The Role of IgLONS in Cardiac Development and Disease

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DESCRIPTION (provided by applicant): Dr. Grossfeld is a highly trained, board-certified pediatric cardiologist who is devoted to studying the genetic basis of congenital heart disease. The purpose of this grant proposal is to obtain support to enable Dr. Grossfeld to become an independent investigator by the end of the proposed funding period. The proposed research will be performed in the laboratory of Dr. Anthony Wynshaw-Boris in the Department of Pediatrics at the University of California, San Diego. During this time, Dr. Grossfeld will receive the necessary training for incorporating human and animal genetic model system approaches for studying genes causing hypoplastic left heart syndrome (HLHS). UCSD and specifically, Dr. Wynshaw-Boris, provide an ideal environment that has been extraordinarily successful for promoting and developing similar research interests. The long-term goal of this project is to study the role of OBCAM and Neurotrimin, two members of the IgLON subfamily of genes, in cardiac development and in the generation of congenital heart defects, including HLHS. HLHS is one of the most severe congenital heart defects, accounting for 20% of all deaths in infants with congenital heart disease. To date, no causative gene for HLHS has been reported. The specific aims of this project are: Specific Aim 1): Characterization of the expression of OBCAM and Neurotrimin in fetal and adult heart; Specific Aim 2): Alteration in the expression of OBCAM and Neurotrimin utilizing mouse and chicken genetic model systems, and Specific Aim 3): Mutation analysis for point mutations and microdeletions in OBCAM and Neurotrimin in patients with isolated heart defects that occur in Jacobsen syndrome, and for single nucleotide polymorphisms in OBCAM and Neurotrimin in patients with Jacobsen syndrome.