Inflammatory Mechanisms in Cerebral Ischemia

脑缺血的炎症机制

基本信息

批准号：
7432541
负责人：
Midori A Yenari
金额：
$ 36.18万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-15 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7432541
关键词：
Address Anatomy Animals Anti-Inflammatory Agents Anti-inflammatory Astrocytes Biological Models Bone Marrow Brain Brain Ischemia Cause of Death Cell Survival Cells Cerebral Ischemia Cerebrum Chimera organism Coculture Techniques Control Animal Country Endopeptidases Event Galactosidase Gene Expression Generations Glutamates Heat shock proteins Heat-Shock Proteins 70 Immunoblotting Infiltration Inflammation Inflammatory Inflammatory Response Injury Interleukins Invaded Ischemia Label Leukocytes Marrow Matrix Metalloproteinases Mediating Mediator of activation protein Microglia Middle Cerebral Artery Occlusion Modeling Molecular Chaperones Mus NF-kappa B Nervous System Trauma Neurologic Neurons Nitric Oxide Nitrogen Nuclear Oxygen Peptide Hydrolases Peripheral Peroxonitrite Physiological reperfusion Play Principal Investigator Property Protein Overexpression Proteins Reperfusion Therapy Reporter Role Stimulus Stress Stroke Superoxides Testing Transgenic Mice Transgenic Organisms Transplantation Tumor Necrosis Factor-alpha Tumor Necrosis Factors brain cell brain tissue cell type chemokine cytokine disability expectation human NOS2A protein human TNF protein improved in vitro Model insight macrophage monocyte mouse model neutrophil prevent programs protein aggregation research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Stroke is a significant cause of death and disability in this country. Treatments are few and available to only a small percentage of stroke victims. We and others have shown that the stress inducible 70 kDa heat shock protein (HSP70) is neuroprotective. The mechanism of protection following cerebral ischemic events is not well known, but has largely been attributed to its chaperone functions whereby HSP70 improves cell survival by preventing protein aggregation. A few recent studies suggest that HSP70 may also have antiinflammatory properties. It is now known that inflammation participates in cerebral ischemic injury by contributing to brain tissue damage acutely, but it is unknown whether HSP70 plays an anti-inflammatory role in stroke. In this proposal, we will explore the effects of selective HSP70 overexpression in regulating the inflammatory response in brain ischemia and ischemia-like insults. In the intact brain, this response appears to be mediated by both the resident microglia and invading peripheral leukocytes. Inflammatory cells produce potentially damaging substances such as reactive oxygen and nitrogen species, cytokines, chemokines, glutamate and various proteases. Using a transgenic mouse model where HSPT0 is constitutively overexpressed, we will first test the hypothesis that HSP70 is associated with a reduction in this inflammatory response in a well characterized stroke model. Using mixed cultures of neurons, astrocytes and microglia, we have observed that microglia increase damage to ischemia-like insults. Therefore, we will examine whether selective overexpression of HSP70 in microglia may reverse the worsened injury, and explore potential mechanisms behind this observation such as suppression of inflammatory mediators and inhibition of the inflammatory transcription factor, nuclear factor kappa B (NFkB). In the final aim, we will then study the participation of peripheral inflammatory cells in a mouse stroke model using bone marrow chimeras, where wildtype animals are transplanted with marrow cells derived from the HSP70 transgenic mice. These studies should provide uniqae insights into a new mechanism by which HSP70 may protect against injury following cerebral ischemic and ischemia-like insults.

描述（由申请人提供）：中风是该国死亡和残疾的重要原因。治疗方法很少，并且只有一小部分中风患者可以获得治疗。我们和其他人已经证明，应激诱导型 70 kDa 热休克蛋白 (HSP70) 具有神经保护作用。脑缺血事件后的保护机制尚不清楚，但很大程度上归因于其伴侣功能，HSP70 通过防止蛋白质聚集来提高细胞存活率。最近的一些研究表明 HSP70 可能还具有抗炎特性。目前已知炎症通过导致脑组织急性损伤而参与脑缺血损伤，但HSP70是否在中风中发挥抗炎作用尚不清楚。在本提案中，我们将探讨选择性 HSP70 过表达在调节脑缺血和缺血样损伤中炎症反应中的作用。在完整的大脑中，这种反应似乎是由驻留的小胶质细胞和入侵的外周白细胞介导的。炎症细胞产生潜在的破坏性物质，例如活性氧和氮、细胞因子、趋化因子、谷氨酸和各种蛋白酶。使用 HSPT0 组成型过表达的转基因小鼠模型，我们将首先在一个充分表征的中风模型中检验 HSP70 与炎症反应减少相关的假设。使用神经元、星形胶质细胞和小胶质细胞的混合培养物，我们观察到小胶质细胞会增加对缺血样损伤的损害。因此，我们将检查小胶质细胞中HSP70的选择性过度表达是否可以逆转恶化的损伤，并探索这一观察结果背后的潜在机制，例如抑制炎症介质和抑制炎症转录因子核因子κB (NFkB)。在最终目标中，我们将使用骨髓嵌合体研究外周炎症细胞在小鼠中风模型中的参与，其中野生型动物被移植来自 HSP70 转基因小鼠的骨髓细胞。这些研究应该为 HSP70 可以防止脑缺血和缺血样损伤后的损伤的新机制提供独特的见解。