Cortical Spreading Depression, Proteases and Ischemia

皮质扩散抑制、蛋白酶和缺血

• 批准号: 7433304
• 负责人: Michael A. Moskowitz
• 金额: $ 16.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433304
• 关键词: 3-nitrotyrosine; Active Sites; Amino Acids; Aminoisobutyric Acids; Area; Autoradiography; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Edema; Brain Injuries; Brain region; Cell surface; Cells; Cerebral Ischemia; Collagen Type IV; Communication; Cysteine; Data; Development; Disease; Disruption; Distal; Edema; Endopeptidases; Evans blue stain; Extracellular Matrix; Extravasation; Frequencies; Gel; Gelatinase A; Gelatinase B; Gelatinases; Generations; Hemorrhage; Hour; Human; In Situ; In Situ Hybridization; In Vitro; Infarction; Injury; Ipsilateral; Ischemia; Knockout Mice; Knowledge; Laminin; Leukocytes; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Migraine; Molecular; Monitor; Mus; Mutant Strains Mice; Neurons; Neutrophil Collagenase; Nitrates; Nitric Oxide; Numbers; Pathogenesis; Pathway interactions; Pattern; Peptide Hydrolases; Permeability; Pharmaceutical Preparations; Plasma Proteins; Protein Isoforms; Proteins; Proteomics; Rattus; Recurrence; Regulation; Role; Specific qualifier value; Spreading Cortical Depression; Stroke; TNFRSF5 gene; Testing; Time; Tissues; Transcriptional Regulation; Traumatic Brain Injury; Up-Regulation; Vascular Permeabilities; Work; inhibitor/antagonist; injured; ischemic lesion; man; neurovascular unit; nitrate; novel; protein function; rat endothelial barrier antigen; research study; tonabersat; transcription factor

DESCRIPTION (provided by applicant): Cortical spreading depression (CSD) develops during experimental stroke and within normal and traumatically injured human brain. Recently, (MMP) have been implicated in stroke pathogenesis and in the integrity of the neurovascular unit by degrading matrix proteins, enhancing blood brain barrier (BBB) permeability and brain edema, and promoting hemorrhage after tPA administration. Although brain injury or vascular mechanisms provide triggers, we recently found that intense neuronal glial depolarization during CSD activated MMP-9 for at least 72 hrs. and promotes perivascular plasma protein leakage. We propose 4 Aims to explore the novel hypothesis that MMP activation during CSD is caused in part by neuronal and glial activation directly and contributes to the development of edema in ischemia and BBB disruption in normal brain. Aim 1 will confirm and extend preliminary data establishing CSD as a trigger for MMP activation and will identify relevant isoforms and cells of origin. Aim 2 will test the hypothesis that CSD is accompanied by leakage of plasma protein caused by MMP activation and will extend preliminary data showing that, (1) permeability of Evans blue increases within ipsilateral vessels and that, (2) antigenicity of endothelial barrier antigen and laminin is decreased by MMP-dependent mechanisms after CSD. Aim 3 will examine upstream mechanisms triggering MMP activation during CSD. Because nitric oxide s-nitrosylates the MMP active site to promote activation, we will examine whether CSD-induced NO generation triggers MMP activation and if so, examine the relevant NOS isoform promoting MMP activation by using selective NOS knockout mice. We will also examine the importance of NFkB and other pathways in the transcriptional regulation of MMP-9. Aim 4 will examine the consequences of CSD-induced MMP activation during ischemia and explore the contributions of MMPs to vascular permeability changes both within the ischemic lesion and in remote brain areas. Using mutant mice lacking MMP-8 expressed on leucocytes, we propose to determine the extent to which MMP-8 causes MMP-induced BBB disruption in ischemic and non-ischemic tissue, and examine the potential for CSD-induced MMP-9 activation by MMP-8 dependent mechanisms in leucocytes. By doing so, we intend to explore ways in which neuronal activity during cerebral ischemia modulates the extracellular matrix and neurovascular unit and contribute to tissue injury.

描述（由申请人提供）：在实验性中风期间以及在正常和创伤性损伤的人脑内，发生皮质扩散性抑制（CSD）。 最近，MMP通过降解基质蛋白、增强血脑屏障（BBB）通透性和脑水肿以及促进tPA给药后出血而与卒中发病机制和神经血管单位的完整性有关。 虽然脑损伤或血管机制提供触发器，我们最近发现，强烈的神经胶质细胞去极化CSD激活MMP-9至少72小时。并促进血管周围血浆蛋白渗漏。 我们提出了4个目的，以探讨新的假设，在CSD期间MMP激活部分是由神经元和胶质细胞激活直接引起的，并有助于在缺血和正常脑血脑屏障破坏的水肿的发展。 目的1将确认和扩展初步数据，建立CSD作为MMP激活的触发器，并将确定相关的亚型和细胞的起源。 目的2将检验CSD伴随MMP激活引起的血浆蛋白渗漏的假设，并将扩展初步数据，表明（1）同侧血管内伊文思蓝的渗透性增加，（2）CSD后MMP依赖性机制降低了内皮屏障抗原和层粘连蛋白的抗原性。 目的3将研究在CSD过程中触发MMP激活的上游机制。 由于一氧化氮s-亚硝基化MMP活性位点，以促进激活，我们将研究是否CSD诱导的NO生成触发MMP激活，如果是这样，研究相关的NOS亚型促进MMP激活使用选择性NOS基因敲除小鼠。 我们还将研究NF κ B和其他途径在MMP-9转录调控中的重要性。 目的4将检查CSD诱导的MMP激活在缺血期间的后果，并探讨MMP的缺血性病变内的血管通透性的变化，并在远程脑区的贡献。 使用突变小鼠缺乏MMP-8表达的白细胞，我们建议确定MMP-8在缺血和非缺血组织中引起MMP-诱导的BBB破坏的程度，并检查CSD诱导的MMP-9激活的可能性MMP-8依赖性机制在白细胞。 通过这样做，我们打算探索脑缺血期间神经元活动调节细胞外基质和神经血管单位并促进组织损伤的方式。