Human Tissue Kallikrein (KLK1) and human plasma kallikrein on metabolism of semaphorins and neurotrophins

• Grant number: 15/01829-4
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): July 01, 2015
• Effective date (End): October 10, 2017
• Field of knowledge: Biological Sciences - Biophysics
• Principal Investigator: Maria Aparecida Juliano
• Grantee: Lilian Caroline Gonçalves de Oliveira
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 12/50191-4 - Synthesis, kinetic studies and applications of substrates and inhibitors for proteolytic enzymes, AP.TEM

Abstract

Proteolytic enzymes are of great medical interest because they are involved in diseases suchas cancer, inflammatory conditions and cardiovascular diseases, and as potential therapeutictargets or biomarkers for prognosis. Kallikreins are members of the serine protease familyand gained attention in recent years due to the fact that they are differentially expressed inpathological processes. Plasma kallikrein (PK) and human tissue kallikrein 1 (KLK1), whichare found in the central nervous system and are related to inflammation, are the focus of thisproject which aims to find new substrates for both. Semaphorins and neurotrophins will beexamined as potential substrates because they are two classes of proteins rich in the centralnervous system and important for their formation and function. Semaphorin proteins aremultifunctional and essential for embryonic development and involved in the establishmentof axonal network of the nervous system, and have functions in the cardiovascular andimmune systems and neoplastic processes. Neurotrophins are proteins expressed in thecentral and peripheral nervous system with essential role in the development, maintenanceand repair of the nervous system; when processed, they have trophic activity, but in theimmature form, they have apoptotic function. This project will focus on the search forpossible new substrates for KLK1 and PK in the context of these two protein families, thesemaphorins and the neurotrophins, the FRET peptide synthesis based on their sequences,and to study possible relationship of these peptidases with neurodegenerative diseases.Innovative aspects and impact of this project: a) semaphorin as the kallikrein substrates isa recently found in the laboratory supervisor of this project; b) Investigation of substrates forPK out of plasma context; c) Synthesis of more than 200 FRET peptide derived fromsemaphorins and neurotrophins sequences that will allow an analysis of the kallikreinspecificity; d) Subsidies for the design of KLK1 and PK inhibitors, that are especiallyimportant for inflammatory and lesions in nervous system.

Scientific publications

(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)

MAREM, ALYNE; OKAMOTO, DEBORA N.; OLIVEIRA, LILIAN C. G.; RUIZ, DIEGO M.; PAGGI, ROBERTO A.; KONDO, MARCIA Y.; GOUVEA, IURI E.; JULIANO, MARIA A.; DE CASTRO, ROSANA E.; JULIANO, LUIZ; et al. Functional roles of C-terminal extension (CTE) of salt-dependent peptidase activity of the Natrialba magadii extracellular protease (NEP). International Journal of Biological Macromolecules, v. 113, p. 1134-1141, JUL 1 2018. (15/01829-4)