FORMATION AND FATE OF CUSHION TISSUE

（改编自申请人摘要）心血管畸形 系统占先天性心脏病造成的过早死亡的大部分 异常其中，大多数是先天性心脏缺陷， 从单个心脏管的异常重塑到四个独立的， 正确对齐的腔室。由间充质细胞形成的心脏垫 胚胎心管壁内的胚胎细胞 重塑的过程。流出道（圆锥动脉干段）是一个 只有心脏的两个区域形成了内膜垫， 重塑过程。了解起源和命运的重要性 锥干段和相关的垫是，这个网站是最 可能与人类心脏的出生缺陷有关， 事实上，这是一个非常常见的畸形部位， 先天性心脏病脊椎动物模型的实验扰动 疾病该项目的主要重点将是调查 导致圆锥干初始形成的分子途径 缓冲段，确定连接段形成的因素， 缓冲间充质形成和细胞相互作用， 不同的发育命运，以形成节，因此， 为潜在缺陷的心脏重塑创造了最终的共同途径。的 第一个具体目标是确定圆锥干“出口”的起源 节及其形态发生机制，并基于五个相互关联的 假设（1）圆锥干段作为一个新的结构添加到 心管的远端来自先前未识别的前心 （2）心前区细胞被心肌细胞募集为心肌细胞系。 （3）心肌前细胞部分通过 骨形态发生蛋白的作用;（4）内皮细胞的募集 通过TGF β在流出道远端边界的中胚层细胞 和蛋白多糖神经聚糖;（5）心脏缺陷基因的表达， 不可替代地需要维持/介导圆锥动脉干的诱导 前体细胞和/或将它们的表型稳定到同心的 流出道的上皮结构。第二个具体目标是 旨在研究片段形成和蛋白质之间的分子联系。 心管内垫状间充质诱导的特定部位。第三 目的是研究位置分化与 （命运）的垫间充质，侵犯神经嵴和 心肌化，即心肌细胞主动侵入圆锥体， 垫，这是重塑U形的关键形态发生机制 心脏管分为四个腔室。

(Adapted from the Applicant's Abstract) Malformations of the cardiovascular system account for most of the premature deaths caused by congenital abnormalities. Of these, the majority are congenital heart defects that arise from the abnormal remodeling of the single heart tube into four separate and properly aligned chambers. The cardiac cushions, formed from mesenchymal swellings, within the wall of the embryonic hear tube are fundamentally linked to the process of remodeling. The outflow tract (conotruncal segment) is one of only two regions of the heart where endocardial cushions form to mediate the remodeling process. The importance of understanding the origin and fate of the conotruncal segment and associated cushions is that this site is most likely to be associated with birth defects of the heart in humans and, in fact, is a very common site of malformations that result from a wide variety of experimental perturbations in vertebrate models of congenital heart disease. The primary focus of this project will be to investigate the molecular pathways that lead to the initial formation of the conotruncal cushion segment, determine the factors that link segment formation with cushion mesenchyme formation and the cellular interactions that impart different developmental fates to the cushion-forming segments and, thereby, create a final common pathway for potentially defective heart remodeling. The first Specific Aim is to determine the origin of the conotruncal "outlet" segment and its mechanism of morphogenesis and is based on five interrelated hypotheses (1) the conotruncal segment is added as a new structure to the distal end of the heart tube from a previously unrecognized anterior heart field; (2) the precardiac cells are recruited into myocardial lineage by the existing myocardium; (3) the premyocardial cells are induced, in part, through the action of bone morphogenic proteins; (4) endocardial cells are recruited by mesodermal cells at the distal boundary of the outflow tract by TGF betas and the proteoglycan neurocan; (5) expression of the heart defect gene is irreplaceably required to sustain/mediate induction of the conotruncal precursor cells and/or stabilize their phenotype into the concentric epithelial architecture of the outflow tract. The second Specific Aim is designed to investigate the molecular links between segment formation and the specific site of cushion mesenchyme induction in the heart tube. The third aim investigates the relationship between the positional differentiation (fate) of the cushion mesenchyme, invasion of neural crest and myocardialization, an active invasion of myocardial cells into the conal cushions, that is the pivotal morphogenetic mechanism for remodeling the U-shaped heart tube into four chambers.