Signaling Mechanisms of Heterotrimeric G proteins

描述(申请人提供)：我们研究的长期目标是了解异三聚体鸟嘌呤核苷酸结合调节蛋白(G蛋白)的信号机制。这一应用的主要焦点是G蛋白Ga13的分子信号机制。Ga13-/-小鼠在E9.5岁时死亡。然而，这种胚胎致死的分子基础尚不清楚。由于Ga13/-小鼠胚胎(E9.5)的卵黄囊没有显示任何血管，因此推测死亡原因是胚胎发育过程中血管形成的缺陷。Ga13-/-小鼠的这种早期胚胎致死性使得研究Ga13在胚胎血管生成中的作用和分子基础变得困难。因此，我们将以肿瘤血管生成为模型，探讨Ga13在成年小鼠血管生成中的作用。在特定目的2，我们将探讨Ga13促进成年血管生成的分子机制。G蛋白是G蛋白偶联受体下游的信号媒介。我们最近发现Ga13在受体酪氨酸激酶启动的信号转导中起关键作用，这立即引出了一个问题，即受体酪氨酸激酶是如何向Ga13发出信号的。在特定的目标3中，我们将研究生长因子受体以不依赖于GPCR的方式向Ga13传递信号的生化和细胞信号机制。 公共卫生相关性：这项研究与人类健康直接相关。细胞迁移和血管生成是血管发育和肿瘤生长所必需的。此外，许多临床前研究表明，内皮祖细胞移植治疗后肢、心肌和脑缺血可有效地诱导新生血管形成，而内皮祖细胞移植治疗慢性和急性冠状动脉疾病的早期临床试验表明，基于细胞的治疗是安全可行的。因此，更好地了解血管生成的机制和内皮祖细胞的迁移/募集将有助于我们与心血管疾病和癌症的斗争。

DESCRIPTION (provided by applicant): The long-term objective of our research is to understand the signaling mechanisms of heterotrimeric guanine nucleotide-binding regulatory proteins (G proteins). The main focus of this application is on the molecular signaling mechanism of G protein Ga13. Ga13 -/- mice died at E9.5. Yet the molecular basis for this embryonic lethality is not clear. Since the yolk sac of Ga13 -/- mouse embryos (at E9.5) did not show any blood vessels, it was postulated that the cause of death was a defective vascularization during embryogenesis. This early embryonic lethality of Ga13 -/- mice makes the study of the role and molecular basis for Ga13 in embryonic angiogenesis difficult. Therefore, we will use tumor angiogenesis as a model to investigate the function of Ga13 in adult angiogenesis in mice in the Specific Aim 1. In the Specific Aim 2, we will explore the molecular mechanism by which Ga13 contributes to adult angiogenesis. G proteins are known as signaling mediators downstream of G protein-coupled receptors. Our recent finding of a critical role for Ga13 in receptor tyrosine kinase-initiated signaling immediately begs the question of how receptor tyrosine kinases signal to Ga13. We will investigate the biochemical and cellular signaling mechanisms by which growth factor receptors transmit the signals to Ga13 in a GPCR-independent manner in the Specific Aim 3. PUBLIC HEALTH RELEVANCE: This research is directly related to human health. Cell migration and angiogenesis are essential for vascular development and tumor growth. Furthermore, effective neovascularization induced by endothelial progenitor cell transplantation for hind limb, myocardial, and cerebral ischemia has been demonstrated in many preclinical studies, and early clinical trials of endothelial progenitor cells transplantation in chronic and acute coronary artery diseases indicate safety and feasibility of cell-based therapies. Therefore, a better understanding of the mechanisms of angiogenesis and of the migration/recruitment of endothelial progenitor cells will advance our combat against cardiovascular diseases and cancers.