Type I diabetes and TRAIL

描述（由申请人提供）：肿瘤坏死因子（TNF）超家族成员在炎症和自身免疫性疾病中起主要作用。TRAIL，其能够诱导细胞凋亡。我们的长期研究目标是阐明TNF相关的凋亡诱导蛋白在自身免疫性疾病中的作用机制。这个建议是基于我们最近发现TRAIL是TNF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小鼠中的TRAIL阻断显著加速了疾病并增强了抗GAD 65 T细胞应答。该提案的目标是阐明TRAIL在I型糖尿病中的作用机制，并操纵TRAIL功能用于治疗该疾病。研究TNF/TNF受体蛋白家族的作用的一个主要挑战是它们通常由执行不同功能的各种细胞类型表达。在TRAIL及其受体的情况下，它们不仅由介导炎症的免疫系统细胞表达，而且由屈服于免疫破坏的靶器官细胞表达。此外，TRAIL相关的凋亡蛋白通常激活细胞中相反的信号通路，其可以促进（通过半胱天冬酶级联）或防止（通过NF-κ B或c-Jun）细胞死亡。TRAIL在不同细胞类型中的作用必须在全面了解其在自身免疫性疾病中的功能之前建立。我们假设TRAIL在I型糖尿病中的作用取决于其靶点和它产生的信号的性质，并且操纵TRAIL信号可以有效治疗I型糖尿病。为了验证这些假设，我们将研究1）由免疫细胞和非免疫细胞表达的TRAIL的作用，2）I型糖尿病中TRAIL作用的靶点，3）体内施用TRAIL和TRAIL基因转移的效果，以及4）I型糖尿病中TRAIL和FasL之间的关系。从这些研究中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，而且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.