Project 3: Nuclear Rheology & Stability in Cancer

项目3：核流变学

• 批准号: 8866927
• 负责人: Dennis E. Discher
• 金额: $ 31.61万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-16 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8866927
• 关键词: A549; Adult; Affect; Aging; Animals; Back; Blood Circulation; Blood Vessels; Cancer Biology; Cancer cell line; Cell Death; Cell Nucleus; Cell Survival; Cell physiology; Cells; Chromatin; Chromosomes; Collagen; Cytoskeleton; DNA; DNA Damage; DNA Maintenance; DNA Repair; DNA repair protein; Development; Disease; Epigenetic Process; Epithelial Cells; Exhibits; Extracellular Matrix; Gel; Genomic Instability; Glioma; Growth; Hepatic Stellate Cell; Hepatocyte; Human; Immunoblotting; In Vitro; Keratin; Lamin B1; Lamin Type A; Lamins; Length; Link; Liver; Liver neoplasms; Liver parenchyma; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Mechanics; Membrane; Memory; Modeling; Mus; Muscle; Mutation; Nuclear; Nuclear Envelope; Nuclear Lamin; Nuclear Physics; Pathway interactions; Patients; Persons; Phenotype; Physics; Plasma; Pluto; Porosity; Premalignant; Primary carcinoma of the liver cells; Proteins; Proteome; Proteomics; Recovery; Regulation; Research Project Grants; Rheology; Role; Science; Shapes; Site; Solid; Stretching; Structure of nail of finger; Syndrome; Testing; The Sun; Tissues; U251; Xenograft procedure; abstracting; cell motility; collagenase; hepatocellular carcinoma cell line; human DNA; in vivo; interest; lamin B2; macrophage; meter; migration; overexpression; pressure; repaired; single molecule; trend; tumor

Abstract for Project-3 Nuclear Rheology & Stability in Cancer The total length of human DNA in each nucleus (~2 meters) multipled by the number of nucleated cells in an adult human (~10 trillion) gives a total length of DNA in each person that would stretch from the Sun to Pluto and back. A lamina of proteins akin to keratins in your fingernails underlies the nuclear envelope and surrounds the chromosomes contained within each nucleus, and while lamin proteins somehow contribute to nuclear shape and DNA stability, roles for lamins in cancer are extremely unclear. This project focuses on nuclear rheology and stability down to the single molecule level, especially in dynamically migrating and invasive cells. Hepatocellular carcinoma (HCC) tumors exhibit atypical nuclei as many cancers do, and initial profiling of HCC suggests significant changes in lamins, which need to be confirmed and understood. We have recently shown that lamin levels can be mechanosensitive in responding to tissue stiffness [Swift Science 2013], which is especially relevant to HCC because the human liver generally stiffens prior to HCC development [Mueller 2010]. We have also recently found in initial studies that at least one lamin isofom can regulate cell migration and survival through constraining pores [Harada J Cell Biol 2014]. Preliminary results further indicate a relation to DNA damage and repair that we seek to clarify mechanistically down to single molecule levels through the expertise of the Greenberg Lab [Shanbhag Cell 2010]. Our Aims to more deeply study lamin effects on nuclear rheology and stability illustrate the potential consequences of liver tumor stiffening studied in Project-1 and the potential downstream mechanosensitive phenotypes for Project-2. Dennis Discher (Eng'g. and Physics): Nucleus, Cell, & Matrix Mechanics in Motility & Cell Fates Roger Greenberg (Cancer Biology): DNA Breaks, Repair, and Epigenetics 1

项目3摘要 核流变学与癌症稳定性 每个细胞核中人类DNA的总长度（约2米）乘以一个细胞中有核细胞的数量， 一个成年人（约10万亿）的DNA总长度可以从太阳延伸到冥王星 然后回来。一层类似于指甲中角蛋白的蛋白质位于核被膜之下， 核纤层蛋白围绕着每个核内的染色体，而核纤层蛋白以某种方式有助于 核形状和DNA稳定性，核纤层蛋白在癌症中的作用非常不清楚。 该项目的重点是核流变学和稳定性下降到单分子水平，特别是在 动态迁移和侵入细胞。肝细胞癌（HCC）肿瘤表现出非典型细胞核， 许多癌症都是如此，HCC的初步分析表明核纤层蛋白发生了重大变化，这需要 确认和理解。我们最近表明，核纤层蛋白水平可以是机械敏感的反应， 组织硬度[Swift Science 2013]，这与HCC特别相关，因为人类肝脏通常 在HCC发展之前硬化[Mueller 2010]。我们最近在初步研究中还发现，至少 一种核纤层蛋白同种型可以通过限制孔调节细胞迁移和存活[Harada J Cell Biol 2014]。 初步结果进一步表明了我们试图从机制上澄清的DNA损伤和修复的关系 通过Greenberg实验室的专业知识[Shanbhag Cell 2010]将其降至单分子水平。我们的目标是 更深入地研究核纤层蛋白对核流变学和稳定性的影响， 项目-1中研究的肿瘤硬化和项目-2的潜在下游机械敏感表型。 Dennis Discher（Eng'g.运动与细胞命运中的原子核、细胞与矩阵力学 罗杰·格林伯格（癌症生物学）：DNA断裂，修复和表观遗传学 1