Cytoskeletal/junction relationships during epithelial remodelling events

上皮重塑事件期间的细胞骨架/连接关系

• 批准号: RGPIN-2018-03727
• 负责人: Vogl, Adalbert
• 金额: $ 7.29万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746608
• 关键词: Cytoskeletal; junction; relationships; during; epithelial

The cell surface is the interface between cells and their environment. Interactions at this interface enable cells to generate movement, to assume specific shapes, to carry out specific functions, and to form multicellular structures. It perhaps is not surprising that the major network of structures, the so-called cytoskeleton, that gives cells their shape and allows them to move is related to the cell surface, particularly to regions of the surface involved in forming connections both with neighboring cells and with supporting substrates. The long-term objective of my research program is to explore the interaction between intercellular junctions and the cytoskeleton in cells within the context of tissues, and determine how the two systems function together to generate complex remodeling events in cell layers (epithelia) that line the many tubes and cavities in animals. We are particularly interested in how the cytoskeleton and junctions interact to allow cells to detach from their neighbors and to move through epithelia from one compartment to another, or to be released from the epithelium. Over the next five years we will explore the mechanism by which the cytoskeleton and junctions function both to move developing sperm cells through the seminiferous epithelium of the mammalian testis and to release fully formed sperm cells. In humans, roughly 85 million sperm are released from the epithelium in each testis per day. We will focus our research on unique cytoskeleton-related structures termed tubulobulbar complexes (TCs)' that we propose are sub-cellular machines' that internalize and degrade intact intercellular junctions during the extensive epithelial remodeling events that occur during the production and release of sperm cells. One aspect of our study will be to develop a more complete catalogue of the proteins that form TCs. Another will be to show that the junction eating' function of TCs is necessary for allowing sperm cells in the early stages of their development to move from one region to another within the epithelium. One of the more exciting aspects of our study will be to determine if calcium, a major signaling molecule in cells, is involved in regulating the formation, structure and function of these subcellular machines. Our results have already generated a paradigm shift in how biologists view junction disassembly related to sperm release. Over the next few years we anticipate that our results will generate a similar shift in how biologist view the movement of the next generation of developing sperm cells from one compartment to another in the seminiferous epithelium. Importantly, our studies will provide insight into how the junctions and junction turnover are regulated which may contribute to our understanding of the causes of certain forms of male infertility, and to our identifying putative targets for the development of male contraceptives.

细胞表面是细胞与环境之间的界面。在这个界面上的相互作用使细胞能够产生运动，呈现特定的形状，执行特定的功能，并形成多细胞结构。赋予细胞形状并允许它们移动的主要结构网络，即所谓的细胞骨架，与细胞表面有关，特别是与与相邻细胞和支持基质形成连接的表面区域有关，这可能并不奇怪。我的研究计划的长期目标是探索组织背景下细胞间连接和细胞骨架之间的相互作用，并确定这两个系统如何共同发挥作用，以产生复杂的重塑事件在细胞层（上皮细胞），内衬许多管和腔在动物。我们特别感兴趣的是细胞骨架和连接如何相互作用，使细胞从它们的邻居分离，并通过上皮从一个区室移动到另一个区室，或从上皮释放。在接下来的五年里，我们将探索细胞骨架和连接功能的机制，既可以通过哺乳动物睾丸的生精上皮移动发育中的精子细胞，也可以释放完全形成的精子细胞。在人类中，每天大约有8500万个精子从每个睾丸的上皮细胞中释放出来。我们将把我们的研究重点放在独特的cytokeraton相关的结构称为tubulobulbar复合物（TC），我们提出的是亚细胞机器，内化和降解完整的细胞间连接在广泛的上皮重塑事件发生在生产和释放精子细胞。我们研究的一个方面是开发更完整的形成TC的蛋白质目录。另一个将是表明TC的连接进食功能对于允许精子细胞在其发育的早期阶段从上皮内的一个区域移动到另一个区域是必要的。我们研究中更令人兴奋的方面之一将是确定钙，细胞中的主要信号分子，是否参与调节这些亚细胞机器的形成，结构和功能。我们的研究结果已经在生物学家如何看待与精子释放相关的连接解体方面产生了范式转变。在接下来的几年里，我们预计我们的结果将在生物学家如何看待下一代发育中的精子细胞从生精上皮中的一个隔室到另一个隔室的运动方面产生类似的转变。重要的是，我们的研究将深入了解连接和连接营业额是如何调节的，这可能有助于我们了解某些形式的男性不育症的原因，并确定男性避孕药开发的假定目标。