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: 10153902
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153902
• 关键词: Adhesions; Animal Model; Area; Astrocytes; Automobile Driving; Axon; Blindness; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Communication; Cells; Central Nervous System Diseases; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Clinic; Clinical; Data; Demyelinating Diseases; Demyelinations; Deposition; Disease; 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; Mediating; Microglia; Microscopy; Modeling; Molecular; Molecular Profiling; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Neuraxis; Neurologic Symptoms; Numbness; Paralysed; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Pharmacology; 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; Tumor-infiltrating immune cells; Validation; Vascular Endothelial Cell; Vascular Endothelium; axon injury; base; blood-brain barrier disruption; brain tissue; cell type; drug repurposing; experimental study; human tissue; hypertension treatment; imaging study; in vivo; in vivo imaging; inhibitor/antagonist; macrophage; migration; monocyte; multiple sclerosis patient; multiple sclerosis treatment; neuroinflammation; neuron loss; pre-clinical; prevent; receptor; receptor expression; recruit; two-photon; vascular abnormality

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）是一种具有广泛范围的中枢神经系统（CNS）的神经炎症性疾病 诸如麻木，瘫痪和视力丧失之类的神经系统表现。疾病病理学有大量 血管周病变，炎症性脱髓鞘会导致轴突损伤，这是神经元丧失的主要罪魁祸首 MS患者的功能。尽管对与疾病病理有关的细胞和分子有很多了解，但是什么细胞 分子机制启动针对中枢神经系统的免疫学级联反应仍然未知。最早的迹象 人类MS患者和MS动物模型的病变都是血脑屏障（BBB）的破坏和激活 小胶质细胞，是中枢神经系统的驻留免疫细胞。我们以前的体内成像研究确定了小胶质细胞 实验性自身免疫性脑脊髓炎的最早反应者（EAE，MS的既定动物模型）。我们发现 小胶质细胞群围绕血管泄漏到中枢神经系统中，从而确定血管周围位置 新病变形成的地方。是什么引起早期血管改变，血管的局部破坏以及招募 形成这些血管周围病变的周围免疫细胞尚不清楚。在此提案中，我们将探索细胞和 EAE和MS中与早期血管改变和BBB破坏有关的分子机制。我们将调查 EAE中血管周围的小胶质细胞积累是否涉及小胶质细胞和血管壁之间的信号传导 引起这种血管改变并驱动中枢神经系统的免疫细胞募集。具体来说，我们将确定是否 活化的小胶质细胞通过内皮素（ET）与脑血管的细胞成分进行通信 系统，这是调节血管张力，血压和调节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，因为它增强 单核细胞和白细胞的内皮通过。 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MS或动物模型中的潜在作用知之甚少。我们的初步结果 先前的研究表明，ET系统是诱导脑血流减少和血管的良好候选途径 EAE和MS的异常。我们提出的实验方法结合了药理和遗传抑制 在经历了血管破坏和小胶质细胞，巨噬细胞和T细胞中的体内成像的方法 EAE课程。此外，我们将寻求验证我们有关ET途径表达的临床前动物模型发现 通过使用独特的人脑组织库，我们在 克利夫兰诊所。由于ET受体拮抗剂是FDA批准用于治疗高血压的，因此我们的研究具有 提供原则验证证明，重新利用这些药物可能是有益的 人类患者。