Tbx5 Protein Networks And Heart/Limb Development Defects

描述(申请人提供)：新生儿的先天性心脏和肢体畸形会导致身体功能的毁灭性丧失，导致生活质量低下甚至死亡。因此，对受影响的个人、家庭和社会的不利影响强调需要更好地了解控制和调节各自发展途径的基本机制。在这些机制的各种参与者中，T-box转录因子似乎扮演着关键角色。特别是，T-box基因Tbx5在发育中的上肢和心脏中显示了独特的表达模式。在控制肢体和心脏模式中发挥作用的直接证据来自缺乏Tbx5的人类和小鼠胚胎中Tbx5的突变。Tbx5蛋白水平降低会导致Holt-Oram综合征(HOS)，这是一种以上肢发育缺陷和心脏间隔为特征的疾病。患有环境诱导型2型糖尿病的母亲的婴儿出现严重的心脏和肢体畸形，这让人想起居屋计划中看到的那些。这些惊人的相似性表明饮食因素与Tbx5基因功能之间存在关系。我们的实验室已经发现了一种新的分子支架蛋白，它与Tbx5结合，可能是胰岛素信号与Tbx5在心脏和肢体中活性之间的分子联系。尽管Tbx5蛋白在发育和疾病中很重要，但它发挥功能的机制尚不清楚。该项目的长期目标是阐明TBX转录因子如何以发育受控的方式在分子调控网络中相互作用，以及这些过程有时是如何以及为什么失败的。本研究旨在研究Tbx5与胰岛素信号的关系，从而探讨环境因素在发育缺陷中的潜在作用。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Tbx5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Tbx5功能的更深入的看法，导致更好地了解与糖尿病和葡萄糖和胰岛素代谢紊乱相关的心脏出生缺陷，并将提供对先前未知的转录因子在发育过程中的调节机制的洞察。

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.