Gliovascular Mechanisms of Blood-Brain Barrier Disruption in Neuroinflammatory Disease

神经炎症疾病中血脑屏障破坏的胶质血管机制

• 批准号: 10615054
• 负责人: Dimitrios Davalos
• 金额: $ 47.94万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615054
• 关键词: Adhesions; Animal Model; Area; Astrocytes; Automobile Driving; Blindness; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Cells; Central Nervous System; Central Nervous System Diseases; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Clinic; Clinical; Communication; Data; Demyelinating Diseases; Demyelinations; Deposition; Disease; Disease remission; Endothelial Cells; Endothelin; Endothelin Receptor; Endothelin Receptor Antagonist; Endothelin-1; Endothelium; Event; Experimental Autoimmune Encephalomyelitis; Extravasation; FDA approved; Genetic; Histologic; Human; Hypertension; Hypoxia; Image; Immune; Immunologics; Infiltration; Inflammatory; Knockout Mice; Label; Lesion; Leukocyte Trafficking; Leukocytes; Link; Location; Macrophage; Mediating; Microglia; Microscopy; Modeling; Molecular; Molecular Profiling; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Neurologic Symptoms; Numbness; Paralysed; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Property; Receptor Inhibition; Regulation; Relapse; Role; Severity of illness; Signal Transduction; Site; Spinal Cord; Spinal Cord Lesions; Stroke; System; T-Lymphocyte; Testing; Therapeutic; Time; Tissue Banks; Tissues; Validation; Vascular Endothelial Cell; Vascular Endothelium; antagonist; axon injury; blood-brain barrier disruption; brain tissue; cell type; drug repurposing; experimental study; glial activation; human tissue; hypertension treatment; imaging study; immune cell infiltrate; in vivo; in vivo imaging; inhibitor; migration; monocyte; multiple sclerosis patient; multiple sclerosis treatment; neuroinflammation; neuron loss; pharmacologic; pre-clinical; prevent; receptor; receptor expression; recruit; two-photon; vascular abnormality; vasoconstriction

Abstract Multiple sclerosis (MS) is a debilitating neuroinflammatory disease of the central nervous system (CNS) with a broad range of neurological manifestations such as numbness, paralysis, and loss of vision. Disease pathology presents with massive perivascular lesions where inflammatory demyelination results in axonal damage, the main culprit for the loss of neuronal function in MS patients. Although a lot is known about cells and molecules involved with disease pathology, what cellular and molecular mechanisms initiate the immunological cascade against the CNS remain unknown. The earliest signs of lesions in both human MS patients and in animal models of MS are blood-brain barrier (BBB) disruption and activation of microglia, which are the resident immune cells of the CNS. Our previous in vivo imaging studies identified microglia as the earliest responders in experimental autoimmune encephalomyelitis (EAE, an established animal model for MS). We found that microglia cluster around vessels that leak blood factors into the CNS and thereby determine the perivascular locations where new lesions form. What causes early vascular alterations, local disruption of blood vessels, and recruitment of peripheral immune cells that form these perivascular lesions is not known. In this proposal, we will explore the cellular and molecular mechanisms involved with early vascular alterations and BBB disruption in EAE and MS. We will investigate whether early perivascular microglial accumulation in EAE involves signaling between microglia and the vessel wall, which causes such vascular alterations and drives immune cell recruitment to the CNS. Specifically, we will determine whether activated microglia communicate with the cellular constituents of the cerebral vasculature through the endothelin (ET) system, which is one of the main molecular mechanisms involved in the regulation of vascular tone, blood pressure, and blood flow. Besides altering vascular properties, ET-1 also has potent pro-inflammatory effects as it enhances trans- endothelial passage of monocytes and leukocytes. ET signaling has been implicated in cardiovascular diseases, such as hypertension and stroke, but little is known about its potential role in MS or its animal models. Our preliminary results and prior studies suggest that the ET system is a good candidate pathway for inducing reduced cerebral blood flow and vascular abnormalities in EAE and MS. Our proposed experimental approach combines pharmacological and genetic inhibition approaches with in vivo imaging of vascular disruption and microglia, macrophages, and T cells in mice undergoing the course of EAE. Moreover, we will seek to validate our preclinical animal model findings on ET pathway expression across different types of lesions from MS patients by using the unique human brain tissue bank that we have available at the Cleveland Clinic. Since ET receptor antagonists are FDA-approved for the treatment of hypertension, our studies have the potential to provide proof-of-principle validation that repurposing these drugs can be beneficial for the treatment of MS in human patients.

抽象的 多发性硬化症 (MS) 是一种使中枢神经系统 (CNS) 衰弱的神经炎症性疾病，具有广泛的影响 神经系统症状，如麻木、瘫痪和视力丧失。疾病病理学表现为大量 血管周围病变，炎症性脱髓鞘导致轴突损伤，这是神经元丢失的主要原因 MS 患者的功能。尽管人们对与疾病病理学有关的细胞和分子了解很多，但细胞到底是什么？ 引发针对中枢神经系统的免疫级联反应的分子机制仍不清楚。最早的迹象 人类多发性硬化症患者和多发性硬化症动物模型中的病变都是血脑屏障 (BBB) 破坏和激活 小胶质细胞是中枢神经系统的常驻免疫细胞。我们之前的体内成像研究确定小胶质细胞是 实验性自身免疫性脑脊髓炎（EAE，一种已建立的多发性硬化症动物模型）的最早反应者。我们发现 小胶质细胞聚集在血管周围，将血液因子泄漏到中枢神经系统，从而确定血管周围的位置 新病灶形成的地方。是什么导致早期血管改变、血管局部破坏和血管募集 形成这些血管周围病变的外周免疫细胞尚不清楚。在本提案中，我们将探索蜂窝和 EAE 和 MS 中涉及早期血管改变和 BBB 破坏的分子机制。我们将调查 EAE 中早期血管周围小胶质细胞的积累是否涉及小胶质细胞和血管壁之间的信号传导，这 引起这种血管改变并促使免疫细胞招募到中枢神经系统。具体来说，我们将确定是否 激活的小胶质细胞通过内皮素 (ET) 与脑血管系统的细胞成分进行通讯 系统，是调节血管张力、血压和血压的主要分子机制之一。 血流（量。除了改变血管特性外，ET-1 还具有有效的促炎作用，因为它可以增强反式- 单核细胞和白细胞的内皮通道。 ET 信号传导与心血管疾病有关，例如 高血压和中风，但对其在多发性硬化症或其动物模型中的潜在作用知之甚少。我们的初步结果和 先前的研究表明，ET 系统是诱导脑血流量和血管减少的良好候选途径。 EAE 和 MS 异常。我们提出的实验方法结合了药理学和遗传抑制 方法对接受血管破坏的小鼠以及小胶质细胞、巨噬细胞和 T 细胞进行体内成像 EAE课程。此外，我们将寻求验证我们关于 ET 通路表达的临床前动物模型研究结果 通过使用我们在该中心拥有的独特的人脑组织库，对多发性硬化症患者的不同类型的病变进行了研究 克利夫兰诊所。由于 ET 受体拮抗剂已获得 FDA 批准用于治疗高血压，因此我们的研究表明 有可能提供原理验证验证，证明这些药物的重新利用可能有益于 MS 的治疗 人类患者。