Grant: CIHR Fellowship

Significance evidence from clinical studies and animal models, indicated that excessive deposition of collagens (Fibrosis) is an important contributor for heart failure. Lysyl oxidase (LOX) protein family members play a critical role in the cross linking of the collagen fibrils that determines the tensile strength of collagens in various organs during pathological conditions. LOX enzymes family members consist of 5 members: Canonical LOX & 4 LOX-like isoforms (LOXL-1, -2, -3, -4). We have identified in a clinical relevant dog cardiac fibrosis model that LOX & LOXL1 are extensively dysregulated in two cardiac cell types, myocytes & fibroblast. As such our research proposal will determine whether LOX/LOXL1 has a direct cell specific role in the heart. We will study their role in mediating cardiac fibrosis using transgenic mouse strains that prevents it from responding to the actions of LOX/LOXL1 in specifically in cardiac cell types. We will examine the heart function & structure in transgenic & normal mice. In addition, we will subject these transgenic & control mice to number of stresses such as heart attack (by blocking a major blood vessel supplying the heart) & pressure overload (by generating a constriction around largest blood vessel to increase a load on the heart). We anticipate that cell specific LOX/LOXL1 transgenic mice could be less susceptible for cardiac stress, develop less cardiac fibrosis, compared to normal mice, thereby suggesting direct actions of LOX proteins in cardiac cell types. We will further study detailed mechanism for cell specificity of LOX & LOXL1 proteins using advanced cell physiology and molecular biology approaches. These results could have significant clinical importance as cardiac fibrosis is important clinical feature for development and progression of heart failure, burden which on rise at an alarming rate in our population & have limited therapeutic approach.