There is currently a deficiency in understanding the events that effect proper cardiovascular development. The long-term goal is to define these events in molecular detail, providing a basis for understanding cardiovascular development in both normal and pathological states. With this goal in mind, the objective of this application is to determine in mechanistic detail how the transcriptional corepressor known as BCOR represses cardiac-specific transcription and how mutations in BCOR contribute to the molecular pathogenesis of cardiovascular developmental defects. In humans, strong clinical evidence suggests that BCOR plays a key role in early heart formation. Although the BCOR repression complex is thought to be involved in chromatin modification in some cell types, little is known about BCOR's specific role in cardiac cells and the purpose of this function in the overall process of cardiovascular development. Thus, the central hypothesis of this application is that BCOR plays an essential role in cardiac development by recruiting chromatin modifying enzymes to regulate the expression of genes involved in cardiovascular development. To test this hypothesis, two specific aims are proposed.
The first aim i s to define the components and candidate transcription factor targets of the BCOR repression complex in cardiac precursor cells. To accomplish this, protein purification and mass spectrometry methods will be used to identify the BCOR complex components in a cardiac precursor cell line. Protein interaction assays will then be utilized to test specific known cardiac transcription factors for interaction with BCOR.
The second aim i s to determine the role of BCOR in murine cardiovascular development. This will involve generating a BCOR null mouse and analyzing the effect of BCOR loss on cardiac development and cardiac- specific gene expression. These experiments are significant because they will increase understanding of the molecular events leading to proper cardiovascular development and, in doing so, will confer an awareness of the processes that are likely to be disrupted in cardiovascular developmental disorders. Relevance to Public Health: This research examines the function of a protein that is involved in regulating cardiac development. Ultimately, the information gained from these studies will lead to a more thorough understanding of normal cardiac development, the pathogenesis of cardiac developmental defects, and potential therapies to prevent those defects.