Type I diabetes and NF-kappa B

1型糖尿病（T1 D）是一种胰岛炎性疾病， 世界各地的人们。虽然引发疾病的病因各不相同，但共同的病理 T1 D的结果是炎症细胞通过一种称为 胰岛炎胰岛炎的发生需要大量基因的协调表达， 炎症细胞的活化、迁移和效应功能。这些基因编码 细胞因子、趋化因子和细胞毒性酶。虽然已经充分认识到这些基因的表达是不稳定的， 在转录水平上受到严格调控，所涉及的转录因子的性质和 它们在T1 D中的作用机制尚未得到很好的理解。几个实验室的最新研究 包括我们的研究表明，核因子（NF）-κ B家族的转录因子在 T1D因此，在小鼠和人类中，T1 D与升高的NF-κ B活化相关，而NF-κ B与T1 D相关。 小鼠缺乏这种蛋白质使它们对这种疾病具有抵抗力。重要的是，抑制NF-κ B活性是非常重要的。 有效抑制T1 D模型。因此，NF-icB已经成为一个长期受欢迎的转录调控因子。 T1 D的调节剂。然而，NF-icB不仅由引起胰岛炎的淋巴细胞和骨髓细胞表达， 而且还被非免疫系统的细胞包括胰岛的P细胞破坏 胰岛炎基于NF-κ B的治疗策略将是最有效的，如果他们选择性地靶向这些细胞， NF-xB通路直接负责T1 D的发病机制。我们假设NF-κ B 不同细胞类型表达的NF-κ B激活不同的基因组，在T1 D：NF-κ B中发挥不同的作用 表达的炎症细胞协调其激活和效应器功能，通过激活前- 而胰腺β细胞表达的NF-κ B则通过以下途径调节其死亡和存活： 激活凋亡基因。该建议的具体目的是：1）为了检验NF-κ B的假设， 由淋巴和骨髓细胞表达，通过激活促炎基因促进1型糖尿病。（二） 为了检验胰腺β细胞表达的NF-κ B通过以下方式决定其在1型糖尿病中的命运的假设： 激活凋亡基因。3)为了验证NF-κ B-IL-23轴在细胞凋亡中起关键作用的假设， 1型糖尿病的发病机制。4)通过阻断诱导型NF-κ B活性治疗1型糖尿病。信息 从拟议的研究中产生的信息将有助于确定应该使用哪种细胞和哪种NF-κ B途径。 选择性靶向治疗T1 D。一种新的NF-κ B抑制药物可能会被开发出来 来治疗T1 D

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.