The primary focus of the proposed research is to delineate the molecular mechanisms through which intracellular tension regulates endothelial cell proliferation. Vascular cell types, including endothelial and smooth muscle cells respond to a variety of cell growth control signals including soluble growth factors, adhesion to the extracellular matrix (ECM), and physical forces resulting from cell spreading (changes in projected cell area) and fluid shear stress. Diseases such as atherosclerosis are characterized by excessive proliferation of vascular cell types, thus a major hurdle to treating vascular disease is a complete understanding of the growth control mechanisms governing the proliferation of vascular cells. Based on preliminary data generated in our laboratory, we hypothesize that intracellular tension generated through the RhoA signaling pathway is a key regulator of endothelial cell proliferation. In this proposal we plan to investigate the signaling pathways which link endothelial cell spreading and establishment of intracellular tension to proliferation. The proposed research will use a molecular genetic approach coupled with microfabrication technologies to investigate tensional pathways leading to cell proliferation. Specifically, we plan to use microcontact printing techniques to limit cell spreading while expressing signaling proteins involved in intracellular tension generation, including RhoA, and ROCK. Furthermore, a novel cellular tension microsensor will be used to directly measure intracellular tension in response to manipulation of these pathways. This project will provide insight into the molecular mechanisms controlling endothelial cell proliferation and ultimately, this understanding may lead to better treatment strategies for vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32HL076060-02
Application #
6951353
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Lograsso, Philip
Project Start
2004-01-15
Project End
2006-01-14
Budget Start
2004-09-30
Budget End
2005-01-14
Support Year
2
Fiscal Year
2004
Total Cost
$16,022
Indirect Cost
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Wendy F; Nelson, Celeste M; Pirone, Dana M et al. (2006) E-cadherin engagement stimulates proliferation via Rac1. J Cell Biol 173:431-41
McBeath, Rowena; Pirone, Dana M; Nelson, Celeste M et al. (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6:483-95