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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默氏病（AD）的经典病理学组分淀粉样蛋白β斑块和神经元缠结在AD脑中具体化并持续存在，引起来自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主要因素。关于导致这些炎症因子表达的分子信号传导机制知之甚少。我们已经完成了AD脑组织中小胶质细胞和原生质星形胶质细胞的C/EBP-β表达的研究。此外，对人小胶质细胞中C/EBP表达的初步研究表明，小胶质细胞在AD脑中和在用聚集的A-β（1-42）或促炎细胞因子处理的小胶质细胞培养物中表现出C/EBP的上调表达。我们将与华盛顿大学的Moeller博士和Garden博士合作，继续并扩展这些研究。我们的假设是，CCAAT-增强子结合蛋白（C/EBP）家族的转录因子是协调神经退行性疾病，如AD的胶质神经炎症反应所必需的。在具体目标1中，我们将确定与非痴呆脑样本（ND-没有神经系统疾病的病史或神经病理学证据）相比，AD中的C/EBP是否上调。在特定目标2中，我们将从死后尸检组织转移到可以测试特定机制的神经胶质细胞系培养。将确定C/EBP表达/活性与促炎或抗炎治疗之间的关键和中间的关键信号传导激酶/蛋白质。该提案的目标既有基础科学，也有转化临床科学的重点。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表达炎症蛋白的调控机制。我们将研究专门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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.