Decoding the mechanisms of cell-cell fusion

解读细胞与细胞融合的机制

• 批准号: 10398965
• 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/10398965
• 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; Mammalian Cell; Mammals; Mechanics; Mediating; Membrane; Membrane Biology; Microscopy; Modeling; Molecular Biology; Mus; Myoblasts; Neoplasm Metastasis; Organism; Physiology; Placenta; Placentation; Pre-Eclampsia; Process; Proteins; Research; Resolution; System; Therapeutic; congenital myopathy; driving force; human disease; in vivo; insight; interdisciplinary approach; myogenesis; novel; reconstitution; response; stem cells; 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.

项目摘要/摘要 细胞-细胞融合对多细胞生物体的概念、发育和生理学至关重要，并且是 参与多种生物学过程，如受精、肌肉发生、胎盘发育、骨骼 重建，免疫反应，肿瘤发生，干细胞介导的组织再生方面。 细胞融合失败会导致不孕、先天性肌病、骨质疏松症、免疫缺陷等缺陷。 缺乏症和先兆子痫。从机理上理解细胞融合不仅对 但也可能为其在治疗环境中的操作提供基础。我的实验室有 一直以果蝇成肌细胞融合为模型，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，在这个过程中，一个细胞 (攻击细胞)利用肌动蛋白推动的膜突起入侵其融合伙伴(接收细胞)以 促进融合孔的形成。基于我们从体内成肌细胞融合中学到的见解，我们有 重组的高效细胞融合在其他非融合、非肌肉细胞系中，并未被覆盖 FusoGen接合中侵入性膜突起的新功能。此外，我们还拥有 在接受融合的伙伴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。到目前为止，我们的研究提供了重要的见解 探讨肌动蛋白细胞骨架在促进细胞膜并列和融合中的作用。在下一个 五年后，我们将把我们的研究扩展到两个新方向。首先，我们将推断这些机制 我们在果蝇中发现了对哺乳动物的作用，并研究了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 肌动蛋白细胞骨架促进细胞融合。第二，我们将对小说进行识别和刻画 重组细胞融合培养中细胞融合中的跨膜蛋白，包括新的融合原 系统作为一种模式。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 拟开展的研究。通过从果蝇扩展到老鼠，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-细胞融合，但也对包括膜在内的广泛领域产生深远影响 生物学、细胞生物学和发育生物学。