THE ROLE OF C/EBP TRANSCRIPTION FACTORS IN BRAIN INFLAMMATION IN ALZHEIMER?S DIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 阿尔茨海默病(AD)的经典病理成分，淀粉样β蛋白斑块和神经原纤维缠结，在AD脑内形成并持续存在，引发小胶质细胞和星形胶质细胞的慢性炎症反应。这些慢性炎症反应被广泛认为是导致神经元损伤和死亡的侮辱的主要因素。关于导致这些炎症因子表达的分子信号机制，我们知之甚少。我们已经完成了AD脑组织小胶质细胞表达C/EBP-β和原浆星形胶质细胞表达C/EBP-epsilon的研究。此外，对C/EBP在人小胶质细胞中表达的初步研究表明，在AD脑和经聚集的A-β(1-42)或促炎细胞因子处理的小胶质细胞培养中，小胶质细胞C/EBPs的表达上调。与华盛顿大学的默勒和加登博士合作，我们将继续并扩大这些研究。我们的假设是，在阿尔茨海默病等神经退行性疾病中，CCAAT-增强子结合蛋白(C/EBP)家族转录因子是协调神经退行性疾病中神经胶质炎症反应所必需的。在具体目标1中，我们将确定与非痴呆大脑样本(无神经疾病病史或神经病理证据的ND)相比，AD患者的C/EBPs是否上调。在特定目标2中，我们将从尸检组织转移到神经胶质细胞系培养，在那里可以测试特定的机制。关键信号通路/蛋白在C/EBP表达/活性和促炎或抗炎治疗之间的关键和中介将被确定。这项建议的目标既有基础科学，也有转化性临床科学。这些重点是在基因转录水平上阐明退行性疾病中神经胶质细胞炎性蛋白表达的调控机制。我们将研究针对这些过程的潜在抗炎药物，从而抑制神经炎症。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The classical pathological components of Alzheimer's disease (AD), amyloid Beta plaques and neurofibrillary tangles, materialize and persist in the AD brain, invoking chronic inflammatory responses from microglia and astrocytes. These chronic inflammatory responses are widely held to be a primary contributor of insults leading to the damage and death of neurons. Little is known regarding molecular signaling mechanisms leading to the expression of these inflammatory factors. We have completed studies of C/EBP-Beta expression by microglia and C/EBP-epsilon by protoplasmic astrocytes in AD brain tissue. Further, preliminary studies of C/EBP expression in human microglia demonstrate that microglial cells exhibit upregulated expression of C/EBPs in the AD brain and in microglial cultures treated with aggregated A-Beta(1-42) or pro-inflammatory cytokines. In collaboration with Drs. Moeller and Garden at the University of Washington we will continue and extend these studies. Our hypothesis is that CCAAT-Enhancer Binding Protein (C/EBP) family of transcription factors are required for orchestrating glial neuroinflammatory responses in neurodegenerative diseases such as AD. In Specific Aim 1 we will determine whether C/EBPs are upregulated in AD compared to non-demented brain samples (ND-without history or neuropathologic evidence of a neurological disorder). In Specific Aim 2 we will move from postmortem autopsy tissue to glial cell line cultures where specific mechanisms can be tested. Key signaling kinases/proteins critical and intermediate between C/EBP expression/activity and pro- or anti-inflammatory treatments will be determined. The goals of this proposal have both a basic science and translational clinical science emphasis. These emphases are to elucidate at the gene transcriptional level the mechanisms that regulate the expression of inflammatory proteins by glial cells in degenerative diseases. We will examine potential anti-inflammatory drugs which specifically target these processes, thereby dampening neuroinflammation.