Gene therapy for reduction of fibrosis in a model of spontenously hypertensive rats

• Grant number: 13/22527-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 14, 2014
• End date: August 23, 2014
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Sang Won Han
• Grantee: Roberta Sessa Stilhano Yamaguchi
• Supervisor: Eduardo A. Silva
• Host Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Institution abroad: University of California, Davis (UC Davis), United States
• Associated to the scholarship: 12/00753-6 - GENE THERAPY FOR REDUCTION OF FIBROSIS IN A MODEL OF SPONTENOUSLY HYPERTENSIVE RATS, BP.DR

Abstract

Fibrosis is a major acquired sequel after muscle. The fibrotic process prevents proper muscle contraction and can lead to muscle contractures and chronic pain. In more severe injuries, in which healing occurs slowly, fibrosis prevents the proper muscle contraction and can lead to chronic pain and muscle contractures. In addition to functional loss, scar tissue tends to suffer further injury due to the changing of nature of tissue.The fibrotic process is the major cause of limitation of muscle regeneration and is aggravated by hypertension. Thus, the SHR rats are a good model for the study relate to skeletal muscle injury and hypertension. The search for strategies that block the AT1 receptor and consequently decrease the pro- fibrotic factors are the way to new therapies for complications of hypertension.Recently, our group and others have demonstrated that GM- CSF was able to promote increased muscle mass and strength, and drastically reduce fibrosis . However, some studies have shown a pro - fibrotic cytokine that, and that its overexpression leads to an increase of TGF - ²1 . G-CSF already has properties that delay fibrosis and decreased the expression of TGF- ²1 and of the AT1 receptor. The relationship among these cytokines and the AT1 receptor is not known, but the discovery of the mechanism of interaction between these factors is essential to the search for an effective therapy.On the basis of this information, the main objective of this project is to study the effect of cytokines in hypertension and fibrosis, and develop procedures for gene therapy for reduction of fibrosis in injured skeletal muscle of SHR . In this proposed project will be a new alternative treatment using lentiviral vectors expressing GM -CSF , GC - SF or artificial miRNAs that block the expression of the AT1 receptor . (AU)