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Elucidating the molecular mechanisms of hematopoietic stem cell expansion

Funding Type: 
Basic Biology V
Grant Number: 
Funds requested: 
$1 134 696
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
Blood stem cell transplantation is an effective treatment for patients with hereditary blood cell disorders which include severe combined immunodeficiency, sickle cell disease, thalassemia, Fanconi anemia, and a possible life-saving treatment for patients of myelodysplastic syndrome, myeloid proliferative neoplasm, and various forms of leukemia. One major limitation of treating these diseases with blood cell transplantation is to find compatible donors. Blood stem cells for transplantation can be from bone marrow, specially mobilized peripheral blood, or umbilical cord blood. A major advantage of using cord blood in transplantation is a significantly lower rate of immune complication, which allows a greater degree of mismatch and results in increasing the donor pool. Furthermore, cord blood collection is simple and there is no risk to mother or infant. However, the biggest hurdle for using cord blood in transplantation is that the number of blood stem cells in a single umbilical cord is insufficient for an adult or older pediatric patient. Hence, methods to expand blood stem cells are urgently needed in the treatment of patients whose lives may be saved or quality of life may be significantly improved with transplantation. In this application, we propose to study the basic biology of using a special gene expression regulator to increase the number of donor blood stem cells in culture. This is highly relevant to the main goals of CIRM.
Statement of Benefit to California: 
Thousands of Californians suffer from blood-related diseases that may potentially be cured with blood stem cell transplantation. However, these life-saving measures are limited by a lack of eligible donors. This problem is much worse for non-Caucasians, who represent a significant proportion of California’s population, due to an insufficient number of non-Caucasian donors in blood stem cell registries. Bone marrow, stimulated peripheral blood, and umbilical cord blood are three resources for transplantation. A major advantage of using cord blood is that it allows for a higher degree of immune mismatching, which would increase the number of suitable donors for blood stem cell transplantation to benefit more patients. A major issue of using cord blood is the limited stem cell number in each umbilical cord. We propose to examine a novel approach to expand the number of blood stem cells from available cord blood for transplantation. One long term benefit of the proposed work is to improve the treatment of thousands of Californian patients who need to receive healthy, functioning blood stem cells to alleviate their disease conditions. In turn, this will benefit California’s financial status in reducing the cost of treating these patients with expensive yet ineffective methods. Furthermore, the proposed research will continue to maintain California’s leadership in the field of stem cell research and provide training and education for some of California’s bright young minds.
Review Summary: 
This Fundamental Mechanisms application aims to identify novel means to expand the hematapoietic stem cells derived from cord blood (CB-HSC) through the study of a transcriptional regulator that mediates HSC expansion. The applicants will assess the impact of expressing the regulator upon the stem cell behavior of human CB-HSCs, both ex vivo and in a rodent model. Next, they plan a series of studies to elucidate the molecular mechanisms whereby the regulator of interest exerts its beneficial effects on HSC expansion. The team hopes to use this information to identify drug targets, and ultimately drugs, to safely expand CB-HSC for clinical applications. Significance and Innovation - The inability to expand HSCs in the laboratory is a major limitation to potentially life saving CB-HSC therapy for adult patients. Even a modest expansion (e.g. 2-fold) of the CB-HSCs would have an immediate clinical impact and be highly significant. - While overall the research plan isn’t very mechanistically focused, the novelty lies in the special form of the transcriptional regulator to be studied. - Safety concerns were expressed as the regulator has been associated with undesirable effects upon the blood system. Feasibility and Experimental Design - The experimental design and plans of the work are relatively straightforward. However, the aims are interdependent, and no alternative plans are proposed in the event that the first aim is not successful. - The timeline proposing parallel work upon the aims is incompatible with their interdependent nature. - Preliminary data left reviewers unconvinced that it would be possible to dissociate the regulator’s efficacy from its previously associated undesirable effects. - It is unclear how the team would determine which targets to pursue for further study if mechanistic studies prove successful. - The study builds upon the group’s preliminary data that the regulator can increase hematopoiesis. Principal Investigator (PI) and Research Team - The PI is a well-established investigator, has a strong track record of publications in high impact journals, and is a recognized expert on the molecular mechanisms of hematopoiesis. - The team has the expertise to carry out the proposed studies. - The level of participation of the key bioinformatics collaborator was unclear. Responsiveness to the RFA - The proposal targets a human HSC mechanism and is responsive to the RFA.

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