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 什么样的空间和时间控制调节亚细胞大分子复合物， 细胞表面（质膜）以及这种空间和时间控制如何影响 各种疾病的状态，是未知的。这项提案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 在多种疾病中出现在质膜的大分子复合物中 癌症、纤毛病如多囊肾病和各种神经病。 这项建议的目的是评估一个关键蛋白质在拴系中的新作用 许多因素对质膜精确控制的位置和时间 参与细胞分裂、生长信号传导和 神经信号转导该提案将采用以下创新组合： 生物、物理和生物化学技术。其中包括最近- 内部开发的技术，使用微流体和光遗传学封装 我们选择了不同大小的细胞质，其中膜组成，细胞 循环状态和蛋白质组成都可以在空间上和 暂时的这项拟议中的研究意义重大，因为它将确定 这些新发现的通路中的蛋白质应该是治疗靶点， 疾病和细胞类型。这也很重要，因为它将开发一个平台， 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，为解剖开辟了新的途径 大分子复合物在质膜在各种情况下。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 立即产生积极的影响，因为他们将建立一个更好的理解， 各种癌症，纤毛病和神经病，并导致新的诊断和 这些疾病的治疗目标，长期的，因为他们奠定了基础， 开发新技术，用于解剖大量不同的复合体， 质膜