FAK(pp125FAK) is a major signaling protein involved in cell-matrix adhesion. Inflammatory cytokines generated by a mechanical injury and infection alter endothelial cell interactions with extracellular matrix and activate peripheral blood monocytes. Cytokines enhance the movement of fluid and inflammatory cells out of the vascular space, and modulate wound healing in the vascular wall. The proposed studies examine the role of FAK in cellular responses to vascular injury. The first specific aim is to define the mechanisms of FAK regulation of endothelial cell motility. Video microscopy and a FAK-green fluorescent protein construct will be used to track FAK dynamics and endothelial cell migration. The effects of FAK over-expression , dominant negative FAK, and mutants defective for interactions with paxillin, talin, and Src-family kinases will be defined in motility assays. The second specific aim is to elucidate pathways of FAK signaling to the nucleus in the regulation of endothelial cell proliferation. FAK signaling will be manipulated by expression of exogenous FAK variants and cells evaluated for cytokine- induced changes in bromodeoxyuridine incorporation and cyclin D1 expression. The third specific aim is to examine the role of FAK in endothelial cell barrier function. FAK expression, activity, and signaling will be studied in models of inflammation including cytokine- treated human endothelial cell monolayers and the intimal surfaces of atherosclerotic vessels. The fourth specific aim is: To define the role of FAK in the function of monocyte-derived macrophages. FAK function will be perturbed in differentiated monocyte-derived macrophages by loading with dominant negative forms of FAK. The effects of adhesion, chemotaxis, and apoptosis will be assessed. The in vitro modeling in the proposed project will allow us to define the consequences of the molecular manipulation of FAK signaling for each of the above components of cellular response to inflammatory vascular injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Comprehensive Center (P60)
Project #
3P60DE013079-01S1
Application #
6300942
Study Section
Project Start
1999-08-01
Project End
2000-07-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
$116,783
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Arce, R M; Caron, K M; Barros, S P et al. (2012) Toll-like receptor 4 mediates intrauterine growth restriction after systemic Campylobacter rectus infection in mice. Mol Oral Microbiol 27:373-81
Qian, Li; Wu, Hung-ming; Chen, Shih-Heng et al. (2011) ?2-adrenergic receptor activation prevents rodent dopaminergic neurotoxicity by inhibiting microglia via a novel signaling pathway. J Immunol 186:4443-54
Arce, R M; Diaz, P I; Barros, S P et al. (2010) Characterization of the invasive and inflammatory traits of oral Campylobacter rectus in a murine model of fetoplacental growth restriction and in trophoblast cultures. J Reprod Immunol 84:145-53
Maile, Laura A; Busby, Walker H; Nichols, Timothy C et al. (2010) A monoclonal antibody against alphaVbeta3 integrin inhibits development of atherosclerotic lesions in diabetic pigs. Sci Transl Med 2:18ra11
Lemmon, Christopher A; Chen, Christopher S; Romer, Lewis H (2009) Cell traction forces direct fibronectin matrix assembly. Biophys J 96:729-38
Qian, Li; Hu, Xiaoming; Zhang, Dan et al. (2009) beta2 Adrenergic receptor activation induces microglial NADPH oxidase activation and dopaminergic neurotoxicity through an ERK-dependent/protein kinase A-independent pathway. Glia 57:1600-9
Light, Kathleen C; Bragdon, Edith E; Grewen, Karen M et al. (2009) Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain 10:542-52
Williams, Ray C (2008) Understanding and managing periodontal diseases: a notable past, a promising future. J Periodontol 79:1552-9
Qian, Li; Wei, Sung-Jen; Zhang, Dan et al. (2008) Potent anti-inflammatory and neuroprotective effects of TGF-beta1 are mediated through the inhibition of ERK and p47phox-Ser345 phosphorylation and translocation in microglia. J Immunol 181:660-8
Qian, Li; Flood, Patrick M (2008) Microglial cells and Parkinson's disease. Immunol Res 41:155-64

Showing the most recent 10 out of 70 publications