Cytoskeleton, Nucleus and Integrin Recycling in Cell Migration

细胞迁移中的细胞骨架、细胞核和整合素回收

• 批准号: 10613943
• 负责人: Gregg G Gundersen
• 金额: $ 60.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613943
• 关键词: Adhesions; Attention; Cell Nucleus; Cells; Complex; Cytoskeleton; Defect; Development; Exocytosis; Immune response; Inflammation; Integrins; Intervention; Knowledge; Laboratories; Lead; Measures; Mechanics; Microfilaments; Microtubules; Molecular Conformation; Movement; National Institute of General Medical Sciences; Neoplasm Metastasis; Nuclear; Organ; Pathologic Processes; Physiological Processes; Positioning Attribute; Postdoctoral Fellow; Process; Property; Recycling; Signal Transduction; Site; System; Testing; Tissues; Training; Travel; adhesion receptor; cell motility; graduate student; non-healing wounds; sensor; tissue regeneration; trafficking; wound healing

SUMMARY Metazoan cell migration contributes to developmental and homeostatic processes, including formation of tissues and organs, wound healing, tissue renewal and immune responses. Alterations in cell migration lead to developmental defects, inflammation, persistent wounds and metastasis. Deciphering mechanisms of cell migration thus has broad significance for understanding both physiological and pathological processes. Considerable effort has led to deep understanding of some of the critical processes that contribute to cell migration, including protrusion of the leading edge and formation of adhesions. Other important aspects of cell migration have received scant attention and there is a gap in our understanding of their mechanism and contribution to cell migration. This proposal seeks to fill this knowledge gap for two such processes: nuclear positioning and integrin recycling. Both these processes are essential for cell migration, but mechanistic understanding of how they do so is lacking. This proposal will build on results previously obtained in two previous projects in the Gundersen laboratory supported by NIGMS. For nuclear positioning, we will examine how the linker of nucleoskeleton and cytoskeleton (LINC) complex is mechanically reinforced to resist the large forces necessary to move the nucleus and will use and develop new tension sensors to directly measure forces on the nucleus. We will determine how the LINC complex selects actin filament or microtubules for nuclear movement and the functional consequences of these interactions for different modes of cell migration. We will test new hypotheses that the nucleus functions as a “tension resistor” for actin filaments and as a polarity factor for microtubule trafficking. For integrin recycling, we will test the overall hypothesis that recycled integrins travel in an active conformation and that this seeds new adhesion formation in a polarized manner near the leading edge. We will use new integrin probes and a new integrin recycling system to identify sites of integrin exocytosis and their relationship to newly formed adhesions. In migrating cells, we will determine whether recycled integrin derives from the cell rear and contributes to nascent adhesion formation near the leading edge. We will identify the microtubule machinery that we hypothesize is responsible for the polarized reformation of adhesions from recycled integrins and test the possibility that the recycled integrin plays a role in integrin signaling. Our proposed studies on these two processes will advance understanding of the basic mechanisms of cell migration and potential identify new targets for intervening in cases when cell migration goes awry. The proposed studies will also provide fertile ground for postdoctoral fellows and graduate students to advance their training and develop their own projects.

概括 后生细胞迁移有助于发育和稳态过程，包括组织和 器官，伤口愈合，组织更新和免疫复杂。细胞迁移的改变导致发育缺陷， 炎症，持续的逻辑和转移。因此，细胞迁移的解密机制具有广泛的意义 了解物理和病理过程。巨大的努力导致对 有助于细胞迁移的一些关键过程，包括前缘的突出和形成 粘连。细胞迁移的其他重要方面受到了很少的关注，我们的理解存在差距 它们的机制和对细胞迁移的贡献。该建议旨在填补这两个这样的知识空白 过程：核定位和整联蛋白回收。这两个过程对于细胞迁移至关重要，但是机械 缺乏了解他们的方式。该提案将基于先前在之前的两个项目中获得的结果 在冈德森实验室中得到了纽格姆斯的支持。对于核定位，我们将研究如何联系 核骨骼和细胞骨架（LINC）配合物在机械上加强以抵抗移动所需的大力 核并将使用并开发新的张力传感器直接测量核上的力。我们将确定 LINC复合物如何为核运动选择肌动蛋白丝或微管以及 这些相互作用用于不同的细胞迁移模式。我们将检验新的假设，即核作为A 肌动蛋白丝的“张力电阻”，也是微管运输的极性因子。对于整联蛋白回收，我们将测试 回收整合素在活动会议上传播的总体假设，并且这是种子的新粘合剂形成 在前沿附近以极化方式。我们将使用新的整联蛋白问题和新的整合素回收系统来 识别整合素外胞菌病的部位及其与新形成的粘附的关系。在迁移细胞中，我们将确定 是否回收整联蛋白源自细胞后部，并在前沿附近有助于新生的广告形成。 我们将确定我们假设的微管机械是依从性的两极分化评论 从回收的整联蛋白中，测试回收的整联蛋白在整联蛋白信号传导中起作用。我们提出的 对这两个过程的研究将提高人们对细胞迁移和潜力的基本机制的理解 确定在细胞迁移出现问题的情况下进行干预的新目标。拟议的研究还将提供肥沃的 博士后研究员和研究生来推进培训并开发自己的项目的理由。