Decoding the mechanisms of cell-cell fusion

解读细胞与细胞融合的机制

基本信息

批准号：
10595802
负责人：
Elizabeth H Chen
金额：
$ 2.14万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-04 至 2025-04-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Cell-cell fusion is critical to the conception, development and physiology of multicellular organisms, and is involved in a variety of biological processes, such as fertilization, myogenesis, placenta development, bone remodeling, immune response, tumorigenesis, and aspects of stem cells-mediated tissue regeneration. Failure in cell fusion leads to defects such as infertility, congenital myopathy, osteopetrosis, immune deficiency, and pre-eclampsia. A mechanistic understanding of cell fusion is not only important for fundamental biology but may also provide basis for its manipulation in therapeutic settings. My lab has been using Drosophila myoblast fusion as a model to study the general mechanisms underlying cell fusion. We have made an unprecedented discover that cell fusion is an asymmetric process in which one cell (attacking cell) invades its fusion partner (receiving cell) using actin-propelled membrane protrusions to promote fusion pore formation. Building on insights we learned from myoblast fusion in vivo, we have reconstituted high-efficiency cell fusion in an otherwise non-fusogenic, non-muscle cell line and uncovered a novel function for invasive membrane protrusions in fusogen engagement. Furthermore, we have discovered dynamic mechanosensory responses in the receiving fusion partner and demonstrated that mechanical tension is a driving force for cell fusion. Our studies to date have provided significant insights into the function of the actin cytoskeleton in promoting cell membrane juxtaposition and fusion. In the next five years, we will expand our research into two new directions. First, we will extrapolate the mechanisms that we uncovered in Drosophila to mammals and investigate the potential function of the actin cytoskeleton in mammalian cell fusion, as well as how transmembrane fusogenic proteins coordinate with the actin cytoskeleton to promote cell fusion. Second, we will identify and characterize novel transmembrane proteins, including new fusogens, in cell fusion using the reconstituted cell-fusion culture system as a model. We will continue to use an interdisciplinary approach including genetics, molecular biology, biochemistry, biophysics, live imaging, super-resolution microscopy and electron microscopy in our proposed research. By expanding from Drosophila to mouse, and from the actin cytoskeleton to transmembrane proteins, our research will not only gain major new insights into the fundamental principles of cell-cell fusion, but also have far-reaching impact on a broad range of fields, including membrane biology, cell biology and developmental biology.

项目摘要/摘要细胞细胞融合对于多细胞生物的概念，发展和生理学至关重要，并且是参与各种生物学过程，例如受精，肌发生，胎盘发育，骨骼重塑，免疫反应，肿瘤发生以及干细胞介导的组织再生的方面。细胞融合失败会导致缺陷，例如不育，先天性肌病，骨质肌术，免疫缺乏症和先兆子痫。对细胞融合的机械理解不仅对基本生物学，但也可能为其在治疗环境中的操纵提供基础。我的实验室有一直在使用果蝇肌细胞融合作为研究细胞融合的一般机制的模型。我们已经使一个前所未有的发现细胞融合是一个不对称的过程，其中一个细胞（攻击细胞）使用肌动蛋白膜状膜突起入侵其融合伴侣（接收单元格）促进融合孔的形成。在我们从体内肌细胞融合中学到的见解的基础上，我们有在原本非菌根，非肌肉细胞系中重构的高效细胞融合，并发现在融合原中，侵入性膜突起的新功能。此外，我们还有在接收融合伙伴中发现了动态机械感应响应，并证明了机械张力是细胞融合的驱动力。迄今为止我们的研究提供了重要的见解进入肌动蛋白细胞骨架在促进细胞膜并置和融合中的功能。在下一个五年来，我们将把研究扩展到两个新的方向。首先，我们将推断机制我们在果蝇中发现了哺乳动物并研究肌动蛋白的潜在功能哺乳动物细胞融合中的细胞骨架，以及跨膜融合蛋白如何与肌动蛋白细胞骨架以促进细胞融合。其次，我们将识别并描述小说跨膜蛋白，包括新的融合蛋白，使用重构的细胞融合培养物在细胞融合中系统作为模型。我们将继续使用跨学科方法，包括遗传学，分子生物学，生物化学，生物物理学，实时成像，超分辨率显微镜和电子显微镜拟议的研究。通过从果蝇扩展到小鼠，从肌动蛋白细胞骨架到跨膜蛋白，我们的研究不仅将获得对基本原理的重大新见解细胞细胞融合，但对包括膜在内的广泛田地具有深远的影响生物学，细胞生物学和发育生物学。