Postnatal heart remodeling is a universal feature in vertebrates to condition the heart to meet the increasing work load in adulthood and is a critical window to exhibit fetal defects in congenitial heart disease. During heart remodeling, gene expression is reprogrammed at both the transcriptional and post-transcriptional levels. While the transcriptional regulation has been intensively studied, the post-transcriptional regulation has received little attention, although it is likely to be just as critical. In the past project period, we investigated how some well-established splicing regulators are involved in heart development and remodeling. By studying a family of splicing factors known as SR proteins, we discovered a critical role of regulated CaMKIIdela splicing during heart remodeling. We found that distinct mRNA isoforms of this gene are specifically targeted to different cellular compartments, which had a profound effect on excitation-contraction coupling when mis-regulated in SR protein deficient heart. Here we propose to continue to analyze regulated splicing by both general and tissue-specific RNA binding splicing regulators using heart as a model. Our attack plan is divided into three specific aims. Our first specific aim is to construct a splicing array to analyze a large number of genes that have been implicated to play critical roles in heart function, and use the array to characterize the splicing program during heart development and remodeling.
Our second aim i s devoted to determine the functional requirement for a number of heart-specific RNA binding splicing regulators in the heart. We will use the splicing array to determine how the splicing program in the heart is controlled by these heart specific RNA binding proteins. Our third specific aim is to use CaMKIIdela as a model to understand the regulation of tissue-specific alternative splicing. We propose to test a hypothesis that SR protein-dependent exon skipping is a central feature for the collaboration between general and tissue-specific splicing factors in regulated splicing. Together, the proposed research has a clear potential in revealing novel regulatory mechanisms for heart development and remodeling, which may shed critical light on heart disease mechanisms.
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