"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”

• 批准号: 7863648
• 负责人: DONNA J WEBB
• 金额: $ 30.26万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/7863648
• 关键词: Actins; Adenomatous Polyposis Coli; Adhesions; Arthritis; Atherosclerosis; Behavior; Binding; Biological; Biological Assay; Birds; Brain; 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; Natural regeneration; 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

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学和病理学过程（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发育性脑缺陷）中很重要，但其尚未得到充分理解。一个新兴的概念是，分子，整合信号组件，协调调节迁移的过程，如肌动蛋白重组，粘附组装和拆卸（周转），并建立极性，是这个过程的关键。我们假设，多域包含蛋白质，Asef2，在这种能力的功能，通过整合这些过程中的关键信号成分，以调节细胞迁移。我们的初步工作导致了工作假设，本提案的目的是严格测试这些假设，如具体目标所述。具体目的我将测试的假设，即Asef2是一个关键的调节迁移通过其整合分子信号的能力，这是很重要的，这一过程。我们将确定介导Asef2这种功能的结构域，以深入了解它调节细胞迁移的分子机制。在特定目标II中，我们将测试Asef2将激酶（如Akt）和Rho家族GT3信号传导结合在一起以调节细胞迁移的假设。在这个目标中，我们将使用表达构建体，基于突变体的策略，药理学抑制剂和siRNA研究来验证这一假设。我们的工作模型是Asef2信号协调调节激酶和Rho GTP酶的活性，以刺激前缘粘附的快速周转，从而导致增强的细胞迁移。特异性目的III将确定Asef2信号传导组分，如Akt和其他激酶效应物，是否调节前缘粘连的周转。在这个目标中，我们将测试我们的假设，使用新的定量分析，我们开发的研究粘附营业额。本提案中概述的研究将有助于更好地理解Asef2调节细胞迁移的信号传导机制。 公共卫生相关性：细胞迁移是许多生物学和病理学过程的核心，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导致治疗这些疾病的新治疗方法。这项提案的目标是确定细胞迁移的关键调节分子。