 was vague and lacking important experimental detail, although conceptually interesting. - Reviewers were unclear on the rationale for the selection of the cell types that will be compared with pluripotent stem cells. Principal Investigator (PI) and Research Team - The PI and research team have good expertise. - There was some concern expressed that the PI does not have a strong publication record in the particular area of this proposal. Responsiveness to the RFA - The proposal was viewed as responsive to the RFA.
Conflicts: 

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