The broad objectives of this proposal are to discover new cellular and molecular pathways of cardiovascular pathologies utilizing zebrafish, a model genetic vertebrate system. The proposed research describes a five-year training plan for the development of an academic career in cardiovascular medicine. This training will be conducted within the highly collegial and scientific environment at the University of California, San Francisco (UCSF). The principal investigator, Dr. Chi, is currently a cardiology fellow in the American Board of Internal Medicine Clinical Investigator Pathway Program at UCSF. He has a firm commitment to becoming a physician-scientist as evidenced by his previous record. The candidate's long-term goals are to establish an investigative research career studying environmentally and genetically acquired heart disease. The comprehensive career development plan incorporated includes mentorship by a scientific advisor and advisory committee; participation in relevant course work, seminars, and scientific retreats both locally and nationally; and an academic appointment providing protected research time to ensure his success in achieving his career goals. The translucent nature of the zebrafish organism allows for easy large-scale mutagenesis screens identifying a diverse array of novel cardiovascular anatomic and physiologic phenotypes. Interestingly, two of these physiologic cardiovascular mutants, pickwick (pik/ttn) and silent heart (sih/tnnt2), have been found to be linked to human cardiomyopathies. However, a piethora of cardiovascular physiologic zebrafish mutants displaying phenotypes similar to other known human cardiovascular disorders remain physiologically and genetically uncharacterized. These mutations can be divided into two subgroups, one of which the contractility of the heart is affected (cardiomyopathies) and the other in which the rhythm of the heart beat is abnormal (arrhythmias). We hypothesize that detailed genetic and physiologic analysis of cardiovascular zebrafish mutants most similar to known human cardiovascular disorders may lead to the discovery of novel cellular and molecular pathophysiologic mechanisms of human cardiac arrhythmias and heart failure. Thus, we propose the following specific aims: 1) To rapidly identify physiologic zebrafish cardiovascular mutants from a forward genetic screen by light microscopy; 2) To perform detailed physiologic, cellular and molecular analysis on those identified mutants from Specific Aim 1; 3) To focus and identify the mutant genes for those mutants whose phenotype most resemble human cardiovascular disorders as characterized by Specific Aim 2. These zebrafish mutants ultimately may serve as a novel gateway to gain new insight into the cellular and molecular mechanisms of human cardiac arrhythmias and heart failure.
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