Abstract

This proposal is a competitive renewal of a study of the role of tissue kallikrein in blood pressure regulation. The investigators have evidence that tissue kallikrein plays a protective role in the pathogenesis of hypertension. They have developed a hypotensive transgenic mouse that overexpresses the human tissue kallikrein gene. They have also demonstrated that somatic gene delivery of human tissue kallikrein induces sustained reduction of blood pressure in spontaneously hypertensive rats (SHR). The current proposal will continue to investigate the role of tissue kallikrein in blood pressure regulation by (1) analyzing tissue kallikrein function by expressing human tissue kallikrein in specific tissues of transgenic mice and rats; (2) using homologous recombination techniques to knock out the kallikrein gene and to introduce a kallikrein antisense construct into transgenic mice; (3) analyzing the regulatory elements controlling the expression of the renal kallikrein gene in hypertensive and normotensive rats; (4) analyzing genetic linkage and association between human tissue kallikrein gene variants and hypertension in selected populations of humans; and lastly, (5) investigating the feasibility of delivering the human kallikrein gene into hypertensive rats by various gene transfer methods for somatic gene therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL029397-15
Application #
2445108
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1986-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
15
Fiscal Year
1997
Total Cost
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