Principal Investigator/Program Director (Last, first, middle): Tzima, Eleni RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? l Yes m No IACUC Approval Date: Animal Welfare Assurance Number A3410-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 4561-Summary.pdf Mime Type: application/pdf 7. * Project Narrative 4200-Narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 5980-References.pdf Mime Type: application/pdf 9. Facilities &Other Resources 3011-Facilities.pdf Mime Type: application/pdf 10. Equipment 1275-Equipment.pdf Mime Type: application/pdf Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Tzima, Eleni 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. 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. Project Description Page 6

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL088632-02S1
Application #
7837087
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Srinivas, Pothur R
Project Start
2009-07-15
Project End
2011-06-30
Budget Start
2009-07-15
Budget End
2011-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$236,032
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
McCormick, Margaret E; Collins, Caitlin; Makarewich, Catherine A et al. (2015) Platelet endothelial cell adhesion molecule-1 mediates endothelial-cardiomyocyte communication and regulates cardiac function. J Am Heart Assoc 4:e001210
Collins, Caitlin; Tzima, Ellie (2014) Rac[e] to the pole: setting up polarity in endothelial cells. Small GTPases 5:e28650
Collins, Caitlin; Osborne, Lukas D; Guilluy, Christophe et al. (2014) Haemodynamic and extracellular matrix cues regulate the mechanical phenotype and stiffness of aortic endothelial cells. Nat Commun 5:3984
Sweet, Daniel T; Chen, Zhongming; Givens, Christopher S et al. (2013) Endothelial Shc regulates arteriogenesis through dual control of arterial specification and inflammation via the notch and nuclear factor-?-light-chain-enhancer of activated B-cell pathways. Circ Res 113:32-39
Liu, Yunhao; Collins, Caitlin; Kiosses, William B et al. (2013) A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress. J Cell Biol 201:863-73
Collins, Caitlin; Tzima, Ellie (2013) RhoA goes GLOBAL. Small GTPases 4:123-6
Givens, Christopher; Tzima, Ellie (2012) S1P1 bridges mechanotransduction and angiogenesis during vascular development. Dev Cell 23:451-2
Sweet, Daniel Timothy; Chen, Zhongming; Wiley, David M et al. (2012) The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis. Blood 119:1946-55
Collins, Caitlin; Guilluy, Christophe; Welch, Christopher et al. (2012) Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway. Curr Biol 22:2087-94
Wang, Shijun; Cao, Canhong; Chen, Zhongming et al. (2012) Pericytes regulate vascular basement membrane remodeling and govern neutrophil extravasation during inflammation. PLoS One 7:e45499

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