Regulation of formins and cell polarity

福尔明和细胞极性的调节

• 批准号: 9028874
• 负责人: Bruce L Goode
• 金额: $ 42.48万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9028874
• 关键词: Actins; Address; Alzheimer' s Disease; Architecture; Binding; Biochemical; Biochemistry; CLIP-170 gene; Cell Polarity; Cell physiology; Cells; Characteristics; Colorectal Cancer; Complex; Cytokinesis; Cytoskeleton; Disease; Endocytosis; Ensure; Event; F-Actin; Family; Feedback; Fibroblasts; Filament; Foundations; Funding; Genetic; Goals; Grant; Growth; Hodgkin Disease; Homologous Gene; Human; Huntington Disease; Image; In Vitro; Kinesin; Length; Life; Ligands; Link; Mammalian Cell; Mammals; Mediating; Microfilaments; Modeling; Molecular; Morphogenesis; Mutation; Myosin ATPase; Organelles; Parkinson Disease; Physiological; Polymers; Protein Family; Protein Isoforms; Proteins; Regulation; Research; Role; Saccharomycetales; Secretory Vesicles; Site; Speed; System; Testing; Thick; Tissues; Total Internal Reflection Fluorescent; Tropomyosin; Work; Yeasts; base; cell growth; cell motility; combinatorial; design; genetic approach; human disease; in vivo; insight; live cell imaging; macrophage; novel; polarized cell; profilin; public health relevance; single molecule

 DESCRIPTION (provided by applicant): The goal of this research is to determine how the assembly dynamics and architecture of the actin cytoskeleton are controlled by formins and the cellular mechanisms regulating their activities. We are studying this question in budding yeast, where formins assemble actin cables of a characteristic length, architecture, and dynamics required for polarized cell growth. Further, we extend this work to mammalian formin regulation. The proposal focuses on several new multi-component mechanisms discovered during the previous funding cycle, which control formin-mediated actin nucleation, or the duration and speed of formin-mediated actin filament elongation events. The project combines genetics, live- cell imaging, biochemistry, and novel multi-wavelength single molecule TIRF microscopy. The Aims are: (1) Test the hypothesis that formin-mediated actin cable nucleation is spatially and temporally controlled by the combinatorial effects of Bud6, profilin, Tpm1, and Tpm2; (2) Test the hypothesis that actin cable length, velocity, and architecture are controlled by dynamic interplay at filament barbed ends involving formins, Bud14-Kel1-Kel2 complex, capping protein, and Smy1; and (3) Test the hypothesis that human CLIP-170 interacts with mDia1 to form a novel barbed end- tracking complex that supports ultrafast actin filament elongation in vitro and in vivo.

 描述（由申请人提供）：本研究的目标是确定肌动蛋白细胞骨架的组装动力学和结构如何由福尔明和调节其活动的细胞机制控制。我们正在芽殖酵母中研究这个问题，其中福明组装具有极化细胞生长所需的特征长度、结构和动力学的肌动蛋白电缆。此外，我们将这项工作扩展到哺乳动物福明调节。该提案重点关注在上一个资助周期中发现的几种新的多组分机制，这些机制控制福尔明介导的肌动蛋白成核，或福尔明介导的肌动蛋白丝伸长事件的持续时间和速度。该项目结合了遗传学、活细胞成像、生物化学和新型多波长单分子 TIRF 显微镜。目标是： (1) 检验福尔明介导的肌动蛋白索成核在空间和时间上受 Bud6、profilin、Tpm1 和 Tpm2 的组合效应控制的假设； (2) 检验肌动蛋白电缆长度、速度和结构由涉及福明、Bud14-Kel1-Kel2 复合物、加帽蛋白和 Smy1 的细丝带刺末端的动态相互作用控制的假设； (3) 测试人类 CLIP-170 与 mDia1 相互作用形成新型倒刺末端追踪复合物的假设，该复合物支持体外和体内超快肌动蛋白丝伸长。