White matter hypoxia in a novel model of MMP-mediated inflammation in SHR/SP

SHR/SP 中 MMP 介导的炎症新模型中的白质缺氧

• 批准号: 8629055
• 负责人: Gary Allen Rosenberg
• 金额: $ 33.03万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629055
• 关键词: Age; Alzheimer' s Disease; Animal Model; Animals; Anti-Inflammatory Agents; Area; Automobile Driving; Behavior; Behavioral; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Carotid Arteries; Cerebral Hypoxia; Cerebrovascular Circulation; Cerebrum; Cessation of life; Chelating Agents; Clinical Trials; Corpus Callosum; Data; Dementia; Diabetes Mellitus; Diet; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Edema; Elderly; Electron Spin Resonance Spectroscopy; Event; Free Radicals; Functional disorder; Gelatinase A; Gelatinase B; Genes; Goals; Grant; Hypertension; Hypoxia; Implant; Inflammation; Inflammatory; Injury; Japanese Population; Lead; Magnetic Resonance Imaging; Matrix Metalloproteinases; Measures; Mediating; Metabolic syndrome; Methods; Minocycline; Modeling; Molecular; Monitor; Myelin; National Institute of Neurological Disorders and Stroke; Oligodendroglia; Oxygen; Pathologic Processes; Patients; Perfusion; Permeability; Phase; Prevalence; Process; Production; Program Review Group; Proteins; Rattus; Recovery; Research; Role; SB 3CT compound; Secondary to; Series; Spin Labels; Stroke; Testing; Therapeutic Agents; Tight Junctions; Tissues; Translating; United States National Institutes of Health; Vascular Cognitive Impairment; Vascular Diseases; angiogenesis; animal model development; artery occlusion; base; behavior measurement; behavior test; capillary; drug testing; feeding; hypoxia inducible factor 1; improved; inhibitor/antagonist; innovation; lithium phthalocyanine; meetings; minimally invasive; neuroinflammation; novel; public health relevance; response; subcortical ischemic vascular disease; white matter; white matter damage; white matter injury

PROJECT SUMMARYABSTRACT Subcortical ischemic vascular disease (SIVD), which is the major form of vascular cognitive impairment (VCI), is common in the elderly due to the prevalence of small vessel disease secondary to hypertension, diabetes, and the metabolic syndrome. There is strong evidence that the white matter damage in SIVD is related to a neuroinflammatory response, and NIH has emphasized the need for animal models to be used to develop new treatments. The long-term goal is to use a novel animal model of white matter damage in spontaneously hypertensive/stroke prone rats (SHR/SP) to define the pathophysiology and to test drugs that could be translated into clinical trials. The SHR/SP animal model was developed by the PI during the prior grant, and is based on strong preliminary data, showing the major role of matrix metalloproteinases (MMPs) that are induced by hypoxia. The animal model for SIVD uses SHR/SP rats that are fed a Japanese Permissive Diet (JPD) at 12 weeks of age and subjected to a unilateral carotid artery occlusion (UCAO). The central hypothesis is that hypertension induces hypoxia in the deep white matter, driving a molecular cascade that begins with production of hypoxia inducible factor-1¿ (HIF-1¿) and leads to expression of MMPs, disruption of the BBB, vasogenic edema, oligodendrocyte death, and ultimately behavioral dysfunction. The rationale of the proposed research is to determine the factors involved in the progressive damage to the white matter, and to use that understanding to test potential treatments. This hypothesis will be tested with three specific aims: 1) Determine the role of hypoxia in white matter damage in chronically hypertensive rats by using electron paramagnetic resonance (EPR) to measure ptO2 with lithium phthalocyanine (LiPc) microcrystals implanted stereotactically into the corpus callosum, and to correlate the impact of hypoxia on the structural changes in white matter with multimodal MRI; 2) Determine the molecular events occurring in the hypoxic white matter that lead to oligodendrocyte death and to determine the relationship of white matter ptO2 to damage to the cerebral capillaries; and 3) To test potential therapeutic agents to reduce white matter damage and improve behavior by interfering with the neuroinflammatory response that leads to oligodendrocyte death. EPR/MRI will be used to noninvasively monitor injury and recovery along with biochemical and behavioral end-points. These studies are innovative because they use EPR to monitor oxygen and multimodal MRI to show white matter damage along with biochemical and behavioral testing to completely characterize the mechanisms of damage, and to allow the course of the injury to be followed in the same animal over several months. The significance is that this novel animal model for VCI provides a means to test potential therapies for a common dementing illness in the elderly and that results from these studies could be translated into clinical trials.

项目摘要 皮质下缺血性血管病（SIVD）是血管性认知障碍的主要形式， 血管损伤（VCI）在老年人中很常见，因为继发于 高血压、糖尿病和代谢综合征。有强有力的证据表明白色物质 SIVD的损伤与神经炎症反应有关，NIH强调需要 动物模型用于开发新的治疗方法。长期目标是使用一种新的动物模型 自发性高血压/卒中易感大鼠（SHR/SP）的白色损害，以确定 病理生理学和测试药物，可以转化为临床试验。SHR/SP动物模型 是由PI在先前的赠款期间开发的，并且基于强有力的初步数据，显示 基质金属蛋白酶（MMPs）的主要作用是由缺氧诱导。SIVD动物模型 使用SHR/SP大鼠，在12周龄时喂食日本允许饮食（JPD），并进行 单侧颈动脉闭塞（UCAO）。中心假设是高血压引起缺氧 在深层白色物质中，驱动一个分子级联， 因子-1 <$（HIF-1 <$），并导致MMPs的表达，BBB的破坏，血管源性水肿， 少突胶质细胞死亡最终导致行为障碍拟议研究的基本原理是 以确定对白色物质的渐进性损害所涉及的因素，并利用这些因素， 了解以测试潜在的治疗方法。这一假设将通过三个具体目标进行检验： 缺氧对慢性高血压大鼠脑白色损害的影响 顺磁共振（EPR）测量与酞菁锂（LiPc）微晶ptO2 立体定向植入胼胝体，并将缺氧对大脑皮层的影响与脑组织的损伤相关联。 多模式MRI下白色物质的结构变化; 2）确定发生在 缺氧白色物质导致少突胶质细胞死亡，并确定白色物质与少突胶质细胞死亡的关系 物质ptO2对脑毛细血管的损害;和3）测试潜在的治疗剂，以减少 白色物质通过干扰神经炎症反应来损害和改善行为， 导致少突胶质细胞死亡EPR/MRI将用于无创监测损伤和恢复沿着 有生化和行为终点。这些研究是创新的，因为他们使用EPR， 监测氧气和多模式MRI，以显示白色物质损伤沿着生化和 行为测试，以完全表征损伤机制，并允许过程中， 在同一只动物身上观察几个月。重要的是这种新奇的动物 VCI模型提供了一种方法来测试老年人常见痴呆症的潜在治疗方法 这些研究的结果可以转化为临床试验。