Extracellular Matrix Modulation of Cell Phenotype

细胞表型的细胞外基质调节

• 批准号: 7941433
• 负责人: Jean E Schwarzbauer
• 金额: $ 8.5万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941433
• 关键词: ADAMTS; Acinus organ component; Actins; Affect; Architecture; Basement membrane; Binding; Biochemical; Biochemical Genetics; Biological; Biological Assay; Biological Models; Caenorhabditis elegans; Carbohydrates; Cell Culture System; Cell Culture Techniques; Cell Polarity; Cell physiology; Cells; Complement; Cues; Cytoskeleton; DNA Sequence Rearrangement; Decision Making; Defect; Deposition; Development; Disease; Distal; Drug or chemical Tissue Distribution; Epithelial Cells; Extracellular Matrix; Extracellular Matrix Proteins; Gene Silencing; Genes; Gonadal structure; Homeostasis; Human; Immigration; In Vitro; Integrins; Laminin; Larva; Learning; Life; Ligands; Link; Mammalian Cell; Mammary gland; Mediating; Membrane Proteins; Microscopic; Microscopy; Molecular; Morphogenesis; Nematoda; Organ; Pathologic Processes; Phenotype; Play; Process; Proteins; RNA Interference; Receptor Cell; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Small Interfering RNA; Surface; Tertiary Protein Structure; Testing; Time; Tissues; Upper arm; Video Microscopy; base; cell growth; cell motility; extracellular; genome wide association study; genome-wide; hatching; human disease; in vivo; indium arsenide; insight; matrigel; migration; mutant; novel; overexpression; polarized cell; public health relevance; receptor; receptor expression; research study; transmission process

DESCRIPTION (provided by applicant): The extracellular matrix (ECM) is critical for cellular decision-making through its role in tissue architecture and its stimulatory effects on cell growth, migration, and differentiation. Transmission of ECM signals is carried out by integrin receptors that link the ECM to the actin cytoskeleton and activate various signaling pathways. To understand how cells coordinate extracellular signals with intracellular processes requires insights into the composition and organization of the ECM as well as information about the intracellular molecules that respond to cell-ECM interactions. We are approaching these questions by analyzing gonadogenesis in the nematode Caenorhabditis elegans. Formation of the C. elegans hermaphrodite gonad occurs after hatching and depends on migration of two distal tip cells (DTCs) along the body wall basement membrane matrix. In a genome-wide screen, we identified 99 genes that are required for this process. Here we will focus on several of those genes that play critical roles in initiation of DTC migration and in DTC turning to form the U- shaped gonad arms. Loss of the conserved basement membrane protein papilin (ppn-1) causes a complete blockade of DTC migration. Tissue distribution, timing and regulation of expression, rescue of mutants, and expression of protein domains will be used to define papilin's role in gonad formation. Complementary in vitro studies of papilin localization and function will be performed using human mammary epithelial cells which also express this gene. To determine how DTCs interact with basement membranes, we will identify the ECM ligands for the C. elegans integrin receptors that mediate migration. The ECM directs cell turning and accompanying changes in cell polarity, processes that are dependent on two novel genes and on expression of the pat-2 integrin during gonadogenesis. Functional analyses of these genes and time-lapse video microscopy of migrating DTCs will define molecular requirements for turning. Results from these aims will provide novel information about the regulatory role of cell-ECM interactions in cell rearrangements and migration during tissue morphogenesis. Public Health Relevance: Progression of most, if not all, human diseases is facilitated by perturbations in the extracellular matrix, the network of proteins and carbohydrates that surrounds cells. The extracellular matrix plays essential roles in organizing cells into tissues and controlling organ function. The proposed studies will provide novel information about how changes in cell connections to the extracellular matrix affect organ development and will provide new ideas about how alterations in extracellular matrix contribute to human disease.

描述（由申请人提供）：细胞外基质（ECM）通过其在组织结构中的作用及其对细胞生长、迁移和分化的刺激作用对细胞决策至关重要。ECM信号的传递通过将ECM连接到肌动蛋白细胞骨架并激活各种信号传导途径的整合素受体进行。为了理解细胞如何协调细胞外信号与细胞内过程，需要深入了解ECM的组成和组织以及有关细胞-ECM相互作用的细胞内分子的信息。我们通过分析秀丽隐杆线虫的性腺发生来探讨这些问题。C.的形成线虫雌雄同体的性腺在孵化后出现，并依赖于两个远端细胞（DTC）沿着体壁基底膜基质的迁移。在全基因组筛选中，我们确定了这一过程所需的99个基因。在这里，我们将集中在这些基因中的几个发挥关键作用的启动DTC迁移和DTC转向形成U形性腺臂。保守的基底膜蛋白乳头蛋白（ppn-1）的丢失导致DTC迁移的完全阻断。组织分布，表达的时间和调节，突变体的拯救和蛋白质结构域的表达将被用来定义乳头蛋白在性腺形成中的作用。将使用也表达该基因的人乳腺上皮细胞进行乳头蛋白定位和功能的补充体外研究。为了确定DTC如何与基底膜相互作用，我们将鉴定C。介导迁移的线虫整联蛋白受体。ECM指导细胞转向和伴随的细胞极性变化，这些过程依赖于两个新基因和性腺发生期间pat-2整联蛋白的表达。这些基因的功能分析和迁移DTC的延时视频显微镜将定义转向的分子要求。从这些目标的结果将提供新的信息，细胞-ECM相互作用的调节作用，在组织形态发生的细胞重排和迁移。 公共卫生相关性：大多数（如果不是全部的话）人类疾病的进展是由细胞外基质（围绕细胞的蛋白质和碳水化合物的网络）的扰动促进的。细胞外基质在将细胞组织成组织和控制器官功能中起着重要作用。拟议的研究将提供有关细胞与细胞外基质连接的变化如何影响器官发育的新信息，并将提供有关细胞外基质改变如何导致人类疾病的新想法。