Spatial genetics investigation of multinucleated cells

多核细胞的空间遗传学研究

• 批准号: 10684329
• 负责人: Pengpeng Bi
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684329
• 关键词: Animals; Award; Behavior; Behavior Control; Biochemical; Biological; Cardiac Myocytes; Cell Communication; Cell Nucleus; Cells; Cellularity; Communities; Development; Environment; Gene Expression; Genetic; Genomics; Giant Cells; Homeostasis; Human; Imaging technology; Investigation; Knowledge; Messenger RNA; Methodology; Modeling; Mononuclear; Muscle; Nature; Polyploidy; Research; Retinal blind spot; Reverse engineering; Stimulus; Syncytiotrophoblast; System; Techniques; Technology; Tissues; body system; cancer cell; cell type; cellular engineering; fascinate; fitness; gene function; human disease; human tissue; in vivo; innovation; intercellular communication; programs; response; single molecule; trafficking; transcriptomics

Project Summary/Abstract Organ systems are composed of a wealth of cellular subpopulations whose spatial organization within a given tissue are deeply intertwined with their functions and homeostasis controls. Similarly, within the space of a single-cell, the biochemical environment is also heterogeneous where the dynamic interactions of molecules determine the fitness, behavior and fate of the cell. Our understanding of the cell interactions and the biomolecule interactions has recently been transformed by the revolutionary single-cell genomics and single-molecule imaging technologies. However, the development and application of these technologies have been exclusively centered on the context of mononuclear cellularity. Hiding in the blind spot are multinucleated cell-types, including myofibers, cardiomyocytes, syncytiotrophoblasts, certain cancer cells, all of which cause devasting human disease when go awry. The syncytial nature of the multinucleated cells, which possess the polyploidy and often the vast cytosolic volumes, raises fascinating questions with respect to the spatial organizations of the cell-cell interactions and biomolecule distributions. The fundamental yet largely unknown questions include: 1) How heterogeneous is the tissue microenvironment that surrounds the syncytial cells? 2) Do nuclei from the shared cell body coordinate gene expression in response to the external stimuli and cell-cell communications? 3) What is the mechanism that governs the transports and localizations of mRNAs in the multinucleated cells? Our research program exploits the unique features of specialized cell-types as a means to understand mechanistic underpinnings of various developmental systems. This proposal leverages myofiber as the uniquely-suited model to investigate the above questions in a spatially defined manner. First, we will develop and deploy new methodologies to probe the spatial transcriptomics for the multiple types of syncytial tissues. Second, we will devise the reverse engineering strategy to assemble the single-syncytium of human muscle with genetic trackabilities and later graft them to live animals for the in vivo study of the cell-cell communication and intra-syncytium mRNA distributions. Third, we will conduct the in-depth gene function and mechanism studies to unveil new paradigms of intercellular communication and the intracellular mRNA trafficking. Broadly, this research program relies on our diverse expertise in genomics, cell engineering and computation such that we can create a virtuous cycle of innovation and discovery over the course of the MIRA award. We anticipate that the knowledge and techniques will benefit the greater biological community, including genetics, cell biologists and developmental biologists.

项目概要/摘要 器官系统由大量细胞亚群组成，其空间组织 给定组织内的功能与其功能和稳态控制密切相关。 同样，在单细胞的空间内，生化环境也是异质的 其中分子的动态相互作用决定了细胞的适应性、行为和命运。 我们最近对细胞相互作用和生物分子相互作用的理解 由革命性的单细胞基因组学和单分子成像技术改造。 然而，这些技术的开发和应用一直集中在 在单核细胞结构的背景下。隐藏在盲点的是多核细胞类型， 包括肌纤维、心肌细胞、合体滋养细胞、某些癌细胞，所有这些 出错时会导致毁灭性的人类疾病。多核细胞的合胞体性质， 具有多倍体并且通常具有巨大的细胞质体积，提出了令人着迷的问题 关于细胞与细胞相互作用的空间组织和生物分子分布。 基本但很大程度上未知的问题包括：1）组织的异质性如何 合体细胞周围的微环境？ 2）从共享细胞体中提取细胞核 协调基因表达以响应外部刺激和细胞间通讯？ 3） 控制 mRNA 在细胞内运输和定位的机制是什么？ 多核细胞？我们的研究计划利用了特殊细胞类型的独特特征 作为理解各种发育系统的机械基础的一种手段。这 该提案利用肌纤维作为独特的模型来研究上述问题 空间定义的方式。首先，我们将开发和部署新的方法来探索 多种类型合胞组织的空间转录组学。其次，我们将设计 利用基因逆向工程策略组装人体肌肉单合胞体 可追踪性，然后将它们移植到活体动物身上，用于细胞间通讯的体内研究 和合胞体内 mRNA 分布。三是深入开展基因功能研究 机制研究揭示细胞间通讯和细胞内通讯的新范式 mRNA 贩运。广泛而言，该研究项目依赖于我们在基因组学、细胞学等方面的多样化专业知识 工程和计算，使我们能够创造创新和发现的良性循环 在 MIRA 奖的过程中。我们预计知识和技术将受益 更大的生物界，包括遗传学家、细胞生物学家和发育生物学家。