Elucidating the roles for discrete actin filaments in maintenance of organelle and cellular homeostasis

阐明离散肌动蛋白丝在维持细胞器和细胞稳态中的作用

• 批准号: 10714068
• 负责人: Rajarshi Chakrabarti
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714068
• 关键词: Actin-Binding Protein; Actins; Affect; Binding; Biology; Cell physiology; Complex; Cytoskeleton; Endoplasmic Reticulum; FMNL1 gene; Filament; Future; Goals; Homeostasis; Human; Intermediate Filaments; Maintenance; Mammalian Cell; Mediating; Microfilaments; Microtubules; Mitochondria; Organelles; Pathologic; Pathology; Physiology; Play; Polymers; Positioning Attribute; Proteins; Regulation; Research; Role; Shapes; Signal Transduction; Stress Fibers; Structure; System; Therapeutic Intervention; Work; biochemical tools; programs; spatiotemporal

Project Summary: The cytoskeleton comprised of the actin filaments, microtubules and the intermediate filaments plays important roles in organelle dynamics including positioning, transport, and crosstalk. While the microtubules have been significantly defined for their roles in regulating the dynamics of several organelles including Endoplasmic Reticulum (ER) and mitochondria, the role of actin filaments in dynamics and interactions of the ER and mitochondria is largely under-studied. The dominant actin structures visible in a cultured mammalian cell include the cortical actin, the stress fibers, and the filaments at the leading edge (lamellipodia) whose prime function is to generate force. However, underneath these overwhelming structures are a myriad of distinct and dynamic pools of actin filaments which are specifically associated with different organelles and whose role in organelle and cellular physiology have not been explored. My research has explored two such actin structures. One of them assembles around the ER, polymerized by an ER-bound actin assembly factor, INF2. The other pool polymerizes strictly around dysfunctional mitochondria mediated by the Arp2/3 complex and formin FMNL. My research showed that both these actin structures are polymerized by distinct set of actin assembly factors and affected ER and mitochondrial dynamics and interactions in contrasting ways. However, the underlying mechanisms and the downstream consequences of these distinct pools of actin filaments on the organelles and overall cellular physiology remain to be defined. My proposed work will unify concepts from both the fields of actin dynamics and organelle biology to understand, both mechanistically and functionally, the specific roles these actin filaments play in controlling ER and mitochondrial biology, dynamics, and crosstalk. My proposed research plan will tackle the following key questions: 1) How do dynamic actin pools act as key regulators of ER-mitochondrial crosstalk; 2) How does the ER associated actin filaments regulate ER function, and 3) What are the distinct cellular effects of these dynamic actin pools on cellular homeostasis. The overall goal of my research program is to identify, characterize and understand the roles that these dynamic pools of actin play in regulating various cellular processes specifically related to organelle dynamics and crosstalk, critically differentiating, and uncoupling them from being the functional consequences of the cortical actin cytoskeleton. In the future we aim to apply these concepts in understanding alteration in organelle dynamics in various pathological system with a hope for specific therapeutic interventions through perturbation of these specific actin filaments along with its associated assembly factors and other actin binding proteins.

项目摘要：由肌动蛋白丝，微管和中间体组成的细胞骨架 细丝在细胞器动力学中起着重要作用，包括定位，运输和串扰。而 微管在调节几个细胞器的动力学中的作用已显着定义 包括内质网（ER）和线粒体，肌动蛋白在动力学和相互作用中的作用 急诊室和线粒体的研究很大。在文化中可见的主要肌动蛋白结构 哺乳动物细胞包括皮质肌动蛋白，应力纤维和丝状纤维（Lamellipodia） 其主要功能是产生力。但是，在这些压倒性的结构下是无数的 肌动蛋白丝的独特而动态的池，这些细丝与不同的细胞器特别相关 尚未探索其在细胞器和细胞生理学中的作用。我的研究探索了两个这样的 肌动蛋白结构。其中一个在ER周围组装，由ER结合的肌动蛋白组装因子聚合， INF2。另一个池严格围绕由ARP2/3复合物介导的功能障碍的线粒体聚合 和Formin fmnl。我的研究表明，这两种肌动蛋白结构均通过不同的肌动蛋白组聚合 组装因子以及以对比方式影响ER和线粒体动力学和相互作用。然而， 这些不同的肌动蛋白丝在 细胞器和整体细胞生理学仍有待定义。我提出的工作将统一两者的概念 肌动蛋白动力学和细胞器生物学领域，从机械和功能上理解 这些肌动蛋白丝在控制ER和线粒体生物学，动力学和串扰方面发挥了特定作用。我的 拟议的研究计划将解决以下关键问题：1）动态肌动蛋白池如何充当关键 ER-Mitochrial串扰的调节剂； 2）ER相关的肌动蛋白丝如何调节ER功能， 3）这些动态肌动蛋白库对细胞稳态的不同细胞作用是什么。 我的研究计划的总体目标是识别，表征和理解这些动态的角色 肌动蛋白在调节各种细胞过程中发挥作用的池 串扰，截然不同，并使它们不再是皮质的功能后果 肌动蛋白细胞骨架。将来，我们旨在将这些概念应用于理解Organelle动态的改变 在各种病理系统中，希望通过扰动特定的治疗干预措施 特定的肌动蛋白丝及其相关的组装因子和其他肌动蛋白结合蛋白。