Extracellular Matrix Modulation of Cell Phenotype

细胞表型的细胞外基质调节

基本信息

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
项目类别：
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

项目摘要

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）对于细胞结构中的作用及其对细胞生长，迁移和分化的刺激影响至关重要。 ECM信号的传输是由整合素受体连接到肌动蛋白细胞骨架并激活各种信号通路的传输。为了了解细胞如何与细胞内过程协调细胞外信号，需要深入了解ECM的组成和组织以及有关对细胞ECM相互作用响应的细胞内分子的信息。我们通过分析线虫秀丽隐杆线虫中的性腺发生来解决这些问题。秀丽隐杆线虫的形成雌雄同体性腺发生在孵化后发生，并取决于两个远端尖端细胞（DTC）沿着身体壁基底膜基质的迁移。在全基因组筛选中，我们确定了该过程所需的99个基因。在这里，我们将重点关注其中的几个基因，这些基因在启动DTC迁移以及DTC转弯以形成U形性腺臂中起着关键作用。保守的地下膜蛋白乳头状蛋白（PPN-1）的丧失会导致DTC迁移的完全阻断。组织分布，表达的时机和调节，突变体的拯救以及蛋白质结构域的表达将用于定义乳头状蛋白酶在性腺形成中的作用。对乳头状蛋白定位和功能的互补研究将使用也表达该基因的人类乳腺上皮细胞进行。为了确定DTC如何与地下膜相互作用，我们将确定介导迁移的秀丽隐杆线虫整联蛋白受体的ECM配体。 ECM指导细胞转弯并伴随细胞极性的变化，取决于两个新基因的过程以及在性腺发生过程中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。这些目标的结果将提供有关细胞 - ECM相互作用在细胞重排和组织形态发生过程中迁移的新信息。公共卫生相关性：大多数（如果不是全部）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网络）促进的。细胞外基质在将细胞组织到组织和控制器官功能方面起着重要作用。拟议的研究将提供有关细胞连接与细胞外基质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的变化如何有助于人类疾病的新想法。