Pro-inflammatory glucocorticoid effects in the CNS

糖皮质激素对中枢神经系统的促炎作用

基本信息

批准号：
7911836
负责人：
ROBERT M. SAPOLSKY
金额：
$ 39.42万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911836
关键词：
Acute Adrenal Cortex Hormones Adrenal Glands Adverse effects Anti-Inflammatory Agents Anti-inflammatory Astrocytes Bacteria Basic Science Biology Brain Brain Injuries Brain region Cells Cellular biology Clinical Cognition Corticosteroid Receptors Cytokine Activation Data Dose Edema Employee Strikes Endocrinology Endothelial Cells Excitatory Neurotoxins Exposure to Gene Expression Genes Glucocorticoids Goals Grant Hippocampus (Brain)Hormones Hour Human Hydrocortisone Hypothalamic structure Inflammation Inflammatory Inflammatory Response Injury Lipopolysaccharides Literature Mediating Microglia Molecular Molecular Profiling Necrosis Nervous system structure Neurologic Neurons Neurosciences Pattern Peripheral Physiologic pulse Prednisone Proteins Rattus Relative (related person)Research Seizures Site Specificity Spinal Steroids Stress Work cell type clinically relevant cytokine fascinate injured insight macrophage migration neurotoxicity neutrophil novel protein expression public health relevance research study response steroid hormone transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Glucocorticoids (GCs), the adrenal steroids secreted during stress, can compromise the ability of neurons to survive necrotic neurological insults. These deleterious effects have often been viewed as counterbalanced by the benefits of the anti-inflammatory actions of GCs in the injured brain. However, GCs are actually less consistently anti-inflammatory in the injured brain than generally assumed. Moreover, as a marked challenge to dogma, recent work from my lab and others has shown that GCs can even potentiate aspects of inflammation in the injured hippocampus and cortex (while being classically anti-inflammatory elsewhere in the brain). Specifically, the hormone augments the migration of inflammatory cells to the injury site, the expression of and protein levels of pro-inflammatory cytokines, and the activation of the pro- inflammatory transcription factor NFkB. These findings are challenging at the basic science level (i.e., uncovering how GCs can have opposite effects on inflammation in different contexts); moreover, they are of considerable potential clinical relevance, given the enormous use of synthetic GCs to control post-insult inflammation in the human brain. This proposal will study the mechanisms underlying these novel GC actions at a more reductive level than in previous studies. In all experiments, intact rats will be exposed to either LPS, a bacteria-derived molecule which stimulates a robust inflammatory response, or a seizure-inducing excitotoxin, which also causes inflammation in the brain. Specific Aim 1 will analyze how the magnitude and duration of GC exposure, its temporal relationship to one of these inflammatory challenges, and the brain region examined determine whether GCs worsen or blunt the inflammation caused by these challenges. From these data, we will identify the most striking contrasts between conditions where GCs augment versus blunt facets of inflammation. In Specific Aim 2, we will identify gene expression profiles that differentiate between those two states; specifically, we will identify genes whose expression is influenced in a contrasting manner by GCs, depending on whether the hormone is enhancing or inhibiting. Specific Aim 3 will then identify the cell types in which these expression differences are occurring (i.e., whether in neurons, astrocytes, microglia, endothelial cells, neutrophils or macrophages). PUBLIC HEALTH RELEVANCE: Glucocorticoids (GCs, including synthetic corticosteroids such as hydrocortisone or prednisone) are anti-inflammatory, and are widely used to decrease the damaging inflammation that occurs after brain injury. However, a growing literature shows that GCs can actually worsen inflammation following some acute neurological insults. The proposal begins to dissect the molecular mechanisms underlying these unexpected and damaging pro-inflammatory GC effects.

描述（由申请人提供）：糖皮质激素（GC）是应激期间分泌的肾上腺类固醇，会损害神经元在坏死性神经损伤中生存的能力。这些有害影响通常被视为可以通过 GC 在受损大脑中的抗炎作用的益处来抵消。然而，GC 在受损大脑中的抗炎作用实际上不如一般假设的那么一致。此外，作为对教条的明显挑战，我的实验室和其他人最近的研究表明，GC 甚至可以增强受损海马体和皮质的炎症（同时在大脑其他部位具有经典的抗炎作用）。具体而言，激素增强炎症细胞向损伤部位的迁移、促炎细胞因子的表达和蛋白质水平以及促炎转录因子NFkB的激活。这些发现在基础科学层面具有挑战性（即揭示GC如何在不同情况下对炎症产生相反的影响）；此外，鉴于合成GC在控制人脑损伤后炎症方面的大量应用，它们具有相当大的潜在临床意义。该提案将在比之前的研究更还原的水平上研究这些新颖的 GC 作用背后的机制。在所有实验中，完整的大鼠将暴露于LPS（一种细菌衍生的分子，可刺激强烈的炎症反应）或诱发癫痫发作的兴奋性毒素（也会引起大脑炎症）。具体目标 1 将分析 GC 暴露的程度和持续时间、其与这些炎症挑战之一的时间关系以及检查的大脑区域如何确定 GC 是否恶化或减弱这些挑战引起的炎症。从这些数据中，我们将确定 GC 增强与钝化炎症方面之间最显着的对比。在具体目标 2 中，我们将确定区分这两种状态的基因表达谱；具体来说，我们将根据激素是增强还是抑制来识别其表达以对比方式受到 GC 影响的基因。然后，具体目标 3 将识别出现这些表达差异的细胞类型（即，是否在神经元、星形胶质细胞、小胶质细胞、内皮细胞、中性粒细胞或巨噬细胞中）。公共卫生相关性：糖皮质激素（GC，包括合成皮质类固醇，如氢化可的松或泼尼松）具有抗炎作用，广泛用于减少脑损伤后发生的破坏性炎症。然而，越来越多的文献表明，GC 实际上会加剧一些急性神经损伤后的炎症。该提案开始剖析这些意想不到的破坏性促炎性GC效应背后的分子机制。