New Faculty II
$3 155 931
Statement of Benefit to California:
This proposal focuses on the role of adventitial cells (a connective tissue layer in blood vessel walls) in the vascular remodeling that occurs during repair of injured arteries. The clinical scenario most relevant to this proposal in humans is that following percutaneous transluminal coronary angioplasty (PTCA), a procedure in which physicians use a guidewire to position a balloon where it can be inflated to open up the lumen of an atherosclerotic artery. In 20-50% of cases, restenosis (re-occlusion of the vessel lumen) occurs. As a response to the vessel wall damage during PTCA, cells are activated to divide and cause obstruction of the arterial blood flow. The applicant’s preliminary results suggest that adventitial cells are activated by an angiogenic cytokine to causes restenosis after vascular injury. In order to study the mechanism of restenosis, the applicant proposes three aims. In the first aim, the applicant seeks to examine the cellular responses of adventitial cells to angiogenic cytokine-mediated signaling by purifying these cells and then analyzing proliferation/apoptosis, differentiation and migration. In the second aim, the applicant attempts to define the roles of specific angiogenic receptors in adventitial cells by studying knock out mice, and assessing the ability of mice with particular gene deletions to repair wire-injured vessels. Finally, in the third aim, the applicant seeks to define the molecular pathways downstream of the angiogenic receptors in adventitial cells by transcriptionally profiling isolated cells that have been treated with anti-receptor antibodies following angiogenesis, and further observing changes of the expression of candidate genes in injured vessels when receptor signaling is inhibited in the knock out mice. Reviewers judged the application to be a logical and well thought out research plan, focusing on a significant clinical problem that is relatively under-investigated. Overall, the reviewers felt the experimental design was well written and within the expertise of the team. The applicant demonstrated availability of the necessary tools to complete to proposed work, notably appropriate mouse models and vectors to dissect the signaling pathways, and the necessary reagents for isolation of cells. A few weaknesses were identified with the proposal. Reviewers were divided in their assessment on whether the adventitial cells were adequately established as stem cells. Two reviewers felt that the preliminary data were weak in this aspect, and would have been more convincing with lineage tracing or classical self-renewal and differentiation experiments proposed. One reviewer expressed concern that the adventitial cell population isolated by the proposed markers could represent a heterogeneous population of cells, and that further work should be done to define the phenotype, localization, and function of these cells in vivo. However, one reviewer expressed great excitement that the applicant could identify a resident stem cell in the adventitia, and that the potential for this research is enormous. This point was underscored by the fact that this area of cell biology is relatively understudied. Reviewers felt the applicant was well trained and qualified to conduct the proposed studies. The candidate has trained in cardiovascular medicine and developmental biology, which are both relevant to the proposed research. The PI has a number of high quality publications, both as a trainee and in the first two years as an independent investigator. The applicant has recruited two senior stem cell scientists as mentors, but no letters accompany the application. One reviewer commented that a mentor with vascular biology expertise would also have been desirable. A career development plan is present, but lacked detail. The institutional supported was judged to be strong. A letter of commitment co-authored by the Chief of Research in the Cardiovascular Division and the Chief of Medicine of the Department of Medicine is included in the application. The candidate has been awarded sufficient laboratory space and funds to equip the laboratory as a start up package. Reviewers noted that the institution has an excellent track record of developing its young faculty. A motion was made to recommend this application be moved to Tier 1 - Recommended for Funding. During programmatic discussion, the panel highlighted the significance of the clinical problem being addressed, and emphasized that the proposal focused on a translational target that was “within reach” of development toward a potential therapeutic. The PI was judged to be a strong physician-scientist candidate who is at the earlier stage of an independent career, and therefore is an excellent candidate for this RFA. The motion to move this application to Tier 1 carried.