Abstract

In this renewal application, the second messenger pathways in thrombin receptor activation will be linked to specific locations in the extracellular domain of the receptor, focusing on protein kinase C (PKC) isoforms and myosin light chain kinase (MLCK). The functional effect studied has been increases in vascular endothelial cell permeability in endothelial cell cultures and in rat lung preparations. New information on the sequence and structure of the thrombin receptor will be used to generate antibodies to specific domains and define the """"""""tethered-ligand"""""""" mediated receptor activation, as defined by PKC and MLCK activity as well as Ca increase, and inositol polyphosphate generation, and for increasing endothelial cell permeability measured in several ways. PKC isoforms and their relation to endothelial cell permeability will be investigated utilizing gene transfection experiments with PKC alpha or Beta-1 in the sense or antisense orientation to overexpress or inhibit the isoenzymes. MLCK phosphorylation and its linkage to endothelial permeability will be explored with the endothelial cell transfection approaches in similar fashion to that for PKC.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL045638-10
Application #
2735183
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1993-06-11
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612

  Publications

Komarova, Yulia; Kruse, Kevin J; Mehta, Dolly et al. (2017) Response by Komarova et al to Letter Regarding Article, ""Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability"". Circ Res 120:e28
Soni, Dheeraj; Regmi, Sushil C; Wang, Dong-Mei et al. (2017) Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca2+ entry regulates disassembly of adherens junctions. Am J Physiol Lung Cell Mol Physiol 312:L1003-L1017
Jiang, Chunling; Liu, Zheng; Hu, Rong et al. (2017) Inactivation of Rab11a GTPase in Macrophages Facilitates Phagocytosis of Apoptotic Neutrophils. J Immunol 198:1660-1672
Cheng, Kwong Tai; Xiong, Shiqin; Ye, Zhiming et al. (2017) Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 127:4124-4135
Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension. Mol Biol Cell 28:1177-1185
Yamada, Kaori H; Kang, Hojin; Malik, Asrar B (2017) Antiangiogenic Therapeutic Potential of Peptides Derived from the Molecular Motor KIF13B that Transports VEGFR2 to Plasmalemma in Endothelial Cells. Am J Pathol 187:214-224
Komarova, Yulia A; Kruse, Kevin; Mehta, Dolly et al. (2017) Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability. Circ Res 120:179-206
Cantelmo, Anna Rita; Conradi, Lena-Christin; Brajic, Aleksandra et al. (2016) Inhibition of the Glycolytic Activator PFKFB3 in Endothelium Induces Tumor Vessel Normalization, Impairs Metastasis, and Improves Chemotherapy. Cancer Cell 30:968-985
Klomp, Jennifer E; Huyot, Vincent; Ray, Anne-Marie et al. (2016) Mimicking transient activation of protein kinases in living cells. Proc Natl Acad Sci U S A 113:14976-14981
Mittal, Manish; Tiruppathi, Chinnaswamy; Nepal, Saroj et al. (2016) TNF?-stimulated gene-6 (TSG6) activates macrophage phenotype transition to prevent inflammatory lung injury. Proc Natl Acad Sci U S A 113:E8151-E8158

Showing the most recent 10 out of 139 publications