Vascular Injury Working Group
Investigators from several departments within the UTHSC have been brought together by the Vascular Biology Center to coordinate research on campus in the area of vascular biology. The core working group consists of several investigators and their projects are described below:
Experiments involve the use of adenoviral vectors expressing wild type and dominant negative mutants of SHP2 as well as the use of blocking antibodies directed against SHP2. If these experiments are successful, an attempt will be made to identify the proteins that interact with SHP2 in the signal transduction pathways that modulate collagen synthesis, for instance the Jak/Stat pathways (Dr. Aviv Hassid and Dr. Larry Pfeffer). Further, appropriate adenoviral vectors will be used to determine the potential significance of SHP2 in collagen synthesis in vivo using an animal model system (Dr. Aviv Hassid and Dr. Hiroko Nishimura).
An evaluation of the potential role of SHP2 as mediator of nitric oxide (NO)-induced endothelial cell motility is another project that is in progress. NO upregulates SHP2 protein in vascular smooth muscle cells. If the same process occurs in endothelial cells, it could explain how NO stimulates endothelial cell motility (Dr. Aviv Hassid and Dr. Lisa Jennings), since SHP2 is necessary for cell motility of all kinds of cells. This hypothesis would be relevant to a model of angiogenesis. In vivo models would involve an angiogenesis model established by Dr. Tarun Patel (Dr. Tarun Patel and Dr. Aviv Hassid) or more exotic models involving cranial windows in mice established by Dr. Charlie Leffler (Dr. Charlie Leffler and Dr. Aviv Hassid).
The contribution of eicosanoids particularly metabolites of arachidonic acid formed via lipoxygenase and cytochrome p-450 pathway, and the underlying mechanism of their action in vascular cells is being investigated. Cell proliferation, hypertrophy, extracellular matrix protein synthesis, angiogenesis, changes in vascular contraction caused by norepinephrine and angiotensin II are being examined. Collaborations have been established to explore the cellular and molecular mechanism of action of eicosanoids in terms of the role of phosphatases and SHP2 (Dr. KU Malik and Dr. Aviv Hassid) Sprouty (Dr. KU Malik and Dr. Tarun Patel) and the Stats/JAK pathway (Dr. KU Malik and Dr. Larry Pfeffer).
Investigations into the role of Sprouty in vascular smooth muscle cell proliferation and migration are also involved. Having shown that Sprouty is a modulator of both processes in VSMC, studies are underway to elucidate the mechanisms and signaling processes which are altered by Sprouty. Alterations in the levels of protein phosphatases (Dr. Tarun Patel and Dr. Aviv Hassid), effects of Sprouty on migration of VSMC toward fibronectin (Dr. Tarun Patel and Dr. Lisa Jennings) and alterations in the tyrosine phosphorylation (Dr. Tarun Patel and Dr. Larry Pfeffer) are being examined.
The final area includes the investigation of the critical role of Tetraspanins in modulating cell adhesion, migration, proliferation and survival. One project involves investigating the role of tetraspanin CD9 in vascular smooth muscle cell and endothelial cell function. Studies have demonstrated the association of CD9 with integrins. To better understand the cellular and molecular mechanisms by which CD9 regulates cell function, investigations are underway to examine the role of CD9 in motility (Dr. Lisa Jennings, Dr. Celia Longhurst and Dr. Tarun Patel), cell proliferation and survival (Dr. Lisa Jennings and Dr Larry Pfeffer) and to elucidate the signaling pathways associated with CD9 mediated functions (Dr. Lisa Jennings, Dr. Al Cook and Dr. Aviv Hassid).
Ongoing Collaborations - Vascular Biology Participating Faculty
Within the Center, research is underway to understand the mechanisms of vascular smooth muscle cell (VSMC) growth, a component of atherosclerosis and restenosis. Previous work indicated a role for oxidants in the regulation of VSMC growth. Phospholipases A2 are a group of enzymes that breakdown membrane phospholipids generating arachidonic acid, a substrate for the production of eicosanoids. In addition to their role in several cellular processes such as vessel wall contraction/relaxation, chemotaxis, inflammation and cell proliferation/apoptosis, eicosaniods act as pro-oxidants. Currently, work is being carried out on the identification of PLA2 that is responsible for the release of arachidonic acid in VSMC and its involvement in the regulation of VSMC growth. (Dr. Rao Gadiparthi)Platelets are critical components for hemostasis. GPIIb-IIIa is the major integrin on the platelet surface and is responsible for mediating platelet aggregation. Upon ligand engagement of GPIIb-IIIa, the receptor undergoes a conformational change resulting in the exposure of neoepitopes or LIBS (ligand induced binding sites). These regions are thought to play an important role in post-receptor occupancy events such as full-scale platelet aggregation and clot retraction. Understanding the mechanisms associated with outside-inside signaling through the ligand occupied GPIIb-IIIa (Dr. Jennings, Dr. Slack and Dr.Grgurevich) is a focus of one projects of the program.
An additional program involving integrin biology is the investigation into the role of integrin cytoplasmic domains and associated proteins such as ICAP-1 in modulating integrin-mediated functions such as cell migration (Dr. Xin Zhang and Dr. Lisa Jennings).
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