Cellular dynamics in division, motility and evolutionary adaptation

分裂、运动和进化适应的细胞动力学

• 批准号: 9265495
• 负责人: RONG LI
• 金额: $ 69.18万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9265495
• 关键词: Actins; Age; Aging; Aneuploidy; Animals; Area; Basic Science; Biochemistry; Biogenesis; Biological Models; Cardiovascular system; Cell Polarity; Cell division; Cell membrane; Cell model; Cell physiology; Cells; Chromosomal Instability; Chromosomes; Congenital Abnormality; Copy Number Polymorphism; Cryoelectron Microscopy; Cytoskeleton; Defect; Dementia; Development; Disease; Disseminated Malignant Neoplasm; Drug resistance; Embryonic Development; Environment; Eukaryotic Cell; Filament; Functional disorder; Funding; Future; Generations; Genetic Techniques; Goals; Grant; Health; Homeostasis; Human; Human body; Image; Immune system; Lead; Link; Lipids; Mechanics; Microbe; Mitochondria; Molecular; Mus; Mutation; National Institute of General Medical Sciences; Organ; Organism; Parkinson Disease; Pathogenicity; Phenotype; Physiology; Primary Cell Cultures; Process; Production; Proteins; Proteome; Research; Research Project Grants; Resistance; Role; Saccharomycetales; Specific qualifier value; Stem cells; Structure; System; Testing; Therapeutic; Tissues; Work; biological systems; cancer cell; cancer therapy; cell motility; cell type; design; dosage; driving force; falls; insight; mathematical model; non-Native; polymerization; public health relevance; regenerative; segregation; self-renewal; tumor

 DESCRIPTION (provided by applicant): The overall goal of this research project is to understand, on a fundamental level, in both molecular and quantitative terms, how eukaryotic cells divide, move, and adapt to their environment. These are inherently systems-level problems, for which we plan to take a fully integrated approach that combines whole-cell quantitative observation and mathematical modeling with traditional structure-function analysis that illuminates molecular mechanisms. In addition to the goal of uncovering fundamental principles, we will actively seek opportunities to apply new insights from basic research to the improvement of human health. The work to be supported by this MIRA grant falls into three general areas that have been funded by three independent NIGMS grants: I) Asymmetric cell division is a major developmental mechanism in the generation of diverse cell types or fates through cell division and is frequently used by stem cells to satisfy both self-renewal and differentiation. Our work will be focused on using the budding yeast as the model system to understand how protein and lipid components of the plasma membrane self-organize to drive cellular symmetry breaking and the establishment of cell polarity; and how the axis of cell polarity directs the segregation of molecular determinants that specify the replicative age of the two progeny cells of each cell division. In particular, we will unravel the role of ER and mitochondria in the consolidation and segregation of proteome damage, and test the hypothesis that this function is directly linked to an asymmetry in mitochondria biogenesis during asymmetric cell division. This research is envisioned to be expanded to mammalian stem cells in the future. II) Cell motility is a critical process required for the development and physiology f animal organisms that also depends on cell polarity and dynamic assembly of the cytoskeleton. Part of the proposed work will be conducted as a PO1 collaborative effort with several labs with leading expertise in electron cryo-microscopy, actin biochemistry, and mathematical modeling of cell dynamics and mechanics. My group will use mouse genetic techniques, primary cell culture and live imaging to probe the role of dendritic actin nucleation in cell motility. Our collective gal is to achieve a quantitative understanding of how actin polymerization and filament organization produce the force driving directional protrusion of the leading edge. A second goal is to use primary motile cells from mice to gain insights into the diversity and plasticity of cell motility mechanisms in different mechanical and geometrical environments. III) Evolvability is the fundamental capacity of biological systems that enables cells and organisms to undergo genetic changes to adapt to internal or environmental perturbations. Evolvability on the cellular level, th focus of our research, also underlies the ability of cancer cells and pathogenic microbes to elude the host immune system or become resistant to therapeutic treatments. Our proposed work is designed to decipher how chromosome copy number variation, or aneuploidy, as a result of chromosome instability produces dramatic phenotypic change and drives rapid cellular adaptation. We will also investigate general defects caused by chromosome dosage imbalance and how such deficiencies may be exploited for anti-cancer treatment.

 描述（由适用提供）：该研究项目的总体目标是从基本层面上以分子和定量术语来理解真核细胞如何分裂，移动和适应其环境。这些是固有的系统级问题，我们计划采用一种完全集成的方法，将全细胞定量观察和数学建模与传统结构函数函数分析结合在一起，以阐明分子机制。除了揭示基本原则的目标之外，我们还将积极寻求机会，将新见解从基础研究到改善人类健康。这项MIRA赠款所支持的工作属于三个由三个独立的Nigms赠款资助的一般领域：i）非对称细胞分裂是通过细胞分裂产生的潜水细胞类型或命运的主要发育机制，并且由干细胞经常用于满足自我更新和差异化。我们的工作将集中在使用芽酵母作为模型系统上，以了解质膜的蛋白质和脂质成分如何自组织以驱动细胞对称性破裂以及细胞极性的建立；以及细胞极性轴如何指导分子确定剂的分离，这些分子确定剂指定每个细胞分裂的两个后代细胞的复制年龄。特别是，我们将阐明ER和线粒体在蛋白质组损伤的巩固和分离中的作用，并检验以下假设：该功能与非对称细胞分裂期间线粒体生物发生的不对称性直接相关。预计将来将扩展到哺乳动物干细胞。 ii）细胞运动是动物生物的发育和生理所需的关键过程，它也取决于细胞极性和细胞骨架的动态组装。拟议的工作的一部分将作为PO1的合作努力与多个实验室的合作努力进行，这些实验室在电子冷冻微镜检查，肌动蛋白生物化学和细胞动力学和力学的数学建模方面进行了领先的专业知识。我的小组将使用小鼠遗传技术，原代细胞培养和活成像来探测树突状肌动蛋白成核在细胞运动中的作用。我们的集体GAL是对肌动蛋白聚合和细丝组织如何产生驱动前缘方向突出的力量进行定量理解。第二个目标是使用小鼠的原发性流动细胞来洞悉不同机械和几何环境中细胞运动机制的多样性和可塑性。 iii）可发展性是生物系统的基本能力，它使细胞和组织能够经历遗传变化以适应内部或环境扰动。我们研究的重点在细胞水平上的发展性，也构成了癌细胞和致病性微生物洗脱宿主免疫系统或对治疗治疗具有抗性的能力。我们提出的工作旨在破译染色体拷贝数变化或非整倍性，这是由于染色体不稳定性导致的，会产生急剧的表型变化并驱动快速的细胞适应性。我们还将研究由染色体剂量不平衡引起的一般缺陷，以及如何探索抗癌治疗的这种缺陷。