Prostaglandins control development by coordinating actin cytoskeletal remodeling

前列腺素通过协调肌动蛋白细胞骨架重塑来控制发育

• 批准号: 9207772
• 负责人: Tina L Tootle
• 金额: $ 32.79万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207772
• 关键词: Acids; Actin-Binding Protein; Actins; Actomyosin; Animals; Automobile Driving; Biological Models; Cardiovascular Diseases; Cardiovascular Physiology; Cell Communication; Cells; Communication; Complement; Complex; Congenital Abnormality; Contracts; Cytoskeleton; Defect; Development; Developmental Biology; Dinoprostone; Disease; Drosophila genus; Elongation Factor; Enzymes; Equilibrium; Eukaryota; Event; Failure; Filament; Genetic; Goals; Homeostasis; Individual; Light; Lipids; Malignant Neoplasms; Mediating; Microfilaments; Molecular; Morphogenesis; Myosin Regulatory Light Chains; Myosin Type II; Nurses; Pathway interactions; Pharmacology; Play; Pliability; Process; Prostaglandins; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Structure; Tissues; Work; alpha Actin; cell motility; egg; fascin; gastrulation; genetic approach; human disease; insight; member; non-muscle myosin; novel; prevent; public health relevance; spatiotemporal

 DESCRIPTION (provided by applicant): Actin is highly conserved across all eukaryotes, and misregulation by alterations in actin binding protein activity results in severe developmental defects and contributes to diseases such as cardiovascular diseases and cancer. The activities of the >100 known actin binding proteins are well studied; but the signaling pathways and mechanisms that coordinate the functions of multiple actin binding proteins to drive actin remodeling necessary for morphogenesis remain poorly understood. To uncover mechanisms coordinating the activities of actin binding proteins, we take advantage of the powerful genetics and well-characterized, actin-dependent process of follicle or egg development in Drosophila. We have made the novel finding that a class of lipid signals termed prostaglandins (PGs) regulates multiple actin remodeling events necessary for Drosophila follicle development. Our long term goal is to determine the means by which specific PG signaling cascades coordinately regulate particular actin binding proteins to control cytoskeletal dynamics. The critical next step towards achieving this goal are to identify the actin binding proteins acting downstream of PG signaling, elucidate the molecular mechanisms of this PG regulation, and determine how the activities of these actin regulators are integrated. The central hypothesis of the proposed work is that distinct PG signaling cascades regulate specific actin binding proteins to restrict actin filament formation, promote bundle formation, and mediate cortical actin contraction necessary for morphogenesis. Aim 1 will define the specific PG signaling cascade that inhibits inappropriate actin filament formation, and the molecular mechanisms by which it regulate the actin elongation factor Enabled. Additional actin binding proteins regulated by this PG signaling pathway to coordinate actin filament formation with developmental stage will be identified. Aim 2 will delineate a different PG signaling pathway that promotes parallel bundle formation, and the means by which this pathway coordinates the opposing action of two actin binding proteins, Enabled and Capping Protein (a barbed end capper). Aim 3 will uncover the PG pathway that regulates cortical actin contraction by regulating Non-Muscle Myosin Regulatory Light Chain. The expected contributions of this study are the identification of specific PG signaling pathways that inhibit or promote actin filament formation and drive acto-myosin contraction, elucidation of the molecular means by which these pathways regulate four conserved actin binding proteins, and identification of the complement of actin binding proteins that are coordinately regulated by these PG pathways. The contributions of this study will be significant because: 1) it will establis a framework to define the roles of other lipid signals during development; 2) it will provide new insight into the roles of individual PGs in tissue morphogenesis; and 3) it will bring together separate fields - lipid, actin cytoskeletal, and developmental biology. Furthermore, these findings should be broadly applicable to other PG-dependent processes, including cell migration, vertebrate gastrulation, cardiovascular function and disease, and cancer.

 描述（由申请人提供）：肌动蛋白在所有真核生物中高度保守，肌动蛋白结合蛋白活性改变引起的失调导致严重的发育缺陷，并导致心血管疾病和癌症等疾病。超过100种已知的肌动蛋白结合蛋白的活性已经得到了很好的研究;但是协调多种肌动蛋白结合蛋白的功能以驱动形态发生所需的肌动蛋白重塑的信号通路和机制仍然知之甚少。为了揭示协调肌动蛋白结合蛋白活性的机制，我们利用果蝇卵泡或卵发育的强大遗传学和良好表征的肌动蛋白依赖性过程。我们已经取得了新的发现，一类脂质信号被称为前列腺素（PGs）调节多种肌动蛋白重塑事件所必需的果蝇卵泡发育。我们的长期目标是确定特定的PG信号级联协调调节特定的肌动蛋白结合蛋白，以控制细胞骨架动力学的手段。实现这一目标的关键下一步是确定肌动蛋白结合蛋白的PG信号下游的作用，阐明这种PG调节的分子机制，并确定这些肌动蛋白调节剂的活动是如何整合的。拟议工作的中心假设是 不同的PG信号级联调节特定的肌动蛋白结合蛋白，以限制肌动蛋白丝的形成，促进束的形成，并介导形态发生所必需的皮质肌动蛋白收缩。目的1将定义特定的PG信号级联，抑制不适当的肌动蛋白丝的形成，和它调节肌动蛋白延伸因子的分子机制。另外的肌动蛋白结合蛋白调节PG信号通路，以协调肌动蛋白丝的形成与发育阶段将被确定。目的2将描绘一个不同的PG信号通路，促进平行束的形成，并通过该途径协调两个肌动蛋白结合蛋白，使能蛋白和加帽蛋白（倒钩端帽）的相反行动的手段。目的3揭示PG通路通过调节非肌肉肌球蛋白调节轻链来调节皮层肌动蛋白收缩。本研究的预期贡献是鉴定抑制或促进肌动蛋白丝形成并驱动肌动蛋白-肌球蛋白收缩的特定PG信号传导途径，阐明这些途径调节四种保守肌动蛋白结合蛋白的分子方式，并鉴定肌动蛋白的补充物由这些PG途径协调调节的结合蛋白。这项研究的贡献将是重要的，因为：1）它将建立一个框架，以定义其他脂质信号在发育过程中的作用; 2）它将提供新的见解，个别PG在组织形态发生中的作用; 3）它将把单独的领域-脂质，肌动蛋白细胞骨架和发育生物学。此外，这些发现应广泛适用于其他PG依赖的过程，包括细胞迁移，脊椎动物原肠胚形成，心血管功能和疾病，和癌症。