Funding opportunities

The Genetic Landscape of Hematopoietic Stem Cells

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07419
Funds requested: 
$663 806
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
Hematopoietic stem cells (HSCs) play crucial roles in maintaining mature, functional cells in various tissues and provide life-saving treatments for multiple hematological disorders. Identifying the genetic factors that govern HSC number/function could thus have important therapeutic implications as well as increase our biological knowledge of this vital regenerative tissue system. In recent years, the power of genome-wide association studies (GWAS) has been overwhelmingly demonstrated in humans where hundreds of novel susceptibility alleles have been identified for a variety of clinical traits. However, human GWAS are primarily applicable to traits that can be obtained in large numbers of subjects, thus limiting the utility of this approach for other biomedically relevant phenotypes, including HSCs. To address this limitation, we will utilize the newly developed Hybrid Mouse Diversity Panel (HMDP) for GWAS in mice. In preliminary studies with ~100 HMDP mouse strains, we have identified over 10 chromosomal regions influencing HSCs. We now propose to confirm and expand these findings. In Aim 1, we will carry out in depth studies to functionally characterize two novel HSC candidate genes identified by this approach. In Aim 2, we will phenotype the remaining HMDP strains to identify additional loci associated with HSCs. These efforts could offer extensive new insight into the biological pathways controlling HSCs as well as provide targets for therapeutic development.
Statement of Benefit to California: 
California is home to over 38 million people and one of the most ethnically diverse states in the country. In 2012, over 17,000 bone marrow transplants were performed in the United States, of which 20% were done in California alone. While hematopoietic stem cells (HSCs) provide life-saving treatments, fewer individuals are able to find suitable donors in California than in less ethnically diverse regions due to biases in the unrelated bone marrow donor registries. One approach for addressing these limitations is to expand the number of HSCs prior to transplantation by either manipulating them in the laboratory or increasing the numbers collected from donors. However efficient methods to implement these procedures have yet to be established. Our overall goals are to carry out a genetics study and identify the genes that control HSC number and/or function. These genes could then serve as targets for therapeutic development in order to increase the yield of HSCs for clinical treatments. This strategy could also serve as a paradigm for studying other types of stem cells.
Review Summary: 
This Exploratory Concepts proposal aims to better understand how hematopoietic stem cells (HSC) are regulated. In the first aim, the investigators propose to perform loss and gain of function studies to determine whether two candidate genes can regulate HSC frequency and function. The second aim will screen for additional genes that could regulate HSC by correlating differences in HSC numbers with genetic differences in a broad panel of genetically diverse mice. Newly associated genes will be validated as in the first aim. Collectively, the results of these studies are expected to lead to a better understanding of mammalian HSC biology and to the identification novel therapeutic targets. Novelty and Transformative Potential - Tangible benefits to human health were inadequately developed in the application, and reviewers did not find the applicant’s rationale for further genome wide association studies (GWAS) compelling. Historically, GWAS data have had an inconsistent track record of increasing our understanding of disease and informing treatments. - Reviewers did not find the application adequately transformative to be competitive in the Exploratory Track. - The usage of the diverse mouse panel to identify additional genes that regulate HSC number is innovative, but it detracts slightly from the emphasis of CIRM on human systems. Feasibility and Experimental Design - The choice of the readout for the screen concerned reviewers, as it lacks a straightforward relationship to HSC function. Further, reviewers cautioned that markers used for the readout are dynamically expressed and may not correlate with HSC function. Thus, results from the work could be misleading. - Reviewers noted that the vast bulk of the proposed studies would be conducted in mice and expressed concern that the results would predict human HSC behavior. - The two aims were regarded as disconnected and not synergestic. The panel suggested that further development of Aim 2 alone could strengthen the proposal. - Reviewers were uncertain how hits from the screen would be prioritized and expressed conflicting opinions regarding increasing the resolution of the genetic assays that to be employed. - There was concern that the in-depth functional analyses of the two factors proposed in Aim 1 can be accomplished in 2 years. - The challenges associated with some of the proposed experimental approaches were not adequately discussed. Principal Investigator (PI) and Research Team - The PI has the appropriate background in genetic analysis and expertise in the mouse panel to execute the proposed studies. - The complementary expertise of the co-investigators will be critical to the success of the project. The panel appreciated the commitments in both biostatistics and biodiversity to the project. - Overall, the team has the background, experience, and institutional support to perform the proposed research. Responsiveness to the RFA - The proposal is responsive to the RFA. Reviewers found use of the mouse model system justified in the study of HSC biology.
Conflicts: 

© 2013 California Institute for Regenerative Medicine