The Role of IgLONS in Cardiac Development and Disease

描述(由申请人提供)： 格罗斯菲尔德博士是一位训练有素、获得董事会认证的儿科心脏病专家，致力于研究先天性心脏病的遗传基础。这项赠款提案的目的是获得支持，使格罗斯菲尔德博士能够在拟议的资助期结束时成为一名独立的调查员。这项拟议的研究将在加州大学圣地亚哥分校儿科安东尼·温肖-鲍里斯博士的实验室进行。在此期间，格罗斯菲尔德博士将接受必要的培训，将人类和动物遗传模型系统方法结合起来，研究导致左心发育不良综合征(HLHS)的基因。加州大学伯克利分校，尤其是温肖-鲍里斯博士，为促进和发展类似的研究兴趣提供了一个非常成功的理想环境。该项目的长期目标是研究IgLON亚家族基因的两个成员OBCAM和Neurotrimin在心脏发育和先天性心脏病(包括HLHS)的发生中的作用。HLHS是最严重的先天性心脏病之一，占先天性心脏病婴儿死亡总数的20%。到目前为止，还没有HLHS的致病基因的报道。本项目的具体目标是：特定目标1)：鉴定OBCAM和Neurotrimin在胎儿和成人心脏中的表达；特定目标2)：利用小鼠和鸡的遗传模型系统改变OBCAM和Neurotrimin的表达，以及特定目标3)：对雅各布森综合征患者的孤立心脏缺陷患者的OBCAM和Neurotrimin基因的点突变和微缺失进行突变分析，并对Jacobsen综合征患者的OBCAM和Neurotrimin基因的单核苷酸多态性进行分析。

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.