The objective of this revised proposal is to elucidate the expression and role of bradykiritin (BK) B2 and B receptors in blood pressure and cardiovascular regulation. Kinins are potent vasodilating peptides that are released from precursor kininogens by kallikreins. Kinins bind to BK receptors and mediate a broad spectrum of biological effects including vasodllation, ion transport, smooth muscle contraction and relaxation, pain and inflammation. There are two types of kinin receptors, B2 and B1 which differ in biological properties and primary structures. This project is based on the hypothesis that the BK receptor plays a role in blood pressure regulation which is supported by our encouraging preliminary results that antisense inhibition of B2 receptors in rats causes an increase of blood pressure while transgenic mice over-expressing human B2 receptors are hypotensive. Since the last submission of this application, we continue to make progress in molecular cloning, expression and locallzation of BK receptors, developed essential biochemical and molecular probes and established technologies which form the basis for the current application.
The specific aims of this proposal are: (l) to clone and characterize the BK receptor genes from human and rat, and to create DNA constructs with and without adenoviral vectors for somatic gene delivery and transgenic mouse development, (2) to analyze elements which regulate the BK receptor genes' transcription in a-cell culture system by deletion analysis, site-directed mutagensis, gel retardation and footprinting assays, and in vivo by deletion analysis via direct gene delivery, (3) to analyze the role of BK receptors in central and peripheral regulation of blood pressure by antisense inhibition and by combination gene delivery in normotensive and hypertensive rats, (4) to develop and characterize transgenic mice over-expressing BK receptor genes and to analyze phenotypic alterations such as blood pressure changes, renal function and smooth muscle contraction. The proposed studies could provide fundamental information about the structure, regulation and function of BK receptors in order to facilitate the design of therapeutic agents for treating hypertension, cardiovascular disease and inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL052196-01A2
Application #
2409204
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1997-08-20
Project End
2001-07-31
Budget Start
1997-08-20
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Biochemistry
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Emanueli, C; Minasi, A; Zacheo, A et al. (2001) Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation 103:125-32
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Emanueli, C; Salis, M B; Chao, J et al. (2000) Adenovirus-mediated human tissue kallikrein gene delivery inhibits neointima formation induced by interruption of blood flow in mice. Arterioscler Thromb Vasc Biol 20:1459-66
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Wang, D; Yoshida, H; Song, Q et al. (2000) Enhanced renal function in bradykinin B(2) receptor transgenic mice. Am J Physiol Renal Physiol 278:F484-91

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