Decoding the mechanisms of cell-cell fusion

解读细胞与细胞融合的机制

• 批准号: 10604372
• 负责人: Elizabeth H Chen
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10604372
• 关键词: Actins; Albers-Schonberg disease; Biochemistry; Biological Process; Biology; Biophysics; Bone remodeling; Cell Line; Cell fusion; Cell membrane; Cells; Cellular biology; Conceptions; Cytoskeleton; Defect; Development; Developmental Biology; Drosophila genus; Electron Microscopy; Failure; Fertilization; Genetic; Image; Immune; Immune response; Infertility; Integral Membrane Protein; Invaded; Learning; Mammalian Cell; Mammals; Mechanics; Mediating; Membrane; Membrane Biology; Modeling; Molecular Biology; Mus; Myoblasts; Neoplasm Metastasis; Organism; Physiology; Placenta; Placentation; Pre-Eclampsia; Process; Proteins; Research; System; Therapeutic; congenital myopathy; driving force; human disease; in vivo; insight; interdisciplinary approach; myogenesis; novel; reconstitution; response; stem cells; superresolution microscopy; tissue regeneration; tumor; tumorigenesis

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.

项目总结/摘要 细胞-细胞融合对于多细胞生物的概念、发育和生理学至关重要， 参与各种生物过程，如受精、肌生成、胎盘发育、骨形成、 重塑、免疫应答、肿瘤发生和干细胞介导的组织再生的各个方面。 细胞融合的失败导致缺陷，如不育症、先天性肌病、骨硬化症、免疫缺陷症、 缺乏症和先兆子痫。对细胞融合机制的理解不仅对 基础生物学，但也可以提供基础，其在治疗环境中的操纵。我的实验室 一直使用果蝇成肌细胞融合作为模型来研究细胞融合的一般机制。 我们有了一个前所未有的发现，细胞融合是一个不对称的过程， （攻击细胞）入侵其融合伙伴（接收细胞）使用肌动蛋白推进膜突起， 促进融合孔形成。基于我们从体内成肌细胞融合中学到的见解，我们 在其他非融合性、非肌肉细胞系中重建高效细胞融合， 一种用于融合体接合中侵入性膜突起的新功能。此外，我们还 在接受融合的伴侣中发现了动态机械感觉反应，并证明 机械张力是细胞融合的驱动力。我们迄今为止的研究提供了重要的见解 肌动蛋白细胞骨架在促进细胞膜并置和融合中的功能。未来 五年内，我们将把研究扩展到两个新的方向。首先，我们将推断出 我们在果蝇身上发现的基因转移到哺乳动物身上，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，我们将识别和表征小说 包括新融合子在内的跨膜蛋白在使用重构细胞融合培养物的细胞融合中的作用 系统作为模型。我们将继续使用跨学科的方法，包括遗传学，分子生物学， 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在我们的 提议的研究。通过从果蝇扩展到小鼠，从肌动蛋白细胞骨架扩展到 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， 细胞与细胞融合，而且对广泛的领域，包括膜， 细胞生物学和发育生物学。