Type I diabetes and NF-kappa B

1型糖尿病(T1D)是一种胰岛炎症性疾病，困扰着数百万人 世界各地的人们。尽管引发这种疾病的病因各不相同，但共同的病理 T1D的结果是炎性细胞通过一个称为 胰岛炎症。胰岛炎症的发展需要大量调节基因的协调表达 炎性细胞的激活、迁移和效应功能。这些基因包括编码 细胞因子、趋化因子和细胞毒酶。虽然众所周知，这些基因的表达是 在转录水平上受到严格调控，所涉及的转录因子的性质以及 它们在T1D中的作用机制尚不清楚。几个实验室的最新研究 包括我们的结果表明，核因子-KB转录因子家族在 T1D。因此，在小鼠和人类中，T1D与高水平的核因子-ICB活性有关，而核因子-KB 老鼠的缺陷使它们对这种疾病具有抵抗力。重要的是，抑制核因子-KB活性是非常重要的 有效抑制T1D模型。因此，核因子-ICB已经成为一个长期受追捧的转录因子。 T1D的调节器。然而，核因子-ICB不仅在导致岛炎的淋巴和髓系细胞中表达， 也包括非免疫系统的细胞，包括胰岛的p细胞，这些细胞被 胰岛炎症。基于核因子-KB的治疗策略将是最有效的，如果他们选择性地针对这些细胞或 与T1D的发病机制直接相关的核因子-xB途径。我们假设核因子-KB 不同细胞类型的表达激活不同的基因集，在T1D：NF-KB中发挥不同的作用 由炎性细胞表达，通过激活前体来协调其激活和效应功能 炎性基因而胰腺/3细胞表达的核因子-kB通过 激活细胞凋亡基因。这项提议的具体目的是：1)检验核因子-KB的假设 淋巴和髓系细胞通过激活促炎基因促进1型糖尿病的表达。2) 为了验证胰腺(3)细胞表达的核因子-KB通过以下途径决定1型糖尿病患者的命运的假设 激活细胞凋亡基因。3)检验核因子-kB-IL-23轴在 1型糖尿病的发病机制。4)阻断可诱导的核因子-kB活性治疗1型糖尿病。信息 将有助于确定哪个细胞(S)和哪个核因子-KB途径(S)应该是 选择性靶向治疗T1D。然后可能开发一类新的核因子-kB抑制药物 治疗T1D。

Type 1 diabetes (T1D) is an inflammatory disease of the pancreatic islets that afflicts millions of people worldwide. Although the etiological factors that trigger the disease vary, the common pathological outcome of T1D is the destruction of insulin-producing p cells by inflammatory cells through a process called insulitis. Development of insulitis requires coordinated expression of a large number of genes that mediate the activation, migration and effector functions of inflammatory cells. These include genes that encode cytokines, chemokines, and cytotoxic enzymes. While it is well recognized that expression of these genes is tightly regulated at the transcriptional level, the nature of the transcription factors involved and the mechanisms of their action in T1D are not well understood. Recent studies from several laboratories including ours indicate that the nuclear factor (NF)-KB family of transcription factors plays crucial roles in T1D. Thus, in both mice and humans, T1D is associated with heightened NF-icB activation, whereas NF-KB deficiency in mice renders them resistant to the disease. Importantly, inhibiting NF-KB activities is highly effective in suppressing models of T1D. Therefore, NF-icB has emerged as a long sought-after transcriptional regulator of T1D. However, NF-icB is expressed not only by lymphoid and myeloid cells that cause insulitis, but also by cells of the non-immune systems including p cells of the pancreatic islets that are destroyed by insulitis. NF-KB-based therapeutic strategies would be most effective if they selectively target those cells or NF-xB pathways that are directly responsible for the pathogenesis of T1D. We hypothesize that NF-KB expressed by different cell types activates different sets of genes and plays different roles in T1D: NF-KB expressed by inflammatory cells orchestrates their activation and effector function by activating pro-\ inflammatory genes whereas NF-KB expressed by pancreatic /3cells regulates their death and survival by activating apoptotic genes. The specific aims of this proposal are: 1) To test the hypothesis that NF-KB expressed by lymphoid and myeloid cells promotes type 1 diabetes by activating pro-inflammatory genes. 2) To test the hypothesis that NF-KB expressed by pancreatic (3cells dictates their fate in type 1 diabetes by activating apoptotic genes. 3) To test the hypothesis that the NF-KB-IL-23 axis plays a key role in the pathogenesis of type 1 diabetes. 4) To treat type 1 diabetes by blocking inducible NF-KB activity. Information generated from the proposed studies will help establish which cell(s) and which NF-KB pathway(s) should be selectively targeted for the treatment of T1D. A new class of NF-KB inhibiting drugs may then be developed to treat T1D.