Signal Transduction by alphavbeta8 Integrin

alphavbeta8 整合素的信号转导

• 批准号: 10524026
• 负责人: Joseph H McCarty
• 金额: $ 39.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524026
• 关键词: Address; Adhesions; Affinity; Arteries; Avidity; Binding; Biochemical; Biological Assay; Biology; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Blood capillaries; Brain; Brain Pathology; Cardiovascular system; Cell Adhesion; Cell Communication; Cell Culture System; Cell physiology; Cells; Central Nervous System; Communication; Complex; Cytoplasm; Cytoplasmic Tail; Cytoskeleton; Data; Development; Disease; Dissection; Docosahexaenoic Acids; Down-Regulation; Endothelial Cells; Endothelium; Event; Extracellular Domain; Extracellular Matrix; Extracellular Matrix Proteins; Fluorescence Microscopy; Focal Adhesions; Functional disorder; Gene Expression; Genetically Engineered Mouse; Growth Factor; Homeostasis; Image; Integrins; Internet; Ions; Knock-in; Knock-in Mouse; Laboratories; Lead; Ligands; Link; Mediating; Membrane; Metabolism; Microglia; Modeling; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurocognitive Deficit; Neuroglia; Neurologic Deficit; Neurons; Organ; Paracrine Communication; Pathogenesis; Pathology; Pathway interactions; Pericytes; Perinatal subependymal hemorrhage; Permeability; Physiology; Play; Polyunsaturated Fatty Acids; Primary Cell Cultures; Property; Proteins; Regulation; Resolution; Retina; Role; Signal Pathway; Signal Transduction; Stroke; Structure; Tight Junctions; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Vascular Dementia; Vascular Endothelial Cell; Vascular System; Vascularization; Veins; age related; age related neurodegeneration; blood vessel development; brain endothelial cell; cell behavior; cell type; developmental disease; experimental study; extracellular; fetal; human disease; insight; integrin alphavbeta8; link protein; mouse model; mutant mouse model; nervous system disorder; neural; neurological pathology; neuropathology; neurovascular; neurovascular unit; pre-clinical; receptor; tool; transcriptome sequencing

Abstract The brain is the most vascularized organ in the mammalian body, with its complex network of blood vessels interacting with neurons and glia in multicellular complexes termed neurovascular units. Growth factors and extracellular matrix (ECM) proteins coordinately regulate adhesion and signaling between neural cells and vascular cells to promote normal brain development and physiology. These events are deregulated in many brain pathologies, including developmental disorders such as germinal matrix hemorrhage and age-related neurocognitive deficits such as Vascular Dementia. We understand surprisingly little about mechanisms that regulate normal neural-vascular cell contact and communication or how these events go awry during disease pathogenesis. Here, we will analyze roles for ECM proteins and their integrin receptors in neurovascular biology and disease. Integrins are a-b heterodimeric proteins that link ECM ligands to the cytoskeleton and control intracellular signaling cascades. While a great deal is known about adhesion and signaling functions for most integrins, the pathways controlled by integrin avb8, which was discovered more than 25 years ago, remain largely unexplored. avb8 is expressed in glial cells of the central nervous system (CNS) and plays critical roles in regulating vascular endothelial cell behaviors via activation of ECM-bound latent-transforming growth factor b (TGFb) protein ligands. In this renewal project, we will develop genetically engineered mouse models and primary cell culture systems to analyze avb8 integrin-mediated adhesion and signaling pathways in neurovascular unit pathophysiology. First, we will characterize a newly developed knock-in mouse model that enables dissection of avb8 integrin extracellular adhesion from intracellular signaling in neural-vascular cell contact and communication. In particular, we will study integrin-dependent blood vessel morphogenesis and endothelial barrier formation in the brain and retina. Second, we will determine functions for the b8 cytoplasmic domain in regulating integrin inside-out activation and ECM affinity/avidity using biochemical assays and primary cell culture models. Third, we will explore paracrine signaling between avb8 integrin in perivascular glial cells and TGFb receptors in endothelial cells. A particular focus will be placed on integrin-dependent regulation of the docosahexaenoic (DHA) transporter Mfsd2a in CNS endothelial cells. Fourth, we will explore links between defective DHA metabolism and BBB dysfunction in the progressive neurodegenerative pathologies that develop in integrin mutant mice. In summary, experiments in this project will reveal new and important mechanisms underlying integrin control of neurovascular development and physiology. The mutant mouse models may also provide valuable insights into pathways involved in the pathogenesis of vascular-related neurological diseases.

抽象的 大脑是哺乳动物体内最血管的器官，其复杂的网络 与神经元相互作用的血管在多细胞复合物中称为神经血管 单位。生长因子和细胞外基质（ECM）蛋白协同调节粘附 以及神经细胞和血管细胞之间的信号传导，以促进大脑正常的发育和 生理。这些事件在许多脑部病理中被放松，包括发育 诸如生发基质出血和与年龄有关的神经认知缺陷等疾病 血管痴呆。我们对调节正常的机制几乎没有理解 神经血管细胞的接触和交流或这些事件在疾病期间的出现 发病。在这里，我们将分析ECM蛋白及其整合素受体的作用 神经血管生物学和疾病。整联蛋白是连接ECM的A-B异二聚体蛋白 配体到细胞骨架并控制细胞内信号传导级联。虽然很多是 关于大多数整合素的粘附和信号传导功能已知，该途径由 25年前被发现的整合素AVB8在很大程度上尚未探索。 AVB8 在中枢神经系统（CNS）的神经胶质细胞中表达，并在 通过激活ECM结合潜在转换来调节血管内皮细胞行为 生长因子B（TGFB）蛋白配体。在这个续签项目中，我们将在遗传上发展 工程的小鼠模型和原代细胞培养系统分析AVB8整合素介导的 神经血管单位病理生理学中的粘附和信号通路。首先，我们会的 表征新开发的敲入鼠标模型，该模型可以解剖AVB8整合素 神经血管细胞接触中细胞内信号转导的细胞外粘附，并 沟通。特别是，我们将研究整联蛋白依赖性血管形态发生和 大脑和视网膜中的内皮屏障形成。其次，我们将确定 B8细胞质结构域在调节整合素内外激活和ECM亲和力/经历中使用 生化测定和原代细胞培养模型。第三，我们将探索旁分泌信号传导 在血管周神经胶质细胞中的AVB8整联蛋白和内皮细胞中TGFB受体之间。一个 特别关注二十六烯（DHA）的整合素依赖蛋白依赖性调节 中枢神经系统内皮细胞中的转运蛋白MFSD2A。第四，我们将探索有缺陷之间的链接 DHA代谢和BBB功能障碍在进行性神经退行性病理学中 在整联蛋白突变小鼠中发展。总而言之，该项目中的实验将显示新的，并且 整联蛋白控制神经血管发育的重要机制和 生理。突变鼠标模型还可以为途径提供有价值的见解 参与与血管相关神经系统疾病的发病机理。