Molecular Mechanisms of Cytokinesis

细胞分裂的分子机制

基本信息

批准号：
10799008
负责人：
Jian-Qiu Wu
金额：
$ 15万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10799008
关键词：
Actins Actomyosin Affect Animals Antifungal Agents Binding Biochemical Biological Assay Biological Models Cell Differentiation process Cell Nucleus Cell Proliferation Cell Separation Cell Wall Cell division Cell membrane Cells Co-Immunoprecipitations Complex Congenital Abnormality Cytokinesis Darkness Data Defect Deposition Development Diabetes Mellitus Digestion Electron Microscopy Endocytosis Enzymes Equilibrium Event Exocytosis Extracellular Matrix Filament Fission Yeast Funding Genetic Goals Health Homeostasis Human In Vitro Label Learning Light Link Microscopic Microscopy Mitochondria Molecular Pattern Play Principal Investigator Proteins Regulation Resolution Role Series Site Solid Testing Tissues Tumor Promotion UNC13B gene Vesicle Work Yeasts beta-Glucans cancer therapy constriction daughter cell electron tomography experimental study fungus glucan synthase improved nervous system disorder novel recruit rho GTPase-activating protein snRNP Structural Core Protein spatiotemporal tomography trafficking ultra high resolution

项目摘要

Project Summary Cytokinesis is essential for cell proliferation, cell differentiation, and tissue homeostasis. Most events and proteins of cytokinesis are conserved from yeast to humans. Majority of the proteins involved in cytokinesis have been identified, however, the mechanisms of actomyosin contractile-ring constriction, plasma-membrane expansion in the cleavage furrow, and extracellular matrix remodeling are still poorly understood; nor do we understand how cells coordinate these events for successful cell division. Here we propose to continue elucidating the molecular mechanisms of cytokinesis using fission yeast as a model system. Previous studies and our solid preliminary data led to the central hypothesis of this proposal that coordination between exocytosis and endocytosis is essential for successful plasma membrane deposition and septum formation during cytokinesis, and septins and Ync13 are among the crucial coordinators. We will use complementary genetic, cellular, microscopic (confocal, TIRFM, electron microscopy, electron tomography, and super-resolution), biochemical, structural, and computational approaches to test this hypothesis by investigating three specific aims: 1) Elucidate how septins define the sites of vesicle tethering by the exocyst and how they affect the sites of endocytosis; 2) Characterize how Ync13 coordinates exocytosis and endocytosis during cytokinesis; 3) Investigate molecular mechanisms of trafficking, anchoring, and regulation of glucan synthases during cytokinesis. Our studies on the relationships between septins, the exocyst, Munc13/UNC-13 protein Ync13, F- BAR protein Rga7, coiled-coil protein Rng10, and glucan synthases will provide molecular links among the main cytokinesis events. Our proposed studies are significant because they will advance the understanding of cytokinesis in three important ways: a) What are the roles of septins in exocytosis and endocytosis during cytokinesis; b) how Ync13 coordinates exocytosis and endocytosis for successful cytokinesis; c) how septum synthases are trafficked and regulated. The concepts learned from this project will be applicable to understand the coordination of septins, the exocyst, plasma-membrane deposition, and extracellular matrix remodeling in human cells because our three specific aims involve the most conserved aspects of cytokinesis. Because the fungal specific essential enzymes such as glucan synthases, which build the septum during cytokinesis, are targets of several antifungals, our studies on the regulators of these synthases proposed here may lead to novel targets for antifungal drugs. Thus, our discoveries on both conserved and fungal-specific aspects of cytokinesis may be harnessed to improve human health.

项目摘要细胞因子对于细胞增殖，细胞分化和组织稳态至关重要。大多数事件和细胞因子的蛋白质是从酵母到人类的保存。大多数参与细胞因子的蛋白质具有然而，已确定了肌球蛋白收缩 - 环的机制，血浆膜裂解沟中的膨胀和细胞外基质重塑仍然很少了解。我们也不是了解细胞如何协调这些事件以成功进行细胞分裂。在这里我们建议继续使用裂变酵母作为模型系统阐明细胞因子的分子机制。先前的研究我们的坚实初步数据导致了这一提议的中心假设，即胞吐作用之间的协调内吞作用对于成功的质膜沉积和隔膜形成至关重要细胞因子以及Septins和YNC13是关键的协调员。我们将使用互补的遗传，细胞，显微镜（共聚焦，TIRFM，电子显微镜，电子断层扫描和超分辨率），生化，结构和计算方法通过研究三个特定目的来检验这一假设： 1）阐明septins如何定义囊泡的位点通过外囊肿及其如何影响它们的位置内吞作用； 2）表征YNC13如何在细胞因子过程中坐标胞吞和内吞作用； 3）研究在运输，锚定和调节葡聚糖合酶期间的分子机制细胞因子。我们对Septins，Exocyst，Munc13/UNC-13蛋白YNC13，F-之间关系的研究 BAR蛋白RGA7，卷曲螺旋蛋白RNG10和葡聚糖合酶将在主要的分子链接中提供分子链接细胞因子事件。我们提出的研究很重要，因为它们将提高对细胞因子以三种重要的方式：a）隔膜在胞吐作用和内吞作用中的作用是什么细胞因子； b）YNC13如何串联胞吞作用和内吞作用成功的细胞因子； c）如何隔离合成酶被贩运和调节。从这个项目中学到的概念将适用于了解 SEPTINS，外囊肿，血浆膜沉积和细胞外基质重塑的配位人类细胞是因为我们的三个特定目标涉及细胞因子的最保守的方面。因为真菌特定的必需酶，例如葡萄糖合酶，在细胞动力学期间构建隔胞胎几种抗真菌剂的靶标，我们对这里提出的这些合成酶调节剂的研究可能导致新颖抗真菌药物的靶标。因此，我们对细胞因子的保守和真菌特异性方面的发现可以利用改善人类健康。