Role of Syntaxin 6 Regulated Post-Golgi Trafficking in Angiogenesis

Synaxin 6调控高尔基体后转运在血管生成中的作用 血管生成指的是从原有的血管系统中建立新的血管。功能障碍 血管生成可导致多种恶性、炎症性和缺血性疾病。新舰艇编队 涉及多种细胞过程，包括细胞增殖和迁移、细胞-细胞和细胞-基质 黏附相互作用和管子形态发生。“膜筏”是质膜上的区域， 富含鞘脂和甾醇。这些结构域还富含信号蛋白，包括 某些激酶、整合素和血管内皮生长因子受体-2(VEGFR2)，所有这些都是 据信在血管生成中发挥作用。到目前为止，膜筏和细胞内转运的作用 相关成分在血管生成中的作用尚不清楚。我们之前已经为 囊泡融合蛋白合成素6(Syn6)在将RAFT相关的脂质和蛋白输送到血浆中的作用 膜(PM)。我们的长期目标是了解(S)贩运人口的机制 膜筏组件影响细胞的运动。这项研究提案的总体目标是确定 “膜筏”组分由内向外运输和传递的分子机制 对内皮细胞表面的影响，并检测这些过程在调节细胞 血管生成过程中的运动性。总体而言，我们的团队在多种功能丧失方法方面拥有专业知识， 细胞成像、分子和细胞生物学技术，以及几种体外和体内血管生成模型， 这将使我们能够解决内皮细胞中的这些重要问题。在目标1中，我们将在体外使用 评估依赖于Syn6的膜筏组成的调节如何影响细胞运动的研究 首相为此，我们将评估膜结构域的形成、招募、组织、激活、 以及焦点黏附相关蛋白的动态变化。在目标2中，我们将进行体外研究，以解开 VEGFR2分泌转运和递送到PM的分子机制在《目标3》中，我们将同时使用 体外和体内模型系统测试syn6调节的膜转运的功能意义 RAFT组件，更具体地，关于内皮细胞形态发生的VEGFR2 和血管生成。这些研究的结果将开始解开syn6介导的机制 膜运输调节血管生成，并可能提供新的候选靶点作为正反向靶点。 血管生成疗法。血管生成涉及从先前存在的血管形成新的血管，并在 健康和几种疾病。细胞表面定位的血管内皮生长因子的信号转导 受体-2(VEGFR2)和“膜筏”在血管生成中起关键作用。然而，我们对 参与维持VEGFR2和RAFT组分定位到细胞表面的运输途径 是有限的。通过研究和了解血管生成调节分子的运输，我们可能会发现 治疗的新靶点。

Title: Role of syntaxin 6 regulated post-Golgi trafficking in angiogenesis Angiogenesis refers to the establishment of new vessels from preexisting vasculature. Dysfunctions in angiogenesis can lead to several malignant, inflammatory, and ischemic disorders. New vessel formation involves multiple cellular processes, including cellular proliferation and migration, cell-cell and cell-matrix adhesion interactions, and tube morphogenesis. "Membrane rafts" are regions of the plasma membrane that are enriched in sphingolipids and sterols. These domains are also enriched in signaling proteins including certain kinases, integrins and vascular endothelial growth factor receptor-2 (VEGFR2), all of which are believed to play roles in angiogenesis. To date, the roles that membrane rafts and the intracellular trafficking of associated components play in angiogenesis remain unclear. We have previously identified a novel role for the vesicle fusion protein syntaxin 6 (syn6) in the delivery of raft-associated lipids and proteins to the plasma membrane (PM). Our long-term objective is to understand the mechanism(s) by which the trafficking of membrane raft components influences cell motility. The overall goals of this research proposal are to define the molecular mechanisms that underlie inside-out trafficking and the delivery of "membrane raft" components to the endothelial cell surface, and to examine the importance of these processes in the regulation of cellular motility during angiogenesis. Collectively, our group has expertise in multiple loss-of-function approaches, live- cell imaging, molecular and cell biological techniques, and several in vitro and in vivo angiogenesis models, and this will allow us to address these important questions in endothelial cells. In Aim 1, we will use in vitro studies to assess how cell motility is affected by syn6-dependent modulation of membrane raft composition at the PM. To this end, we will evaluate the membrane domain formation, recruitment, organization, activation, and dynamics of focal adhesion-associated proteins. In Aim 2, we will perform in vitro studies to unravel the molecular mechanism behind secretory transport and delivery of VEGFR2 to the PM. In Aim 3, we will use both in vitro and in vivo model systems to test the functional significance of syn6-regulated trafficking of membrane raft components generally, and of VEGFR2 more specifically, with respect to endothelial tube morphogenesis and angiogenesis. Findings from these studies will begin to unravel the mechanisms by which syn6-mediated membrane trafficking regulate angiogenesis, and may provide novel candidate targets for pro- or anti- angiogenic therapies. Angiogenesis involves the formation of new vessels from preexisting ones, and plays an important role in health and several diseases. Signaling via the cell surface-localized vascular endothelial growth factor receptor-2 (VEGFR2) and "membrane rafts" plays key role in angiogenesis. However, our knowledge about the trafficking pathways involved in the maintenance of VEGFR2 and raft component localization to the cell surface is limited. By studying and understanding the trafficking of angiogenesis-regulatory molecules, we may identify a novel target for therapy.