Type I diabetes and TRAIL

描述(申请人提供)：肿瘤坏死因子超家族成员在炎症和自身免疫性疾病中起主要作用。TRAIL，能够诱导细胞凋亡。我们的长期研究目标是阐明肿瘤坏死因子相关的凋亡诱导蛋白在自身免疫性疾病中的作用机制。这一建议是基于我们最近的发现，即TRAIL是肿瘤坏死因子家族的抗炎成员。缺乏TRAIL的小鼠对I型糖尿病的易感性增加，NOD小鼠的TRAIL阻断显著加速了疾病的发生，并增强了抗GAD65T细胞反应。该建议的目的是阐明TRAIL在I型糖尿病中的作用机制，并操纵TRAIL的功能用于该疾病的治疗。研究肿瘤坏死因子/肿瘤坏死因子受体家族蛋白的一个主要挑战是它们通常由执行不同功能的不同类型的细胞表达。就TRAIL及其受体而言，它们不仅由介导炎症的免疫系统细胞表达，也由屈从于免疫破坏的靶器官细胞表达。此外，TRAIL相关的凋亡蛋白经常激活细胞中相反的信号通路，这可以促进(通过caspase级联)或防止(通过核因子-kappaB或c-jun)细胞死亡。在全面了解TRAIL在自身免疫性疾病中的作用之前，必须确定TRAIL在不同细胞类型中的作用。我们假设TRAIL在I型糖尿病中的作用是由它的靶点和它产生的信号的性质决定的，并且操纵TRAIL信号可以有效地治疗I型糖尿病。为了验证这些假说，我们将研究1)免疫细胞和非免疫细胞表达TRAIL的作用，2)TRAIL在I型糖尿病中的作用靶点，3)TRAIL给药和体内TRAIL基因转移的作用，以及4)TRAIL与FasL在I型糖尿病中的关系。这些研究产生的信息不仅有助于阐明TRAIL在I型糖尿病中的作用机制，还有助于开发治疗该疾病的新策略。

DESCRIPTION (provided by applicant): Members of the tumor necrosis factor (TNF) superfamily play cardinal roles in inflammation and autoimmune diseases. TRAIL, that is capable of inducing apoptosis. Our long-term goal of research is to elucidate the mechanisms of action of TNF-related apoptosis-inducing proteins in autoimmune diseases. This proposal is based on our recent discovery that TRAIL is an anti-inflammatory member of the TNF family. Mice deficient in TRAIL had an increased susceptibility to type I diabetes, and TRAIL-blockade in NOD mice significantly accelerated the disease and enhanced anti-GAD65 T cell responses. The goals of this proposal are to elucidate the mechanisms of TRAIL action in type I diabetes mellitus and to manipulate TRAIL functions for the treatment of the disease. A major challenge to study the roles of TNF/TNF-receptor families of proteins is that they are often expressed by a variety of cell types that perform different functions. In the case of TRAIL and its receptors, they are expressed not only by cells of the immune system that mediate inflammation but also by cells of target organs that succumb to immune destruction. Additionally, TRAIL-related apoptotic proteins often activate opposing signaling pathways in cells, which can either promote (through caspase cascade) or prevent (through NF-kappaB or c-Jun) cell death. The roles of TRAIL in different cell types must be established before a comprehensive understanding of its function in autoimmune diseases can be achieved. We hypothesize that the roles of TRAIL in type I diabetes is dictated by its targets and the nature of the signals it generates, and that manipulating TRAIL signals can be effective for the treatment of type I diabetes. To test these hypotheses, we will study 1) the roles of TRAIL expressed by immune cells and non-immune cells, 2) the targets of TRAIL action in type I diabetes, 3) the effects of TRAIL administration and TRAIL gene transfer in vivo, and 4) the relationship between TRAIL and FasL in type I diabetes. Information generated from these studies may not only help elucidate the mechanisms of TRAIL action in type I diabetes but also aid in developing a novel strategy to treat the disease.