NEURAL-CREST RELATED HEART DEFECTS

描述（改编自申请人摘要）：圆锥动脉干心脏 畸形是由于主动脉和肺动脉干不能 在胚胎发育期间分成两个不同的血管。 几 证据表明，这些缺陷是由于不充分的 心脏神经嵴（NC）细胞迁移到并定殖于 发展流出道，斑点（Sp2 H）突变提供了一个小鼠模型， 研究NC细胞迁移与 心血管发育 申请人假设（i）Sp2 H突变体 NC细胞是固有缺陷的，（ii）Sp2 H NC细胞迁移不足 来自神经管和/或（iii）神经管和直接 周围基质在Sp2 H胚胎中是不允许的，这是由于 突变体Pax 3负调节分子的表达，这些分子已知是 参与细胞粘附。 本提案的总体目标是确定 该机制是导致圆锥动脉干心脏缺陷的原因 通过确定Sp2 H NC细胞数量的减少何时以及如何发生， 改变Sp2 H胚胎中候选分子的功能， 心脏缺陷，利用遗传定义的哺乳动物模型， 申请人将通过监测NC细胞迁移的进展来实现这一点 时间和空间，并通过补充培养的整个胚胎与 额外的NC细胞，其可以纠正 组织微环境，通过该微环境，NC细胞迁移或增加 迁移NC细胞数

DESCRIPTION (adapted from the applicant's abstract): Conotruncal heart malformations result from a failure of the aorta and pulmonary trunk to separate into two distinct vessels during embryonic development. Several lines of evidence suggest that these defects are the result of insufficient numbers of cardiac neural crest (NC) cells migrating to and colonizing the developing outflow tract, The Splotch (Sp2H) mutation provides a mouse model system in which to study the relationship between NC cell Migration and cardiovascular development. The applicant hypothesizes that (i) Sp2H mutant NC cells are inherently defective, (ii) insufficient Sp2H NC cells emigrate from the neural tube and/or (iii) the neural tube and the immediate surrounding matrix is non-permissive in Sp2H embryos due to a failure of the mutant Pax3 to negatively regulate the expression of molecules known to be involved in cell adhesion. The overall goal of this proposal is to identify which mechanism is responsible for the resultant conotruncal heart defects by determining when an how the reduction in Sp2H NC cell numbers occurs and, to alter the function of the candidate molecules in Sp2H embryos to correct the heart defect, utilizing a genetically-defined mammalian model, The applicant will achieve this by monitoring the progress of NC cell migration temporally and spatially, and by supplementing cultured whole embryos with additional NC cells that can either correct the functional defect in the tissue microenvironment through which NC cells migrate or increase the number of migratory NC cells