Type I diabetes and NF-kappa B

描述（由申请人提供）：1型糖尿病（T1D）是一种胰岛炎症性疾病，困扰着全世界数百万人。尽管引发该疾病的病因各不相同，但T1D的常见病理结果是炎症细胞通过称为胰岛素炎的过程破坏产生胰岛素的B细胞。胰岛素的发展需要大量基因的协调表达，这些基因介导炎症细胞的激活、迁移和效应功能。这些基因包括编码细胞因子、趋化因子和细胞毒性酶的基因。虽然众所周知，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T1D中的作用机制尚不清楚。包括我们在内的几个实验室最近的研究表明，核因子(NF)-KB家族转录因子在T1D中起关键作用。因此，在小鼠和人类中，T1D都与NF-KB激活升高有关，而小鼠中NF-KB缺乏使它们对该疾病具有抵抗力。重要的是，抑制NF-KB活性在抑制T1D模型中非常有效。因此，NF-KB已成为T1D的转录调节因子。然而，NF-KB不仅在引起胰岛素炎的淋巴细胞和髓细胞中表达，也在被胰岛素炎破坏的非免疫系统细胞中表达，包括胰岛的p细胞。如果基于NF-KB的治疗策略选择性地靶向与T1D发病机制直接相关的细胞或NF-KB通路，将是最有效的。我们假设不同细胞类型表达的NF-KB激活不同的基因组，并在T1D中发挥不同的作用：炎症细胞表达的NF-KB通过激活促炎基因来协调其激活和效应功能，而胰腺B细胞表达的NF-KB通过激活凋亡基因来调节其死亡和存活。本研究的具体目的是：1)验证淋巴细胞和髓细胞表达的NF-KB通过激活促炎基因促进1型糖尿病的假设。2)验证胰腺细胞NF-KB表达通过激活凋亡基因决定1型糖尿病患者命运的假说。3)验证NF-KB-IL-23轴在1型糖尿病发病中起关键作用的假说。4)通过阻断诱导NF-KB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些细胞和哪些NF-KB途径应该选择性地靶向治疗T1D。一类新的NF-KB抑制药物可能会被开发出来治疗T1D。

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.