A Role for Bone Morphogenetic Protein 6 (BMP6) in the Development of Canine Myxomatous Mitral Valve Disease (MMVD)
Fellow: Shana Mintz
Mentor: N. Sydney Moise
Co-Mentor: Jonathan Butcher
DESCRIPTION (provided by applicant):
Myxomatous mitral valve disease (MMVD) is the most common heart disease in canines. The disease is characterized by a transition of mitral valve endothelial cells from an endothelial phenotype to a mesenchymal phenotype, which is characterized by a decrease in collagen and an increase in glycosaminoglycans within the spongiosum layer of the mitral valve. Previous studies have attempted to understand key transcripts involved in the disease process using oligonucleotide microarray technology. One of the transcripts that is consistently elevated in myxomatous valves compared to normal valves is bone morphogenetic protein 6 (BMP6). The objective of this study is to identify a role for BMP6, it’s receptors, and downstream pathways in the pathophysiology of naturally occurring canine MMVD. Mitral valve tissue will be collected from affected and normal dogs for RNA and protein analysis, as well as culture of valvular endothelial cells. The specific aims of the study are to: (1) Evaluate whether BMP6 applied to canine valvular endothelial cells is sufficient to initiate the endothelial to mesenchymal transition of these cells; and (2) Evaluate which BMP6 pathway(s) are upregulated in myxomatous valvular endothelial cells. Aim 1 will be achieved using normal or mildly affected valvular endothelial cells in culture – recombinant BMP6 will be applied to the cells alone and with a specific antagonist to determine if the protein initiates transition of the cells. Aim 2 will be achieved by examining RNA and protein expression in severely affected valves for upregulation and/or phosphorylation of BMP receptors and their downstream effectors. We hypothesize that BMP6 will induce canine valvular endothelial cells to undergo the endothelial to mesenchymal transition through one or both of established BMP receptor-mediated pathways.