Spatial Regulation of Cytoskeletal Asymmetry

细胞骨架不对称的空间调节

• 批准号: 7793552
• 负责人: Irina Kaverina
• 金额: $ 28.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793552
• 关键词: Ablation; Accounting; Actins; Address; Adhesions; Animals; Binding; Binding Proteins; Biological Assay; Build-it; Cell Polarity; Cells; Centrosome; Cytoskeleton; Data; Embryo; Embryonic Development; Event; Exocytosis; Goals; Golgi Apparatus; Growth; Immune response; Knowledge; Label; Lasers; Life; Location; Malignant Neoplasms; Membrane; Microsurgery; Microtubules; Mitotic; Modeling; Molecular; Morphogenesis; Organism; Peripheral; Pharmaceutical Preparations; Physiological; Process; Public Health; Radial; Recovery; Recruitment Activity; Regulation; Research; Role; Side; Site; Supporting Cell; System; Testing; Tubulin; Wound Healing; base; cancer cell; cancer invasiveness; cancer therapy; cell motility; genetic regulatory protein; migration; novel; polarized cell; polymerization; research study; trafficking; trans-Golgi Network

DESCRIPTION (provided by applicant): Cell migration in higher organisms is essential for multiple physiological and pathophysiological processes, including embryonic development and immune responses. Alteration of cell motility in cancer cells is one of the most dangerous features of malignant tumors, as it builds up their invasive and metastatic potential. Polarized organization of microtubule arrays is essential for polarized cell motility. However, the principles of this regulation are not yet understood. It is generally assumed that microtubules in vertebrate cells are formed by the centrosome. We have recently demonstrated that a large number of microtubules originate from the Golgi apparatus (Efimov et al, 2007). We have identified two molecular players critical for this novel phenomenon: microtubule regulatory proteins CLASPs are required for the formation of Golgi-derived microtubules, and golgin GCC185 serves as an anchor for CLASPs at the trans-Golgi network (TGN) at the Golgi periphery. In sharp contrast to symmetric microtubule arrays organized by the centrosome, microtubules nucleated at the peripheral Golgi compartment are preferentially oriented toward the leading edge in motile cells. Preliminary data suggest that the migratory potential of cells lacking Golgi-originated microtubules is compromised. Within this proposal, we will test the hypothesis that asymmetric microtubule nucleation at the Golgi is critical for motile cell polarization. We will test whether Golgi-originated microtubules exert their effect on cell polarity via regulation of the actin cytoskeleton or directional post-Golgi transport to the cell front, or both. We will also address molecular mechanisms that regulate microtubule formation at the TGN. Our specific aims are: 1. Determine the role of Golgi-derived microtubules in the cytoskeletal polarity of motile cells. 2. Determine the role of Golgi-derived microtubules in polarized Golgi trafficking in motile cells. 3. Determine if dynamic CLASP anchoring underlies the microtubule-organizing potential of the Golgi. PUBLIC HEALTH REVELANCE: Knowledge of the molecular events that underlie cell motility is critical for understanding major health-related processes, including embryonic morphogenesis, wound healing, the immune response and cancer invasiveness. As major anticancer therapies include microtubule-specific drugs, knowledge their potential targets is especially valuable. In this proposal, we will carry out research that will determine the role of a novel Golgi-derived asymmetric microtubule array in cell motility.

描述（由申请人提供）：高等生物体中的细胞迁移对于多种生理和病理生理过程至关重要，包括胚胎发育和免疫反应。癌细胞中细胞运动性的改变是恶性肿瘤最危险的特征之一，因为它建立了它们的侵袭和转移潜力。微管阵列的极化组织对于极化细胞运动是必不可少的。然而，这项规定的原则尚未得到理解。一般认为，脊椎动物细胞中的微管是由中心体形成的。我们最近证明了大量的微管起源于高尔基体（Efimov et al，2007）。我们已经确定了这一新现象的两个关键分子的球员：微管调节蛋白CLASPs所需的高尔基体衍生的微管的形成，和golgin GCC 185作为一个锚CLASPs在高尔基体外围的trans-Golgi网络（TGN）。与中心体组织的对称微管阵列形成鲜明对比的是，在外周高尔基体室成核的微管优先朝向运动细胞的前缘。初步数据表明，缺乏高尔基体起源的微管的细胞的迁移潜力受到损害。在这个建议中，我们将测试的假设，不对称微管成核在高尔基体是运动细胞极化的关键。我们将测试是否高尔基体起源的微管发挥其对细胞极性通过调节肌动蛋白细胞骨架或定向后高尔基体运输到细胞前，或两者兼而有之。我们还将讨论调节TGN微管形成的分子机制。我们的具体目标是：1.确定高尔基体衍生的微管在运动细胞的细胞骨架极性中的作用。2.确定高尔基体衍生微管在运动细胞中高尔基体极化运输中的作用。3.确定动态CLASP锚定是否是高尔基体微管组织潜力的基础。 公共卫生部门：了解细胞运动的分子事件对于理解主要的健康相关过程至关重要，包括胚胎形态发生，伤口愈合，免疫反应和癌症侵袭。由于主要的抗癌疗法包括微管特异性药物，因此了解其潜在靶点尤其有价值。在这项提案中，我们将进行研究，以确定一种新的高尔基体衍生的不对称微管阵列在细胞运动中的作用。