"A signaling integrator plays a critical role in regulating cell migration"

“信号整合器在调节细胞迁移中发挥着关键作用”

基本信息

批准号：
8146108
负责人：
DONNA J WEBB
金额：
$ 30.12万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8146108
关键词：
Actins Adenomatous Polyposis Coli Adhesions Arthritis Atherosclerosis Behavior Binding Biological Assay Biological Process Birds Brain Cell Adhesion Cells Complex DH Domain Data Defect Development Disease Embryo Embryonic Development Family Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases In Vitro Inflammatory Response Lead Malignant Neoplasms Mediating Modeling Molecular N-terminal Osteoporosis PH Domain Pathologic Processes Phosphotransferases Play Process Protein-Serine-Threonine Kinases Proteins Role Signal Transduction Small Interfering RNA Testing Time Tumor Suppressor Proteins Work Wound Healing base cell motility cellular imaging computerized data processing in vivo inhibitor/antagonist insight intravital microscopy migration mutant novel therapeutic intervention protein protein interaction public health relevance response rho rho GTP-Binding Proteins spatiotemporal tissue regeneration

项目摘要

DESCRIPTION (provided by applicant): The signaling mechanisms that regulate cell migration are not well understood despite its importance in numerous biological and pathological processes, including embryogenesis, the inflammatory response, tissue repair and regeneration, cancer, arthritis, atherosclerosis, osteoporosis, and congenital developmental brain defects. An emerging concept is that molecules, which integrate signaling components to coordinately regulate processes underlying migration, such as actin reorganization, adhesion assembly and disassembly (turnover), and the establishment of polarity, are critical for this process. We hypothesize that the multi-domain containing protein, Asef2, functions in this capacity by integrating critical signaling components of these processes to regulate cell migration. Our preliminary work has lead to working hypotheses and the objective of this proposal is to rigorously test these hypotheses as outlined in the specific aims. Specific Aim I will test the hypothesis that Asef2 is a critical regulator of migration through its ability to integrate molecular signals, which are important to this process. We will determine the domains that mediate this function of Asef2 to gain insight into the molecular mechanisms by which it regulates cell migration. In Specific Aim II, we will test the hypothesis that Asef2 brings together kinases, such as Akt, and Rho family GTPase signaling to modulate cell migration. In this aim, we will use expression constructs, mutant based strategies, pharmacological inhibitors, and siRNA studies to test this hypothesis. Our working model is that Asef2 signaling coordinately regulates the activities of kinases and Rho GTPases to stimulate the rapid turnover of leading edge adhesions, which leads to enhanced cell migration. Specific Aim III will determine if Asef2 signaling components, such as Akt and other kinase effectors, regulate the turnover of leading edge adhesions. In this aim, we will test our hypothesis by using new quantitative assays that we developed to study adhesion turnover. The studies outlined in this proposal will lead to a greater understanding of the signaling mechanisms by which Asef2 regulates cell migration. PUBLIC HEALTH RELEVANCE: Cell migration is central to many biological and pathological processes, such as cancer, arthritis, atherosclerosis, and congenital brain defects. Understanding the molecules that regulate migration will lead to new therapeutic approaches to treating these disorders. The goal of this proposal is to identify molecules that are critical regulators of cell migration.

描述（由申请人提供）：尽管调节细胞迁移的信号传导机制在许多生物和病理过程中很重要，包括胚胎发生、炎症反应、组织修复和再生、癌症、关节炎、动脉粥样硬化、骨质疏松症和先天性疾病，但其信号传导机制尚未得到充分理解。大脑发育缺陷。一个新兴的概念是，分子整合信号成分来协调调节迁移过程，例如肌动蛋白重组、粘附组装和拆卸（周转）以及极性的建立，对于这一过程至关重要。我们假设含有多结构域的蛋白质 Asef2 通过整合这些过程的关键信号成分来调节细胞迁移，从而发挥这种功能。我们的初步工作提出了工作假设，该提案的目的是严格测试具体目标中概述的这些假设。具体目标我将测试 Asef2 通过其整合分子信号的能力而成为迁移的关键调节因子的假设，这对该过程很重要。我们将确定介导 Asef2 功能的域，以深入了解它调节细胞迁移的分子机制。在 Specific Aim II 中，我们将测试 Asef2 将 Akt 等激酶和 Rho 家族 GTPase 信号传导结合在一起来调节细胞迁移的假设。为此，我们将使用表达构建体、基于突变的策略、药理学抑制剂和 siRNA 研究来检验这一假设。我们的工作模型是 Asef2 信号传导协调调节激酶和 Rho GTPases 的活性，以刺激前缘粘附的快速周转，从而增强细胞迁移。具体目标 III 将确定 Asef2 信号成分（例如 Akt 和其他激酶效应器）是否调节前缘粘连的周转。为此，我们将通过使用我们为研究粘附周转而开发的新定量测定法来检验我们的假设。该提案中概述的研究将有助于更好地了解 Asef2 调节细胞迁移的信号机制。公共健康相关性：细胞迁移是许多生物和病理过程的核心，例如癌症、关节炎、动脉粥样硬化和先天性脑缺陷。了解调节迁移的分子将带来治疗这些疾病的新治疗方法。该提案的目标是确定细胞迁移关键调节分子的分子。