New Faculty II
$2 408 665
Coronary artery disease, which often results in congestive heart failure, cannot be cured with conventional treatments, suggesting the need of alternate and novel methodologies to confront this disease and its associated pathologies. In the current context, stem cell-based therapy points to one of the most promising alternatives for the cure of coronary disease. Our main focus of the research is the analysis of the mechanisms that regulate the formation of the coronary vasculature from precursor cells in the epicardium, which is the outermost layer of the heart near where the coronary vessels develop. We have gathered data that indicates that human embryonic stem cells can be used as a source of epicardial progenitors for coronary vessel repair and cardiac regeneration. This proposal aims to lay groundwork for coronary vascular therapy and cardiac repair based on embryonic stem cell technology.
Statement of Benefit to California:
Heart disease is a leading cause of mortality in California. In particular, coronary artery disease, which often results in congestive heart failure, cannot be cured with conventional treatments, suggesting the need of alternate and novel methodologies to confront this disease and its associated pathologies. In the current context, stem cell-based therapy points to one of the most promising alternatives for the cure of coronary disease.
The focus of this application is analysis of the mechanisms that regulate the formation of the coronary vasculature from precursor cells in the epicardium, which is the outermost layer of the heart near where the coronary vessels develop. The long-term goal of this proposal is to determine if human embryonic stem cell (hESC)-derived epicardial progenitor cells (EPCs) can form coronary vascular structures and other cardiac cell types for use in patients with heart disease. In the first aim, the applicant proposes to use a transgenic mouse model to establish the lineage of EPCs. The second aim will investigate the potential of mouse and human ESCs to form epicardial progenitor cells. In the final aim, the applicant proposes to evaluate whether EPCs can be used as therapeutic agents in cardiac injury models. Reviewers recognized the potential clinical significance of the proposed work, and called the proposal exciting and innovative. However, reviewers were mixed in their opinions of the design and feasibility of the research plan. Reviewers generally liked the first aim, noted that the investigator had the research tools already in hand, and felt that the clonal analysis proposed had the potential to conclusively determine the fate of the EPCs, offering advantages beyond fate mapping. One reviewer commented that the array analysis proposed to determine the signature of the EPCs under the first aim might not be necessary, since markers already exist. Reviewers questioned the feasibility of the second aim, which was judged to be key to the proposal. All reviewers commented that it was unknown if the applicant will be able to differentiate hESCs to EPCs, and noted that this was a necessary milestone to perform the proposed experiments in the third aim. One reviewer expressed concern that the time course of emergence of the EPCs is likely to differ between the mouse and human ES cell systems, and the proposed markers may not be specific to the cell lineages. Finally, reviewers felt the third aim to be important but only briefly described by the applicant, and noted that it is dependent on the ability of the applicant to generate the desired ES cell-derived EPCs. For these reasons the overall enthusiasm for the proposal was subdued. Reviewers judged the applicant to be qualified to perform the proposed work. Though limited in direct stem cell experience, the applicant has secured two very experienced stem cell researchers as mentors, and the mentoring plan is convincing that sufficient interaction could effectively develop these skills in the applicant. Reviewers noted the applicant’s strong record in working with transgenic mouse models, a key aspect of this proposal. Reviewers noted a few first author publications, with most being either co-authored manuscripts or book chapters. Reviewers noted a renewed NIH R01 grant. The applicant’s career development path had a clear focus on understanding the proepicardium and derivatives, but it was not clear to reviewers how the applicant’s career would progress (i.e. what are the milestones, the projected timeline for promotion, and how trainees will be mentored). The institutional support was judged to be strong. Laboratory space, start-up funding and core services are provided to the applicant. Additionally, reviewers noted a strong institutional support letter, with a clear goal and plan to foster outside interaction between the applicant and the greater stem cell community. In summary, although the proposal has two strong components: the principal investigator and the institutional commitment, reviewers had significant concern with the feasibility of the research plan. This dampened the overall enthusiasm for this proposal.