I propose a 5-year training program for the development of an academic career in cardiovascular research. I completed a fellowship in Cardiology in the Investigator Track at Mount Sinai School of Medicine and am currently an Assistant Professor at Oregon Health &Science University. My previous research has focused primarily on the characterization of cardiomyocytes from embryonic stem cells. My current program will focus on translating this technology, with a focus on the creation of induced pluripotent cell models of disease. The training plan will allow me to develop valuable skills in stem cell biology, molecular electrophysiology, genetics, proteomics, medical informatics and trial recruitment. It is designed to provide training through class work, didactic sessions with mentors and hands-on laboratory experiences. The primary mentors, Dr. Markus Grompe and Dr. Zhengfeng Zhou, are experts in the fields of stem cell biology and cellular physiology, respectively. An advisory committee, consisting of medical scientists with various backgrounds, will also provide guidance. The overall objective of this proposal is to develop new mechanistic insights and diagnostic tools for long QT syndrome using induced pluripotent stem (iPS) cells. Long QT syndrome is a cardiovascular disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmia. Many mutations have been identified that cause inherited long QT syndrome, but genotypes demonstrate incomplete penetrance. Hence, genetic testing lacks prognostic value. Furthermore, anti-arrhythmic pharmacologic therapy is often ineffective and poorly tolerated. New systems are needed to improve our fundamental understanding of long QT syndrome, to discover novel therapeutics, and to develop improved risk assessment strategies. The candidate has recently created an iPS line from a patient with long QT 2. Preliminary studies suggest this line retains genotypic and phenotypic qualities of the patient from which it was derived. The central hypothesis of this proposal is that iPS cell-derived cardiomyocytes can be used to evaluate the cumulative sum of repolarization abnormalities in patients with long QT syndrome. To explore this hypothesis we will generate IPS cell lines from patients with both inherited and acquired forms of long QT. These cardiomyocytes will then be subjected to extensive genomic, proteomic and physiologic analysis. Repair of mutations will be performed to elucidate mechanisms responsible for the phenotype. This work will help translate recent technological advances in stem cell biology into a clinically relevant tool for the study, diagnosis and treatment of long QT.
The objective of the proposal is to study long QT syndrome, a disease that increases the risk of sudden cardiac death. We will generate cardiac cells from patients with long QT and use these to determine the underlying mechanisms responsible for the patients'abnormal heart rhythms. We believe the work will lead to the development of new technologies for predicting and preventing death in long QT, and possibly, foster the development of other stem cell related diagnostic and prognostic tools.