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: 10501101
• 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/10501101
• 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; Foundations; 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体 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。这项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 在各种疾病中出现在质膜上的大分子复合体中 从癌症，纤毛疾病，如多囊肾病，和各种神经疾病。 这项建议的目的是评估一种关键蛋白质在系留中的新作用。 众多因素对质膜的精确控制位置和时机 亚细胞复合体的形成，参与细胞分裂、生长信号和 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。其中包括最近- 使用微流体和光遗传学自行开发的技术来封装 细胞质在我们选择的不同大小的膜中组成，细胞 循环状态和蛋白质组成都可以在空间和空间上精确控制 暂时的。这项拟议的研究意义重大，因为它将决定 这些新发现的通路中的蛋白质应该是治疗的靶点 疾病和细胞类型。它还具有重要意义，因为它将开发一个平台 这可以扩展到其他蛋白质，以研究它们在质膜上的作用 单独或与其他因素结合，为解剖开辟新途径 在不同的环境下，质膜上的大分子复合体。这项工作将 开发可供其他研究人员使用的基础资源。结果将会是 立即产生积极影响，因为他们将建立更好的理解 各种癌症、纤毛病和神经病的诊断和治疗 这些疾病的治疗目标，以及长期目标，因为它们奠定了基础 为了开发新的技术来解剖大量不同的复合体 质膜。