NF-kB control of neuronal apoptosis in Alzheimer disease

NF-kB 控制阿尔茨海默病神经元凋亡

• 批准号: 8552398
• 负责人: RANJAN SEN
• 金额: $ 31.21万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552398
• 关键词: Alzheimer' s Disease; Apoptotic; B-Lymphocytes; CD4 Positive T Lymphocytes; Categories; Cell Death; Cell Line; Cell Survival; Cell surface; Cells; Cessation of life; Dose; Down-Regulation; Family member; Genes; Genetic; Genetic Models; Goals; In Vitro; Inflammatory; Manuscripts; Mitochondria; Mus; NF-kappa B; NFKB Signaling Pathway; Neurodegenerative Disorders; Neurons; PTGS2 gene; Role; Signal Transduction; Stress; T-Lymphocyte; TNF gene; TNFRSF1A gene; Testing; Up-Regulation; celecoxib; extracellular; inhibitor/antagonist; neuron apoptosis; neuron loss; novel; prevent; programs; receptor; transcription factor

During FY12 we accomplished the following: 1. Determined that 3 out of 5 COX-2 inhibitors suppressed c-Rel activation in CD4+ T cells. All those that inhibited Rel also prevented up-regulation of several Rel-responsive TNF and TNF-R super family members that we previously identified as targets of celecoxib. 2. We found that celecoxib inhibited differentiation to inflammatory TH17 cells in vitro This was not due to suppression of the lineage-determining transcription factor RORϒ-T. 3. Using celecoxib at different doses we found that maximal suppression of Rel coincided with activation of ER stress. Earlier studies have indicated that ER stress leads to up-regulation of NF-κB. Our observations provide a novel connection between ER stress and down-regulation of a specific NF-κB family member. A manuscript describing these findings is currently under revision.

2012 财年我们完成了以下工作： 1. 确定 5 种 COX-2 抑制剂中有 3 种抑制 CD4+ T 细胞中的 c-Rel 激活。 所有抑制 Rel 的药物还可以阻止我们之前确定为塞来昔布靶点的几种 Rel 反应性 TNF 和 TNF-R 超家族成员的上调。 2.我们发现塞来昔布在体外抑制炎症TH17细胞的分化，这并不是由于谱系决定转录因子RORϒ-T的抑制。 3.使用不同剂量的塞来昔布，我们发现Rel的最大抑制与ER应激的激活同时发生。 早期研究表明 ER 应激会导致 NF-κB 上调。 我们的观察结果提供了 ER 应激与特定 NF-κB 家族成员下调之间的新联系。 描述这些发现的手稿目前正在修订中。