Tbx5 Protein Networks And Heart/Limb Development Defects

Tbx5 蛋白质网络和心脏/肢体发育缺陷

• 批准号: 6803234
• 负责人: HANS-GEORG SIMON
• 金额: $ 14.2万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803234
• 关键词: biological signal transduction; chick embryo; congenital heart disorder; congenital skeletal disorder; cytoskeleton; developmental genetics; histogenesis; immunocytochemistry; immunoprecipitation; in situ hybridization; insulin; insulin receptor; limbs; posttranslational modifications; protein binding; protein localization; protein protein interaction; protein structure function; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Congenital heart and limb malformations in newborns can lead to devastating losses of body function, resulting in poor quality of life or even death. Thus, the detrimental impact on the affected individuals, families, and society emphasize the need for a better understanding of the underlying mechanisms that control and regulate the respective developmental pathways. Among the various players in those mechanisms, T-box transcription factors appear to have key roles. In particular, the T-box gene Tbx5 reveals a unique expression pattern in developing upper limbs and the heart. Direct evidence for a role in controlling limb and heart pattern comes from mutations in TBX5 in humans and mouse embryos lacking Tbx5. A reduced level of Tbx5 protein causes Holt-Oram syndrome (HOS), a disease characterized by developmental defects of the upper limbs and heart septation. Major cardiac and limb malformations in infants of mothers with environmentally induced type 2 diabetes are reminiscent to those seen in HOS. These striking similarities suggest a relationship between dietary factors and Tbx5 gene function. Our laboratory has identified a novel molecular scaffolding protein that binds Tbx5 and may be the molecular link between insulin signaling and Tbx5 activity in the heart and limb. In spite of its importance in development and disease, the mechanisms by which the Tbx5 protein exerts its functions are not yet understood. The long-term objective of this project is to elucidate how Tbx transcription factors interact in a molecular regulatory network in a developmentally controlled manner, and how and why these processes sometimes fail. We aim in this study to characterize the relationship of Tbx5 with insulin signaling, and thereby investigate a potential environmental role in developmental defects. We will utilize molecular biology, cell biology, and biochemistry to determine the expression, localization, and interactions of the novel protein LMP-4 with Tbx5 and the insulin receptor. Ultimately, these studies will provide a more in-depth view of Tbx5 function, lead to a better understanding of cardiac birth defects associated with diabetes and disturbed glucose and insulin metabolism, and will provide insight into a previously unknown mechanism for transcription factor regulation in development.

描述（由申请人提供）：新生儿先天性心脏和肢体畸形可导致身体功能的破坏性丧失，导致生活质量差甚至死亡。因此，对受影响的个人、家庭和社会的不利影响强调了更好地了解控制和调节各自发展途径的基本机制的必要性。在这些机制中的各种参与者中，T-box转录因子似乎具有关键作用。特别是，T-box基因Tbx 5揭示了发育中上肢和心脏的独特表达模式。控制肢体和心脏模式的直接证据来自于缺乏Tbx 5的人类和小鼠胚胎中TBX 5的突变。Tbx 5蛋白水平降低会导致Holt-Oram综合征（HOS），这是一种以上肢和心脏分隔发育缺陷为特征的疾病。环境诱发的2型糖尿病母亲的婴儿的主要心脏和肢体畸形与HOS中所见相似。这些惊人的相似性表明饮食因素和Tbx 5基因功能之间的关系。我们的实验室已经确定了一种新的分子支架蛋白，它与Tbx 5结合，可能是心脏和肢体中胰岛素信号传导与Tbx 5活性之间的分子联系。尽管其在发育和疾病中的重要性，但Tbx 5蛋白发挥其功能的机制尚未被理解。该项目的长期目标是阐明Tbx转录因子如何以发育控制的方式在分子调控网络中相互作用，以及这些过程如何以及为什么有时会失败。本研究的目的是描述Tbx 5与胰岛素信号传导的关系，从而研究发育缺陷中潜在的环境作用。我们将利用分子生物学、细胞生物学和生物化学来确定新蛋白LMP-4与Tbx 5和胰岛素受体的表达、定位和相互作用。最终，这些研究将提供对Tbx 5功能的更深入的了解，更好地了解与糖尿病以及葡萄糖和胰岛素代谢紊乱相关的心脏出生缺陷，并将深入了解发育中转录因子调控的先前未知机制。