This proposal describes a five-year mentored career development program designed to prepare Dr. Rima Arnaout for her long-term career goal to be an independent investigator. This proposal builds upon Dr. Arnaout's background as a cardiologist and a basic scientist in cardiovascular development by providing training in bioinformatics approaches to genome analysis as well as other techniques critical to success of the research approach. Dr. Shaun Coughlin, Director of the Cardiovascular Research Institute at the University of California, San Francisco and an expert in cardiovascular research, will serve as the primary mentor for this project. Dr. Coughlin's mentorship is part of a training plan that includes formal mentorship by an advisory committee of leaders in cardiovascular development, formal coursework and skills training, and a research plan that will provide rigorous training in developmental biology and genetics. This work will be supported in an outstanding environment for cardiovascular research rich with the intellectual and programmatic support and infrastructure necessary for the development of an independent physician-scientist. In preliminary work, Dr. Arnaout has created tools that can be used to study the thickening and remodeling of the ventricular myocardium to form trabeculae. Trabeculation is an essential process in normal heart development and function, and several congenital and heritable heart diseases are characterized by hypo- or hyper- trabeculation. The overall goal of the studies proposed is therefore to illuminate the mechanisms governing initiation of trabeculation in development and regeneration. This goal will be achieved by exploiting specific strengths of the zebrafish model systems and by using natriuretic peptide A (nppa) as a tool to mark and manipulate trabeculated myocardium. Dr. Arnaout will first test the hypothesis that nppa participates in the initiation of trabeculation during development by performing knockout and expression studies in zebrafish. To interrogate roles of endocardial-myocardial contact in trabeculation in vivo, Dr. Arnaout will use the GFP Reconstitution Across Synaptic Partners (GRASP) system. She will then test the hypothesis that the regenerative growth in adult zebrafish hearts arises from nppa-positive cells when trabeculae are selectively injured. Compared to prior models for heart injury, Dr. Arnaout's model for heart injury more closely approximates the most common kind of human heart injury. Finally, Dr. Arnaout will extend her analysis of trabeculated vs non-trabeculated myocardium, using RNA-Seq to compare gene programs in trabecular myocardium at baseline and in regeneration and discover novel genes and pathways to investigate across vertebrate systems. By identifying the mechanisms responsible for the initiation and maintenance of trabeculation in development and after heart injury, the work proposed will provide valuable insight into the pathogenesis of several congenital heart diseases and also lay important groundwork for mastering cardiac regeneration after injury.
The experiments proposed investigate how the heart grows and thickens (trabeculates) during development to become a spongy, thick-walled heart necessary for normal heart function. This work will help further our understanding of inherited and acquired heart muscle diseases, and lay the groundwork for us to one day is able to grow back injured heart muscle.
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|Orr, Nathan; Arnaout, Rima; Gula, Lorne J et al. (2016) A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat Commun 7:11303|