This is a five year mentored career development plan aimed at providing the principal investigator (PI), who is a well trained Pediatric Cardiologist, with the necessary skills to establish herself as an independent physician-scientist in the field of molecular genetics of cardiomyopathies. This training plan includes a hypothesis driven research proposal developed by the PI along with a plan for structured didactics and mentoring, which will allow her to gain expertise in the techniques of molecular genetics and murine and cellular modeling of cardiovascular diseases. The mentor is a pioneer in the field of molecular genetics of cardiomyopathies and arrhythmias and will oversee this training, along with an advisory committee of well established scientists in this field. The research focuses on Dilated Cardiomyopathy (DCM), a devastating myocardial disease with a five year heart mortality rate of 50% and is based on the hypothesis that inherited dysfunction of mechanical stretch-sensing and stretch-based signaling forms the pathogenic basis for a subset of DCM patients. The hypothesis is supported by the fact that targeted disruption of p1-lntegrin and Melusin, proteins with stretch-sensing function, leads to DCM in mouse models. In addition, genes like Titin, Telethonin and MLP, identified as human DCM-causing genes have stretch-sensing and signaling properties. The PI has identified ANKRD1, as a novel DCM associated gene. ANKRD1 encodes for Cardiac Ankyrin Repeat Protein, a transcription-co-inhibitor which is a member of the Titin-N2A mechanosensory complex and is upregulated in heart failure and cardiac hypertrophy.
In Specific Aim#1, the PI will identify other DCM associated genes encoding for proteins in the (31-lntegrin and Titin-N2A mechanosensory complexes, using a candidate gene approach.
In Specific Aim#2 the PI will study the functional effects of the mutations identified in Specific Aim#1 using in vitro cellular models with special focus on stretch-based signaling. These studies will be limited to four selected genes.
In Specific Aim#3 the PI will characterize the cardiac phenotype of the DCM associated mutations identified in the ANKRD1 gene, using transgenic mice with cardiac specific overexpression of these mutations. The institutional environment, available resources and the mentoring plan are ideal for meeting the goals of this career development proposal and will establish the PI as an independent physician-scientist.
