Decoding the mechanisms of cell-cell fusion

解读细胞与细胞融合的机制

• 批准号: 10799036
• 负责人: Elizabeth H Chen
• 金额: $ 7.07万
• 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/10799036
• 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-细胞融合是多细胞生物的概念、发育和生理学的关键 生物体，并参与各种生物过程，如受精，肌生成， 胎盘发育、骨重塑、免疫反应、肿瘤发生以及 干细胞介导的组织再生细胞融合失败会导致不育等缺陷， 先天性肌病、骨硬化症、免疫缺陷和先兆子痫。一种机械的 了解细胞融合不仅对基础生物学很重要， 在治疗环境中操作的基础。我的实验室一直在用果蝇成肌细胞 融合作为模型来研究细胞融合的一般机制。我们做了一个 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）利用肌动蛋白推进的膜突起侵入其融合伴侣（接收细胞）， 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 在一种非融合性的非肌肉细胞系中重建了高效的细胞融合 并揭示了侵入性膜突起在融合体接合中的新功能。 此外，我们还发现了接收融合中的动态机械感觉反应 合作伙伴，并证明了机械张力是细胞融合的驱动力。我们的研究 迄今为止，已经提供了关于肌动蛋白细胞骨架在促进细胞增殖中的功能的重要见解。 细胞膜并置和融合。在接下来的五年里，我们将把我们的研究扩展到 两个新方向首先，我们将推断我们在果蝇中发现的机制， 研究肌动蛋白细胞骨架在哺乳动物细胞中的潜在功能 融合，以及跨膜融合蛋白如何与肌动蛋白细胞骨架协调 促进细胞融合。其次，我们将鉴定和表征新的跨膜蛋白， 包括新的融合子，在细胞融合中使用重建的细胞融合培养系统作为 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 显微镜在我们的研究中。通过从果蝇到小鼠的扩展， 肌动蛋白细胞骨架跨膜蛋白，我们的研究不仅将获得重大的新见解 细胞与细胞融合的基本原理，也对广泛的 一系列领域，包括膜生物学，细胞生物学和发育生物学。