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: 8720069
• 负责人: Gary Allen Rosenberg
• 金额: $ 32.7万
• 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/8720069
• 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; Microvascular Dysfunction; 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; hypoperfusion; 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

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：皮质下缺血性血管疾病(SIVD)是血管认知障碍(VCI)的主要形式，由于高血压、糖尿病和代谢综合征继发的小血管疾病在老年人中很常见。有强有力的证据表明，SIVD中的白质损伤与神经炎性反应有关，NIH强调了使用动物模型开发新治疗方法的必要性。长期目标是使用一种新的自发性高血压/卒中易感大鼠(SHR/SP)白质损伤的动物模型来确定其病理生理学，并测试可转化为临床试验的药物。SHR/SP动物模型是在前一次资助期间由PI建立的，基于强大的初步数据，显示了缺氧诱导的基质金属蛋白酶(MMPs)的主要作用。SIVD动物模型采用SHR/SP大鼠，12周龄时给予日本许可饮食(JPD)，并进行单侧颈动脉闭塞(UCAO)。中心假说是，高血压导致深层白质缺氧，驱动分子级联反应，从产生缺氧诱导因子-1(HIF-1)开始，导致MMPs表达，血脑屏障破坏，血管源性水肿，少突胶质细胞死亡，最终导致行为功能障碍。这项拟议的研究的基本原理是确定白质进行性损害所涉及的因素，并利用这一理解来测试潜在的治疗方法。该假说将有三个特定的目的进行验证：1)利用电子顺磁共振(EPR)技术测量慢性高血压大鼠脑白质损害中ptO2的变化，并用多模式磁共振成像研究缺氧对白质结构变化的影响；2)确定缺氧白质中发生的导致少突胶质细胞死亡的分子事件，并确定白质ptO2与脑微血管损害的关系；3)测试可能的治疗药物，通过干预导致少突胶质细胞死亡的神经炎症反应来减少白质损害和改善行为。EPR/MRI将用于无创监测损伤和恢复以及生化和行为终点。这些研究具有创新性，因为他们使用EPR来监测氧气，使用多模式MRI来显示白质损伤，以及生化和行为测试，以全面描述损伤的机制，并允许在同一动物身上跟踪几个月的损伤过程。重要的是，这种新的VCI动物模型提供了一种方法来测试一种常见的老年痴呆疾病的潜在治疗方法，这些研究的结果可以转化为临床试验。