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Cell and molecular biology of the renin-antiotensin and kalikrein-kinins systems

Grant number: 02/00807-7
Support type:Research Projects - Thematic Grants
Duration: December 01, 2002 - February 28, 2007
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:João Bosco Pesquero
Grantee:João Bosco Pesquero
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Co-Principal Investigators:Antonio Cechelli de Mattos Paiva ; Clovis Ryuichi Nakaie ; Laerte de Oliveira ; Suma Imura Shimuta

Abstract

The Renin-Angiotensin (RAS) and Kalikrein-Kinin (KKS) systems play an important role in the regulation of several physiological and pathologic processes related to the control of blood pressure and also affect a large number of processes such as cell growth and proliferation, pain and inflammation, among others. The main effector substance of the RAS is angiotensin II (Ang II), and those of the KKS are bradykinin (BK) and other kinins. Kinins, as well as Ang II act through the activation of G protein coupled receptors (GPCRs): angiotensin receptors AT1 and AT2, and BK receptors B1 e B2 Due to their importance in physiopathological processes involving the regulation of the blood pressure, and because of the great homology between their receptors, the RAS and the KKS have been the object of study of our laboratories, involving molecular modeling and site-directed mutagenesis of the AT1 receptor, conformational studies of synthetic peptides related to the AT1 receptor and their interaction with membranes, and various aspects of the molecular biology of the two systems. The present project proposes to continue these studies through the investigation of the following topics: A) Structure-activity relationships of the Angll AT1 receptor I. Molecular modeling of G protein coupled receptors II. Conformational properties of peptides containing GPCR and protein G sequences III. Mutational study of the AT1 receptor signal transduction mechanisms; IV. Structural requisites for A T1 receptor dimerization; V. Trafficking and processing of the Angll-AT1 receptor complex; VI. Synthesis and structure-activity studies of Angll and BK analogs in solution and in the presence of membrane models; VII. Role of untranslated regions of the AT1 gene in the functional regulation of the receptor; B) Molecular Biology of the Kallikrein-kinin system VIII. Regulation and expression of the human carboxipeptidase M gene; IX. Production and studies of transgenic rats overexpressing BK receptor B2 in the heart; X. Production and characterization of transgenic mice overexpressing endothelial kinin B1 receptor; C) Role of the kallikrein-kinin system in pathological processes XI. Role of the kallikrein-kinin system in the development of mammary cancer and its implication in the angiogenesis process; XII. Role of the kallikrein-kinin system in the genesis and maintenance of endotoxic schock; D) Development of Angll and BK receptor antagonists XIII. Development of antagonists for the kinin B1 and B2 and for the Angll AT 1 receptors employing SELEX; XIV. Identification of mutations in the kinin B1 receptor and their role in obesity. (AU)

Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GUIMARAES, PAOLA B.; ALVARENGA, ERIKA C.; SIQUEIRA, PAULA D.; PAREDES-GAMERO, EDGAR J.; SABATINI, REGIANE A.; MORAIS, RAFAEL L. T.; REIS, ROSANA I.; SANTOS, EDSON L.; TEIXEIRA, LUIS G. D.; CASARINI, DULCE E.; MARTIN, RENAN P.; SHIMUTA, SUMA I.; CARMONA, ADRIANA K.; NAKAIE, CLOVIS R.; JASIULIONIS, MIRIAM G.; FERREIRA, ALICE T.; PESQUERO, JORGE L.; OLIVEIRA, SUZANA M.; BADER, MICHAEL; COSTA-NETO, CLAUDIO M.; PESQUERO, JOAO B. Angiotensin II Binding to Angiotensin I-Converting Enzyme Triggers Calcium Signaling. Hypertension, v. 57, n. 5, p. 965-U200, MAY 2011. Web of Science Citations: 17.
SANTOS, EDSON LUCAS; SOUZA, KELY DE PICOLI; DA SILVA, ELTON DIAS; BATISTA, ELICE CARNEIRO; FORCINA MARTINS, PAULO J.; D'ALMEIDA, VANIA; PESQUERO, JOAO BOSCO. Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats. Biochemical Pharmacology, v. 78, n. 8, p. 951-958, OCT 15 2009. Web of Science Citations: 58.
SABATINI‚ R.A.; GUIMARÃES‚ P.B.; FERNANDES‚ L.; REIS‚ F.C.G.; BERSANETTI‚ P.A.; MORI‚ M.A.; NAVARRO‚ A.; HILZENDEGER‚ A.M.; SANTOS‚ E.L.; ANDRADE‚ M.C.C.; OTHERS. ACE activity is modulated by kinin B2 receptor. Hypertension, v. 51, n. 3, p. 689-695, 2008.
SANTOS‚ E.L.; DE PICOLI SOUZA‚ K.; GUIMARÃES‚ P.B.; REIS‚ F.C.G.; SILVA‚ S.M.A.; COSTA-NETO‚ C.M.; LUZ‚ J.; PESQUERO‚ J.B. Effect of angiotensin converting enzyme inhibitor enalapril on body weight and composition in young rats. International Immunopharmacology, v. 8, n. 2, p. 247-253, 2008.
SANTOS‚ E.L.; REIS‚ R.I.; SILVA‚ R.G.; SHIMUTA‚ S.I.; PECHER‚ C.; BASCANDS‚ J.L.; SCHANSTRA‚ J.P.; OLIVEIRA‚ L.; BADER‚ M.; PAIVA‚ A.; OTHERS. Functional rescue of a defective angiotensin II AT1 receptor mutant by the Mas protooncogene. Regulatory Peptides, v. 141, n. 1, p. 159-167, 2007.

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