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血管最多的器官，其复杂的网络 血管与多细胞复合体中的神经元和神经胶质细胞相互作用，称为神经血管 单位。生长因子和细胞外基质 (ECM) 蛋白协调调节粘附 以及神经细胞和血管细胞之间的信号传递，以促进正常的大脑发育和 生理。这些事件在许多大脑病理学中不受管制，包括发育障碍 疾病，例如生发基质出血和与年龄相关的神经认知缺陷，例如 血管性痴呆。令人惊讶的是，我们对调节正常的机制了解甚少。 神经血管细胞接触和通讯或这些事件在疾病期间如何出错 发病。在这里，我们将分析 ECM 蛋白及其整合素受体在 神经血管生物学和疾病。整合素是连接 ECM 的 a-b 异二聚体蛋白 细胞骨架的配体并控制细胞内信号级联。虽然有很多是 已知大多数整合素的粘附和信号传导功能，这些途径由 整合素 avb8 于 25 多年前被发现，但很大程度上仍未被探索。 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 结合的潜在转化来调节血管内皮细胞行为 生长因子 b (TGFb) 蛋白配体。在这个更新项目中，我们将开发基因 工程小鼠模型和原代细胞培养系统来分析 avb8 整合素介导 神经血管单位病理生理学中的粘附和信号传导途径。首先，我们将 表征新开发的敲入小鼠模型，该模型能够解剖 avb8 整合素 神经血管细胞接触中细胞内信号传导的细胞外粘附和 沟通。特别是，我们将研究整合素依赖性血管形态发生和 大脑和视网膜内皮屏障的形成。其次，我们将确定功能 b8细胞质结构域在调节整合素内向外激活和ECM亲和力/亲合力中的作用 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 血管周围胶质细胞中的 avb8 整合素与内皮细胞中的 TGFb 受体之间的关系。一个 将特别关注二十二碳六烯酸 (DHA) 的整合素依赖性调节 CNS 内皮细胞中的转运蛋白 Mfsd2a。第四，我们将探讨缺陷之间的联系 进行性神经退行性病变中的 DHA 代谢和 BBB 功能障碍 在整合素突变小鼠中发育。总之，该项目的实验将揭示新的和 整合素控制神经血管发育的重要机制 生理。突变小鼠模型也可能为通路提供有价值的见解 参与血管相关神经系统疾病的发病机制。