The program project application """"""""Interactive signaling modules in vascular remodeling"""""""" is proposed from the Center for Vascular Biopsy at the University of Connecticut Health Center, Farmington. This program is composed of four projects and five cores and is focused on the process of vascular remodeling. The program brings together seven independent investigators interested in the vascular remodeling processes. The theme of the program is to define molecular mechanisms important for physiologic and pathologic vascular remodeling processes. The theme of the program is to define molecular mechanisms important for physiologic and pathologic vascular remodeling. The central hypothesis is that distinct signal transduction pathways interact with each other to modulate fundamental cellular processes such as cell migration, proliferation, differentiation, death and cell-cell interaction, ultimately leading to alterations in the structure of the vasculature. Each project in the program focuses on a unique aspect of the theme to advanced our understanding of vascular remodeling. Project 1 (H1a) proposes to investigate the physiological basis of the platelet-derived lysophospholipid mediator, sphingosine 1-phosphate (S1P). Signaling of S1P via the G-protein- coupled receptors of the EDG family to regulate endothelial cell migration, endothelial cell/pericyte interactions and vascular maturation will be investigated. This project shares several common interests with Project 2 (Fong), which is focused on how hypoxia affects vascular endothelial cells during the morphogenesis of the nascent vasculature in the embryo. A hypoxia-sensitive transcription factor, HIF-2alpha will then be investigated to understand signaling pathways that regulate vascular remodeling. Project 3 (Wu/Claffey) addresses pathological vascular remodeling; the specific role of PI-3-kinase-gamma, PLCbeta2/3 pathways, which modulate G-protein-dependent monocyte activation and chemotaxis will be investigated in vitro and in vivo. This project shares considerable common goals as projects 1 and 4. Project 4 (Han) focuses on the process of cell-cell recognition process by which apoptotic cells are cleared from the vascular wall. Thus, this project has common interests as projects 3 and 1 and deals with the issue of pathologic vascular remodeling. All the projects utilizes molecular, biochemical, cell biological and in vivo models. Thus five cores, administrative, fluorescence imaging, histology, proteomics and gene manipulation cores, are proposed to support the projects in state-of-the- art technology. All the projects and cores interact and mutually reinforce each other to achieve the goals of the program in a synergistic manner. Coupled with strong institutional support to the Center for Vascular Biology, it is anticipated that significant new insights on vascular remodeling will be forthcoming from this program project application.
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