Hypertrophic cardiomyopathy (HCM) is a common genetic malformation of the heart that results in increased left ventricular mass. The clinical course is highly variable; with some patients remaining asymptomatic, some declaring symptoms of heart failure, and some dying suddenly without warning. Human molecular genetics studies have identified mutations in sarcomere genes as the cause of HCM. However, the mechanisms responsible for pathogenesis and clinical diversity in HCM still remain elusive. We developed a novel methodology called polony multiplex analysis of gene expression (PMAGE) to obtain comprehensive mRNA profiles that include rare and potentially important transcripts expressed at levels as low as < 1 copy per cell. PMAGE incorporates next-generation high throughput DNA sequencing technology to digitalize gene expression at a massively parallel scale. The central hypothesis of this proposal is that HCM will have a unique transcriptional profile compared with other cardiomyopathies, and that identification of these mRNAs using sensitive methods can identify critical mediators of the hypertrophic response. We propose using PMAGE to discern molecular pathways distinct for HCM by comparative analysis with transcriptomes of cardiomyopathies from differing etiologies. We will also determine whether markers specific for HCM identified in mouse models are recapitulated in human heart tissue. The dissection of transcriptional responses in HCM at a genome-wide scale should help to identify new molecular targets for diagnosis and therapeutic intervention. ? ? Candidate: This proposal describes a training program to develop Jae Bum Kim from a postdoctoral trainee to an independent physician-scientist in cardiovascular medicine. The initial mentored phase combines training and research in a multi-disciplinary approach to acquire the requisite skills necessary for a sustainable and prolific career in scientific investigation. An advisory committee of highly regarded scientists in the fields of cardiovascular medicine, molecular biology, genetics, and systems biology will guide the candidate in his transition to autonomy. ? ? ?
