Elucidating Key Mechanisms Regulating Cell Invasion In Vivo

阐明体内调节细胞侵袭的关键机制

• 批准号: 8387740
• 负责人: David R Sherwood
• 金额: $ 28.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387740
• 关键词: Adopted; Advanced Malignant Neoplasm; Arthritis; Asthma; Automobile Driving; Basement membrane; Behavior; Binding; Caenorhabditis elegans; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Chromosome Mapping; Collagen Type IV; Complex; Data; Development; Developmental Process; Disease; Dissection; Endothelium; Epithelium; Excision; Extracellular Matrix; Extracellular Matrix Proteins; Family; Genetic; Genetic Programming; Genetic Screening; Genomics; Goals; Health; Human; Immune; Immunologic Surveillance; In Vitro; Infection; Injury; Invaded; Lead; Life; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Membrane Proteins; Mission; Mitotic; Modeling; Molecular Analysis; Neoplasm Metastasis; Orthologous Gene; Pathway interactions; Peptide Hydrolases; Play; Pre-Eclampsia; Process; Proteins; RNA Interference; Regulation; Reporter Genes; Research; Role; Screening procedure; Site; Therapeutic; Tissues; Visual; Work; cell motility; cellular imaging; crosslink; genetic analysis; human disease; in vivo; in vivo Model; insight; novel therapeutics; overexpression; pregnancy disorder; programs; promoter; trafficking; transcription factor

DESCRIPTION (provided by applicant): Basement membrane is a dense, highly cross-linked form of extracellular matrix that surrounds most tissues. During development and immune surveillance, specialized cells acquire the ability to breach basement membrane to disperse and traffic to sites of infection and injury. The cell invasion program is also co-opted or misregulate during many diseases, including asthma, arthritis, the pregnancy disorder pre-eclampsia, and cancer. Understanding how cells invade through basement membrane is thus of great importance to human health. Cell invasion involves dynamic interactions between the invading cell, the tissue being invaded, and the basement membrane separating them. Owing to an inability to recapitulate these complex interactions in vitro, and the challenge of experimentally examining invasion in vivo, the key mechanisms underlying cell invasive behavior remain poorly understood. Anchor cell invasion in C. elegans is an experimentally accessible in vivo model of cell invasion that uniquely combines single cell visual analysis with powerful genetic and genomic approaches. Using these strengths, we have identified two conserved transcription factors that regulate distinct steps in acquiring an invasive cell fate. NHR-67, an ortholog of the vertebrate Tailless protein, maintains the anchor cell in a post-mitotic state. Exit from the cell cycle appears necessary to then permit the C. elegans Fos family transcription factor ortholog FOS-1A to initiate the invasion program. Preliminary data indicate that FOS-1A regulates the expression of three matrix metalloproteinases (MMPs) in the anchor cell, implicating a specific pathway that controls basement membrane removal. Finally, we have found that elevated levels of the extracellular matrix protein SPARC, which is overexpressed in most advanced cancer malignancies, decreases type IV collagen levels in basement membrane, and dramatically enhances anchor cell invasion. The goal of this proposal is to use live-cell imaging with genetic and molecular analysis to determine: (1) How NHR-67 maintains the anchor cell in a post-mitotic state and allows the cell invasion program to initiate, (2) the role of FOS-1A in regulatin MMP expression and the function of MMPs in breaching the BM, (3) the role of SPARC in enhancing cell invasion. These studies are relevant to NIH's mission as they will lead to new insights into the importance of cell cycle exit for invasion, the specific role of MMPs in breachin basement membrane and the role of SPARC in facilitating the invasive process, thus allowing the development of better therapeutic strategies to limit invasive behavior in human diseases such as cancer. PUBLIC HEALTH RELEVANCE: Cell invasion through basement membrane plays pivotal roles in numerous cell migrations in development and immune cell trafficking. This behavior is also co-opted in many human diseases, most notably during the spread of cancer. Our proposed work will elucidate the function of a specific genetic program that shuts down cell proliferation t allow cell invasion to occur and a key pathway that promotes the ability of invasive cells to penetrate through basement membrane barriers. These studies will advance our understanding of the fundamental mechanisms underlying cell invasion and generate new therapeutic strategies to regulate cell invasive behavior in human diseases such as cancer.

描述（由申请人提供）：基膜是一种致密的、高度交联的细胞外基质，包围着大多数组织。在发育和免疫监视过程中，特化细胞获得了突破基底膜的能力，以分散和运输到感染和损伤部位。在许多疾病中，包括哮喘、关节炎、妊娠障碍先兆子痫和癌症，细胞入侵程序也被征用或失调。因此，了解细胞如何通过基底膜侵入对人类健康具有重要意义。细胞入侵包括入侵细胞、被入侵组织和将它们分开的基膜之间的动态相互作用。由于无法在体外概括这些复杂的相互作用，以及在体内实验检查入侵的挑战，细胞入侵行为的关键机制仍然知之甚少。秀丽隐杆线虫的锚定细胞入侵是一种实验可获得的细胞入侵体内模型，它独特地将单细胞视觉分析与强大的遗传和基因组方法相结合。利用这些优势，我们已经确定了两个保守的转录因子，它们调节获得侵袭性细胞命运的不同步骤。NHR-67的同源物