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We are interested in understanding the molecular basis of vascular development in the glomerulus and disease using zebrafish.
Our overall goals are to identify kidney endothelial cell precursors and the underlying pathways that specify these cells. Vascular injury in the glomerulus is a common and significant problem of kidney dysfunction. Understanding normal developmental pathways and endothelial function is critical for prevention and recovery from vascular injury. These studies may lead to identifying new therapeutic targets as well as advancing our knowledge on cell-based therapies for glomerular vascular disease. In addition, we are studying other organ-specific vessels including the heart.
Mapping the glomerular vasculature lineage:
We are using transgenic fish embryos to map the cells that contribute to the mature glomerulus. By knowing how cells migrate to form the glomerulus and the process of their specification, we will know whether glomerular cells are different from other endothelial cells and, for instance, how the processes of capillary fenestration occurs. We are also aiming to understand the specific contribution of glomerular endothelial cells as a vital component of the glomerular filtration barrier.
Hemangioblast and vascular development:
The hemangioblast, a stem cell for both endothelial and hematopoietic cells, was proposed a century ago, which is now identified in mouse embryonic stem cells-derived embryoid bodies and zebrafish embryos. However, it remains unclear how the hemangioblast is generated from the brachyury+ mesodermal cells, and what are the molecular signaling pathways underlying the specification of hemangioblasts. Cloche was initially discovered in a large-scale mutagenesis screen of the zebrafish genome in Dr. Mark C. Fishman's laboratory many years ago. Cloche lacks all flk1+ and scl+ cells, and fails to form vessels, blood and the endocardium. Therefore, cloche may encode a determination gene for the hemangioblast. We have recently cloned a novel acyltransferase (lycat) from the cloche mutant locus as well as its mouse orthologue lycat. Lycat is essential and sufficient for the generation of embryonic vessels and blood in zebrafish and embryoid bodies. We are actively working on the lycat gene and protein function in vascular development, and identifying its interacting and target proteins using biochemical, molecular and genetic approaches in zebrafish and mouse embryonic stem cells. We are also studying other zebrafish vascular mutants and their associated glomerular phenotypes. We are isolating the mutated genes using positional cloning, as well as will examine these genes function by embryological and molecular imaging approaches.
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