Area:
Cell Biology, Physiology Biology, Genetics
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High-probability grants
According to our matching algorithm, Eleni Tzima is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2008 — 2012 |
Tzima, Eleni |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Endothelial Cell Junctions in Mechanotransduction @ University of North Carolina Chapel Hill
[unreadable] DESCRIPTION (provided by applicant): Shear stress, the frictional force due to blood flow, regulates arterial pressure, vascular remodeling, cardiac and vascular embryogenesis, atherogenesis and immune responses, including migration of leukocytes into tissue. The observation that atherosclerotic plaque forms preferentially at sites of disturbed blood flow suggests that flow patterns can regulate the chronic inflammation associated with atherogenesis. Despite the importance of mechanotransduction in vascular function and pathology, the molecular mechanisms by which endothelial cells sense and respond to fluid shear stress are not well understood. Our long term goal is to understand how shear stress-dependent inflammatory signaling can be modulated for preventive and therapeutic purposes. The objective of this application is to determine how endothelial cells sense and transduce shear stress. Based on our preliminary data, we hypothesize that PECAM-1 senses mechanical force while VE-cadherin plays an accessory signaling role in inflammatory and atherogenic signals in response to flow. In particular, we hypothesize that these junctional receptors regulate cytoskeletal rearrangements, transcriptional responses, adhesion molecule expression and leukocyte transmigration under flow. By expanding our understanding of PECAM-1- and VE-cadherin-mediated signaling, we are in an excellent position to refine the present understanding of how cells respond to shear stress. To do this, we propose three aims: Specific aim #1: Determine regions in PECAM-1 required to initiate signaling in response to shear stress; Specific aim #2: Determine the role of PECAM-1 and VE-cadherin in shear stress-dependent inflammatory responses; Specific aim #3: Determine the role of PECAM-1 in inflammatory and atherogenic signals in a mouse model of carotid flow-mediated remodeling. [unreadable] [unreadable] Altogether, this research will improve our understanding of how endothelial cells sense physiological fluid shear stress and thus "promote" atherogenesis and inflammation. In addition to the basic science, delineation of these pathways should be of value from an applied perspective: development of therapies that interrupt mechanochemical signaling pathways in endothelial cells will have the potential to alter the course of cardiovascular disease and inflammation. The proposed research will improve our understanding of why atherosclerosis plaques develop in specific regions in the vascular tree and may lead to development of therapies for cardiovascular disease and inflammation. [unreadable] [unreadable] [unreadable]
|
1 |
2014 |
Tzima, Eleni |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Neovascularization in Response to Ischemia @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Neovascularization in response to ischemia is an important repair process, which is severely compromised in the setting of chronically elevated cholesterol. Therapeutic neovascularization trials have revealed dramatically reduced responses in hypercholesterolemic patients; however, there is little information on the effects of hypercholesterolemia on arteriogenesis. Arteriogenesis, the outward remodeling of collateral vessels that form bridges between arterial networks, is critical for recovery of blood perfusion to the ischemic tissue after occlusion. Collateral remodeling is driven by a sudden increase in hemodynamic forces, especially shear stress, resulting from the drastic increase in flow through collaterals. This increase in shear stress is sensed by mechanosensory proteins expressed in endothelial cells (ECs), which initiate signal transduction pathways that induce processes such as cell proliferation and inflammation. Despite significant efforts to increase collateral growth and perfusion recovery in the setting of ischemia using small molecules and gene therapy approaches, results have been largely disappointing, underscoring the importance of studies on understanding the molecular mechanisms that drive arteriogenesis. Recently published work from our group, coupled with nascent observations provided in this application, identify the signaling protein adaptor protein Src homologous and collagen protein (Shc) as an essential regulator of neovascularization. To better understand the role of Shc in neovascularization, three interrelated aims are proposed. Aim 1 will determine the role of Shc in neovascularization in response to ischemia in the setting of hypercholesterolemia. Aim 2 will determine the role of Shc in endothelial mechanotransduction under defined collateral hemodynamic conditions in vitro. Aim 3 will determine the molecular determinants in Shc that facilitate neovascularization. Experiments proposed in this proposal will contribute to our understanding of molecular mechanisms of arteriogenesis and collateral remodeling. Elucidation of some of the signals that regulate post-ischemic neovascularization is needed in order to develop therapeutic strategies for diseases such as peripheral vascular disease, arteriosclerosis and wound healing.
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0.988 |