MECHANISTIC REGULATION OF SEGMENTAL CARDIAC REGULATION

节段性心脏调节的机械调节

• 批准号: 6565099
• 负责人: DEEPAK SRIVASTAVA
• 金额: $ 18.67万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565099
• 关键词: DNA binding protein; DiGeorge's syndrome; animal genetic material tag; apoptosis; cell line; congenital heart disorder; developmental genetics; embryo /fetus; embryogenesis; genetic manipulation; genetic models; genetically modified animals; heart; heart ventricle; high performance liquid chromatography; histogenesis; laboratory mouse; neural crest; subtraction hybridization; transcription factor

Congenital heart defects are the result of abnormal development of mesodermal cells, which form the muscular portion of the heart, or neural crest-derived cells, which populate the cardiac outflow tract and aortic arches. Defects in the two population of cells usually occur in a segmental fashion resulting in abnormalities of distinct regions of the heart with neighboring regions being relatively normal. The long term goal of this proposal is to understand the independent molecular pathways and mechanisms which could control segmental cardiac development. This type of understanding is the first step in identifying the genes which cause heart defects in distinct regions of the heart. Specifically, we focus on elucidating the pathogenesis of DiGeorge/CATCH-22 syndrome, which is a defect of cardiac and pharyngeal neural crest development, and of hypoplastic right and left ventricle syndromes. The recent discovery of the basic helix-loop-helix transcription factors, dHAND and e-HAND, provide the impetus for study in these two areas because of their expression in both cardiac mesoderm and cardiac neural crest. Furthermore, d-HAND and e-HAND, provide the impetus for study in these two areas because of their expression in both cardiac mesoderm and cardiac neural crest. Furthermore, dHAND and eHAND are expressed in unique segments of the developing heart and serve as an entrance point to dissect the upstream and downstream members of chamber-specific pathways. dHAND-null embryos have a hypoplastic right ventricle and fail to form neural crest-derived aortic arch arteries. The mechanism of dHAND action may be mediated through inhibition of programmed cell death (apoptosis) by directly regulating a potential member of the apoptotic pathway. Identification of genes downstream of dHAND have led to the discovery of cot-22, a novel gene located in the minimal DiGeorge critical region of chromosome 22 and expressed in the heart and branchial arches The three major aims of this proposal are as follows: 1) to determine, in mice and humans, if cot-22 is the gene or one of the genes responsible for DiGeorge/CATCH-22 syndrome, 2) to define the role of apoptosis in development of hypoplastic right ventricle and arch malformations in dHAND-null mice, and 3) to determine the dominant effects of dHAND and eHAND in cardiac development and post-natal cardiac disease by over-expressing the HAND genes in a cardiac and neural crest specific manner; this aim will supplement the goals of aims 1 and 2 by addressing potential mechanistic issues. The aims utilize an in vivo model which is relevant to human disease and are complemented by the studies on hypoplastic ventricles syndromes and neural crest defects proposed by other investigations in this grant. By both elucidating a molecular pathway of segmental cardiac development and positional cloning of responsible loci of specific diseases, it will be possible to identify genes responsible for distinct cardiac defects, similar to the manner in which cot-22 was discovered.

先天性心脏缺陷是中胚层细胞（形成心脏的肌肉部分）或神经嵴衍生细胞（形成心脏流出道和主动脉弓）异常发育的结果。 两个细胞群中的缺陷通常以节段的方式发生，导致心脏的不同区域异常，而邻近区域相对正常。 该提案的长期目标是了解可以控制节段心脏发育的独立分子途径和机制。 这种理解是识别导致心脏不同区域心脏缺陷的基因的第一步。 具体来说，我们重点阐明 DiGeorge/CATCH-22 综合征的发病机制，该综合征是心脏和咽部神经嵴发育缺陷以及左右心室发育不良综合征。 最近发现的基本螺旋-环-螺旋转录因子 dHAND 和 e-HAND 为这两个领域的研究提供了动力，因为它们在心脏中胚层和心脏神经嵴中都有表达。 此外，d-HAND 和 e-HAND 为这两个领域的研究提供了动力，因为它们在心脏中胚层和心脏神经嵴中都有表达。 此外，dHAND 和 eHAND 在发育中的心脏的独特片段中表达，并作为切入室特定通路的上游和下游成员的入口点。 dHAND 缺失胚胎的右心室发育不全，无法形成神经嵴衍生的主动脉弓动脉。 dHAND 的作用机制可能是通过直接调节细胞凋亡途径的潜在成员来抑制程序性细胞死亡（细胞凋亡）来介导。 dHAND 下游基因的鉴定导致了 cot-22 的发现，这是一种位于 22 号染色体最小 DiGeorge 关键区域的新基因，在心脏和鳃弓中表达。该提案的三个主要目标如下：1)确定小鼠和人类中 cot-22 是否是导致 DiGeorge/CATCH-22 综合征的基因或基因之一，2) 确定细胞凋亡在右心室发育不良中的作用dHAND 缺失小鼠的足弓畸形，3) 通过以心脏和神经嵴特异性方式过度表达 HAND 基因，确定 dHAND 和 eHAND 在心脏发育和产后心脏病中的显着效应；这一目标将通过解决潜在的机制问题来补充目标1和2的目标。 该目标利用与人类疾病相关的体内模型，并辅以本次资助中其他研究提出的脑室发育不良综合征和神经嵴缺陷的研究。 通过阐明节段性心脏发育的分子途径和特定疾病的责任位点的定位克隆，将有可能鉴定出导致不同心脏缺陷的基因，类似于发现 cot-22 的方式。