Developing biological vascular grafts can potentially revolutionize the treatment of patients who need new blood vessels. The most obvious way to assemble vessels for therapeutic use is to recapitulate the developmental processes that lead to vessel assembly. My first goal will be to obtain an understanding of vascular development so that the goal of therapeutic assembly can be realized. The signaling roles of blood vessel components and the biological molecules involved in vascular assembly and patterning will contribute to the engineering of biological vascular grafts. Conceivably, these molecules can be applied in bioengineering to promote assembly of blood vessels and to define the boundary of vascular growth once the vascular graft is implanted into a site in vivo. Ca2*/Calcineurin/NF-ATc pathway is crucial for proper vascular development. Disruption of this pathway leads to disassembly of endothelial and smooth muscle cell layers of the blood vessel wall, and aberrant vascular invasion into tissues that normally form the anatomic vascular boundary. To address the spatiotemporal regulation of calcineurin/NF-ATc signaling during angiogenesis, mouse genetic models in which the calcineurin signaling is disrupted only in endothelial cells or vascular smooth muscle cell progenitors will be generated to study the contribution of this signaling pathway in either cell type to the recruitment of smooth muscle cells to the vascular wall. Signaling roles of calcineurin B in vascular patterning and development of arterial and venous systems will also be assessed using these mouse models. In addition, DNA microarray technology will be employed to identify novel genes regulated by the Ca2+/Calcineurin/NFATc pathway during angiogenesis. Emphasis will be placed on genes that promote the vascular assembly and genes that define the anatomic vascular paths. The expression profile of candidate genes will be studied using in situ hybridization, and their functions will be studied with various in vitro angiogenesis assays.
| Chang, Ching-Pin; Neilson, Joel R; Bayle, J Henri et al. (2004) A field of myocardial-endocardial NFAT signaling underlies heart valve morphogenesis. Cell 118:649-63 |
| Chang, Ching-Pin; McDill, Bradley W; Neilson, Joel R et al. (2004) Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery. J Clin Invest 113:1051-8 |
