Abstract

This competing renewal application will continue to explore the role of tissue kallikrein in blood pressure regulation and in cardiovascular and renal function. Our hypothesis is that high tissue kallikrein levels have a protective role in the pathogenesis of hypertension and related diseases. Using a novel gene transfer approach, we showed that kallikrein gene delivery attenuated hypertension, cardiac hypertrophy and renal injury and inhibited neointama formation in balloon injured artery, suggesting a potential role of the tissue kallikrein-kinin system in cardiovascular and renal function. We identified a polymorphic site with 14 alleles in the transcription initiation site of the proximal promoter region of the human kallikrein gene that may serve as a powerful genetic marker for linkage analysis in hypertensive populations. These recent findings are the basis for the current application and the specific aims are as follows: 1) To develop new viral vectors harboring the human tissue kallikrein gene under the control of various promoters for long-term and high efficiency gene transfer in hypertensive rats; 2) To analyze the potential role of tissue, kallikrein in acute myocardiac ischemia and chronic heart failure following myocardial infarction in rats; 3) To analyze the potential role of tissue kallikrein for protection against renal injury 4) To analyze the potential role of tissue kallikrein in vascular cell growth and neointima formation in rat artery after balloon angioplasty, and 5) To analyze the promoter region of the human tissue kallikrein gene, and genetic linkage and association between the human kallikrein gene and hypertension in selected hypertensive populations, affected siblings, and family pedigrees. This proposed study will employ gene transfer technology as a research tool to study the role of the kallikrein-kinin system in the development of hypertension and related diseases in various animal models. Information generated from this study could provide new tools and technologies for improved detection and treatment of human hypertension, cardiovascular and renal diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029397-20
Application #
6536817
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Lin, Michael
Project Start
1986-07-01
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
20
Fiscal Year
2002
Total Cost
$272,126
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Li, Pengfei; Guo, Youming; Bledsoe, Grant et al. (2015) Kallistatin treatment attenuates lethality and organ injury in mouse models of established sepsis. Crit Care 19:200
Chao, Julie; Bledsoe, Grant; Chao, Lee (2014) Tissue kallikrein-kinin therapy in hypertension and organ damage. Prog Drug Res 69:37-57
Gao, Lin; Li, Pengfei; Zhang, Jingmei et al. (2014) Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. J Am Heart Assoc 3:e001194
Li, Pengfei; Bledsoe, Grant; Yang, Zhi-Rong et al. (2014) Human kallistatin administration reduces organ injury and improves survival in a mouse model of polymicrobial sepsis. Immunology 142:216-26
Zhang, Jingmei; Yang, Zhirong; Li, Pengfei et al. (2013) Kallistatin antagonizes Wnt/*-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6. Mol Cell Biochem 379:295-301
Yao, Yuyu; Sheng, Zulong; Li, YeFei et al. (2013) Tissue kallikrein-modified human endothelial progenitor cell implantation improves cardiac function via enhanced activation of akt and increased angiogenesis. Lab Invest 93:577-91
Gao, Lin; Bledsoe, Grant; Yin, Hang et al. (2013) Tissue kallikrein-modified mesenchymal stem cells provide enhanced protection against ischemic cardiac injury after myocardial infarction. Circ J 77:2134-44
Zhou, J; Zhang, J; Chao, J (2012) Porphyromonas gingivalis promotes monocyte migration by activating MMP-9. J Periodontal Res 47:236-42
Liu, Yuying; Bledsoe, Grant; Hagiwara, Makato et al. (2012) Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation, and organ remodeling. Am J Physiol Renal Physiol 303:F1230-8
Gao, Lin; Chao, Lee; Chao, Julie (2010) A novel signaling pathway of tissue kallikrein in promoting keratinocyte migration: activation of proteinase-activated receptor 1 and epidermal growth factor receptor. Exp Cell Res 316:376-89

Showing the most recent 10 out of 187 publications