Type I diabetes and NF-kappa B

描述（由申请人提供）：1型糖尿病（T1 D）是一种胰岛炎性疾病，困扰着全世界数百万人。尽管引发该疾病的病因因素各不相同，但T1 D的常见病理结果是炎症细胞通过称为胰岛炎的过程破坏产生胰岛素的B细胞。胰岛炎的发展需要大量基因的协调表达，这些基因介导炎性细胞的活化、迁移和效应功能。这些包括编码细胞因子、趋化因子和细胞毒性酶的基因。虽然公认这些基因的表达在转录水平上受到严格调控，但所涉及的转录因子的性质及其在T1 D中的作用机制还不清楚。包括我们在内的几个实验室最近的研究表明，核因子（NF）-KB家族的转录因子在T1 D中起着至关重要的作用。因此，在小鼠和人类中，T1 D与增强的NF-κ B活化相关，而小鼠中的NF-κ B缺乏使它们对该疾病具有抗性。重要的是，抑制NF-κ B活性在抑制T1 D模型中非常有效。因此，NF-κ B已成为T1 D的长期受欢迎的转录调节因子。然而，NF-κ B不仅由引起胰岛炎的淋巴样和骨髓样细胞表达，而且还由非免疫系统的细胞表达，包括被胰岛炎破坏的胰岛β细胞。如果基于NF-κ B的治疗策略选择性地靶向直接导致T1 D发病机制的那些细胞或NF-κ B通路，则它们将是最有效的。我们假设不同细胞类型表达的NF-κ B激活不同的基因组，并在T1 D中发挥不同的作用：炎症细胞表达的NF-κ B通过激活促炎基因协调其激活和效应功能，而胰腺B细胞表达的NF-κ B通过激活凋亡基因调节其死亡和存活。该提议的具体目的是：1）检验淋巴细胞和骨髓细胞表达的NF-κ B通过激活促炎基因促进1型糖尿病的假设。2)为了检验由胰腺β细胞表达的NF-κ B通过激活凋亡基因决定其在1型糖尿病中的命运的假设。3)验证NF-κ B-IL-23轴在1型糖尿病发病机制中起关键作用的假设。4)通过阻断诱导型NF-κ B活性治疗1型糖尿病。从拟议的研究中产生的信息将有助于确定哪种细胞和哪种NF-κ B途径应该被选择性地靶向用于治疗T1 D。然后可以开发一类新的NF-κ B抑制药物来治疗T1 D。

DESCRIPTION (provided by applicant): 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 B 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-KB 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-KB has emerged as a long sought-after transcriptional regulator of T1D. However, NF-KB 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-KB 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 B cells 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 (3 cells 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.