The candidate for this award is a research fellow with a PhD in cell biology and postdoctoral experience in developmental genetics of the mouse, who wants to study genetic basis of cardiovascular aging, and desires to learn the zebrafish embryology, genetics and vascular diseases for this end. The career development plan will focus initially on acquiring basic knowledge and experimental skills, and subsequently on establishing an independent research program on aging and vascular diseases applying his combining expertise in the zebrafish and mouse genetic organisms as a member of the Cardiovascular Research Center under the leadership of Dr. Mark Fishman. The institutional environment is the Massachusetts General Hospital and Harvard Medical School, which supports many world-class scientists in the field of developmental biology and aging. The training site will be the laboratories of Drs. Mark Fishman and Paul Huang. Dr. Fishman is an internationally recognized leader in developmental biology of the zebrafish and mouse. Dr. Huang is a world-class mouse geneticist in atherosclerosis and stroke. Drs. Fishman's and Huang's laboratories are replete with well trained personnel and state-of-the-art supplies, equipment, and well-established fish and transgenic mouse facility, that will be crucial to carry out the proposed research and career development plan. The long-term goal of this project is to utilize therapeutic angiogenesis to grow new blood vessels for aging and aging-related ischemic heart diseases. The proposed studies focus on cloning and functional analysis of the most upstream gene, cloche, in establishing the first endothelial and blood cells in the embryo, and its roles in postnatal vessel formation of adult fish and mouse models for aging and atherosclerosis. We have identified cloche mutants in large-scale mutagenesis screens of the zebrafish genome. cloche lacks all flk-l-expressing cells, and fails to form both vessels and blood. Cell transplantation studies revealed that the endocardial deletion is a cell- autonomous lesion. These observations have led us to hypothesizing that cloche encodes a determination gene for both endothelial and hematopoietic cells, specifying a stem cell with dual fate, termed the hemangioblast. To examine this hypothesis, we will isolate the cloche gene by using complementary approaches of positional cloning and transgenic PAC rescue, and characterize cloche by gain-of-function in zebrafish embryos and adults. We will further isolate and characterize cloche homolog(s) in mouse embryos and adults and mouse models for aging and atherosclerosis. These studies will allow us to decipher cloche gene functions during normal and abnormal differentiation, proliferation and aging of endothelial cell and its stem cells. Therefore, the proposed project is directly addressing roles of cloche in cardiovascular aging and its implication in stem cell biology and therapies. Ultimately, our findings may have impact on the understanding and management of pathological processes of angiogenesis, and application of endothelial and hematopoietic stem cells in human is ischemic heart diseases.
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