Dissecting the Diverse Roles of Importin α at the Plasma Membrane

剖析输入α在质膜上的不同作用

• 批准号: 10673789
• 负责人: Christopher William Brownlee
• 金额: $ 38.87万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673789
• 关键词: Address; Alzheimer' s Disease; Biochemical; Biological; Biological Models; Cell Cycle; Cell division; Cell membrane; Cell surface; Cells; Complex; Cytoplasm; Defect; Diagnostic; Disease; Dissection; Encapsulated; Goals; Growth; Homeostasis; Lead; Location; Macromolecular Complexes; Malignant Neoplasms; Membrane; Microfluidics; Molecular Structure; Neurodegenerative Disorders; Neuropathy; Pathway interactions; Polycystic Kidney Diseases; Proteins; Public Health; Research; Research Personnel; Resources; Role; Science; Signal Transduction; Structure; Techniques; Tissues; Work; alpha Karyopherins; cell type; ciliopathy; innovation; neurotransmission; new therapeutic target; novel; novel diagnostics; optogenetics; therapeutic target

Project Summary What spatial and temporal controls regulate subcellular macromolecular complexes at the cell surface (plasma membrane) and how such spatial and temporal controls impact various disease states, is not known. The long-term goal of this proposal is to find new targets for diagnostic and treatment approaches that address the subcellular changes that occur in macromolecular complexes at the plasma membrane in diseases ranging from cancer, ciliopathies such as polycystic kidney disease, and various neuropathies. The objective of this proposal is to assess the novel role of a key protein in tethering numerous factors to the plasma membrane to precisely control the location and timing of the formation of subcellular complexes involved in cell division, growth signaling and nerve signaling transduction. The proposal will use an innovative combination of techniques from biological, physical and biochemical sciences. These include recently- in-house-developed techniques using microfluidics and optogenetics to encapsulate cytoplasm in various sizes of our choosing in which the membrane composition, cell cycle state, and protein composition can all be precisely controlled both spatially and temporally. The proposed research is significant, because it will determine which proteins in these newly identified pathways should be therapeutic targets for which diseases and in which cell types. It is also significant because it will develop a platform that can be extended to other proteins to study their roles at the plasma membrane alone or in combination with other factors, opening new avenues for dissecting macromolecular complexes at the plasma membrane in various contexts. This work will develop foundational resources that will be used by other researchers. The results will have a positive impact immediately because they will establish a better understanding of various cancers, ciliopathies and neuropathies and lead to new diagnostic and therapeutic targets for these diseases, and long-term because they lay the groundwork to develop new techniques for dissection of a multitude of different complexes at the plasma membrane.

项目摘要 什么空间和时间控制调节亚细胞大分子复合物在 细胞表面（质膜）以及这种空间和时间控制如何影响 各种疾病状态尚不清楚。该提议的长期目标是找到新的 针对亚细胞变化的诊断和治疗方法的目标 在疾病的质膜的大分子复合物中发生 从癌症中，纤毛病如多囊性肾脏疾病和各种神经病。 该提案的目的是评估关键蛋白在束缚中的新作用 质膜的许多因素可以精确控制位置和时机 涉及细胞分裂，生长信号传导和 神经信号转导。该提案将使用创新的组合 来自生物，物理和生化科学的技术。这些包括最近 - 使用微流体和光遗传学封装的内部开发技术 我们选择的各种尺寸的细胞质，其中膜组成，细胞 循环状态和蛋白质成分都可以在空间和 暂时。拟议的研究很重要，因为它将确定哪个 这些新鉴定的途径中的蛋白质应该是治疗靶标的 疾病以及哪种细胞类型。这也很重要，因为它将开发一个平台 可以将其扩展到其他蛋白质以研究其在质膜上的作用 单独或与其他因素结合使用，为解剖开放新途径 在各种情况下，质膜上的大分子复合物。这项工作将 开发其他研究人员将使用的基本资源。结果将 立即产生积极影响，因为他们将建立更好的理解 在各种癌症，纤毛病和神经病中，导致了新的诊断和 这些疾病的治疗靶标，并且长期是因为它们奠定了基础 开发新技术以解剖多种不同的复合物 质膜。