THE ROLE OF ADAMTS-A IN REGULATING CNS STRUCTURE AND RESTRICTING CELL MIGRATION

ADAMTS-A 在调节 CNS 结构和限制细胞迁移中的作用

基本信息

批准号：
9402234
负责人：
James Benjamin Skeath
金额：
$ 33.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-28 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9402234
关键词：
ADAMTS Adopted Alpha Cell Astrocytes Atomic Force Microscopy Basement membrane Biological Models Biology Cell membrane Cells Characteristics Collagen Type IV Computer Simulation Development Distant Drosophila genus Electron Microscopy Extracellular Matrix Genes Genetic Genetic Screening Goals Grant Growth Growth and Development function Head and Neck Cancer Heparan Sulfate Proteoglycan Human Individual Integrin beta Chains Integrins Laminin Larva Link Malignant Neoplasms Membrane Metalloproteases Methods Modeling Molecular Neoplasm Metastasis Nerve Neuraxis Neuroglia Neurons Nidogen Organ Pathway interactions Peptide Hydrolases Peripheral Phenotype Plant Roots Play Polymers Process Proteins Proteomics Role Shapes Site Structure Surface System Testing Thick Time Tissues Work animal tissue cell motility extracellular fly human disease insight loss of function migration mutant neoplastic cell perineural perlecan physical property rapid growth relating to nervous system resilience response transcriptome sequencing yeast two hybrid system

项目摘要

Abstract: The union of form and function is a core tenet of biology. In animals, tissues often adopt their characteristic form early in development and maintain it through periods of tremendous growth, a process that often demands that cells remain largely fixed in place. Tissue shape and cell migration is dictated in large part by the basement membrane, a special type of extracellular matrix that surrounds tissues, bestowing on them structural support and resiliency. Yet, how tissues adopt and retain their form and how cells remain anchored in place during growth and development remain key questions in biology. The Drosophila larval CNS is an ideal system in which to explore the genetic and molecular mechanisms that govern tissue structure and anchor cells in place. The CNS is fully enwrapped by a thick basement membrane that provides structural support to the CNS via its physical properties and interactions with underlying surface glia; the CNS grows rapidly during larval stages, maintaining its form despite tremendous growth, and during this time, neural lineages remain largely fixed in place. The CNS basement membrane must then maintain its structure and that of the CNS while continually remodeling itself and its interactions with glia to allow for its growth and that of the CNS. The genetic and molecular principles that bestow upon the CNS basement membrane, and likely most basement membranes, this power remain cloudy – their elucidation represents the focus of this proposal. We identify AdamTS-A, an extra-cellular metalloprotease, as a key organizer of CNS structure. Reduction in AdamTS-A function disrupts CNS structure and induces a mass exodus of neurons and cortex glia out of the CNS. Our studies indicate that AdamTS-A acts in surface glia, the outermost cell layer of the CNS that directly underlies the CNS basement membrane, to maintain CNS structure and to anchor the underlying neural cells in place by opposing the actions of collagen IV and integrin, which promote tissue stiffness. Increased tissue stiffness has been shown to promote cell migration. Thus, we hypothesize that reduction of AdamTS-A function in surface glia increases the stiffness of the overlying CNS basement membrane, which in a cell non- autonomous manner then triggers hundreds of CNS neurons and cortex glia to tunnel through the nerves that project from the CNS toward peripheral tissues fully enwrapped the entire time by the membranes of surface glia. In this grant, we leverage the strengths of the fly system to clarify the underlying genetic and molecular mechanisms through which AdamTS-A maintains tissue structure and keeps cells rooted in place in the CNS. Our specific aims are – (i) to complete a systematic phenotypic characterization of AdamTS-A in the CNS, (ii) to identify the substrates and interacting proteins of AdamTS-A in the CNS, and (iii) to uncover the genes and pathways activated in the migrating cells in response to reduced AdamTS-A function in surface glia.

摘要：形式和功能的结合是生物学的核心原则，在动物中，组织通常采用它们。特征在发育早期形成，并在巨大的生长时期保持它，这个过程通常要求细胞在很大程度上保持固定在适当的位置，并且细胞迁移在很大程度上是决定性的。由基底膜（一种围绕组织的特殊类型的细胞外基质）赋予组织然而，组织如何采用和保持其形状以及细胞如何保持锚定。在生长和发育过程中发生的变化仍然是生物学中的关键问题。果蝇幼虫中枢神经系统是探索遗传和分子机制的理想系统控制组织结构和锚定细胞的中枢神经系统被厚厚的基底完全包裹。膜通过其物理特性和与中枢神经系统的相互作用为中枢神经系统提供结构支持下表面神经胶质细胞；中枢神经系统在幼虫阶段迅速生长，尽管巨大生长，在此期间，中枢神经系统基底膜基本上保持固定。然后必须保持其结构和中枢神经系统的结构，同时不断重塑自身及其相互作用神经胶质细胞的生长和中枢神经系统的生长遗传和分子原理。中枢神经系统基底膜，可能还有大多数基底膜，这种力量仍然是浑浊的——它们的阐明是本提案的重点。我们确定 AdamTS-A（一种细胞外金属蛋白酶）是中枢神经系统结构还原的关键组织者。 AdamTS-A 功能破坏中枢神经系统结构并诱导神经元和皮质神经胶质细胞大量外流我们的研究表明 AdamTS-A 作用于表面神经胶质细胞，即中枢神经系统的最外层细胞层，直接作用于中枢神经系统。位于中枢神经系统基底膜下方，维持中枢神经系统结构并锚定下面的神经细胞通过对抗 IV 型胶原蛋白和整合素的作用，促进组织硬度增加。硬度已被证明可以促进细胞迁移，因此，我们致力于减少 AdamTS-A 功能。表面神经胶质细胞增加了覆盖的中枢神经系统基底膜的硬度，这在细胞中非然后，自主方式触发数百个中枢神经系统神经元和皮质神经胶质细胞穿过神经，从中枢神经系统投射到周围组织，始终被表面膜完全包裹在这笔资助中，我们利用果蝇系统的优势来阐明潜在的遗传和分子。 AdamTS-A 维持组织结构并使细胞在 CNS 中扎根的机制。我们的具体目标是 – (i) 完成中枢神经系统中 AdamTS-A 的系统表型表征，(ii) 鉴定 AdamTS-A 在中枢神经系统中相互作用的底物和蛋白质，以及 (iii) 揭示基因和迁移细胞中响应表面胶质细胞 AdamTS-A 功能降低而激活的通路。