New Antiinflammatory Agents to Prevent Damage to Islets

防止胰岛损伤的新型抗炎剂

• 批准号: 6576060
• 负责人: JERRY L. NADLER
• 金额: $ 27.75万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576060
• 关键词: NOD mouse; antiinflammatory agents; apoptosis; cell line; cellular pathology; clinical research; combinatorial chemistry; disease /disorder prevention /control; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; enzyme linked immunosorbent assay; fluorescence microscopy; human tissue; immunocytochemistry; insulin; insulin dependent diabetes mellitus; interferon gamma; interleukin 1; interleukin 12; oral administration; pancreatic islet function; pancreatic islet transplantation; pancreatic islets; terminal nick end labeling; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Type 1 diabetes is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic ( cells. Several pro-inflammatory cytokines, such as interleukin 1 beta, IL-1beta, Tumor necrosis factor alpha (TNFalpha) and Interferon gamma (IFN-gamma) participate in the immune destruction of beta cells in the islet. Furthermore, interleukin 12 (IL-12) by inducing Th1 cell development has been shown to be an important factor in Type 1 diabetes development. Recurrence of autoimmune damage to transplanted islets also is one factor limiting the full realization of reversal of Type 1 diabetes with transplantation. Therefore, development of new methods to prevent autoimmune damage to beta cells or its recurrence after transplantation could provide a major advance in the field. Lisofylline (LSF) is an anti-inflammatory compound that has been shown to block IL-12 signaling and Th1 cell development. LSF can reduce IL-1-induced beta dysfunction in isolated rat beta cells. New results indicate that LSF can prevent cytokine-induced damage in part by maintaining normal mitochondrial function in beta cells. In addition, data suggests that LSF can significantly reduce spontaneous Type 1 diabetes development in the NOD mouse. However, LSF will have limited use clinically since it has a very short half-life and almost no oral bioavailability and is a relatively weak agent, requiring 20muM concentration in vitro for these effects to be seen. The current pilot proposal will use a focused combinatorial chemistry design to develop more potent, selective, and orally bioavailable anti-inflammatory agents with the same spectrum of activity of LSF. Aim #1 will be to design and synthesize this library and evaluate agents likely to be orally stable. Aim #2 will be to screen candidates with potential oral stability and absorption using both the beta cell protection assays and IL-12 signaling assays we have developed. Aim #3 will test the 2 lead compounds in the NOD mouse to determine their effects in preventing Type 1 diabetes development. Functional and histological studies will be performed. The ultimate goal of this proposal is to identify a lead oral candidate for further detailed in vitro and in vivo development for a Phase 1/2 clinical trial to prevent Type 1 diabetes. This same compound(s) should also provide benefit to maintain beta cell function after islet cell transplantation.

描述（由申请人提供）： 1 型糖尿病是一种自身免疫性疾病，其特征是产生胰岛素的胰腺细胞遭到破坏。多种促炎细胞因子，例如白细胞介素 1β、IL-1β、肿瘤坏死因子 α (TNFα) 和干扰素 γ (IFN-γ)此外，白介素 12 (IL-12) 通过诱导 Th1 细胞发育参与胰岛 β 细胞的免疫破坏，已被证明是 1 型糖尿病发展的重要因素。移植胰岛自身免疫损伤的复发也是限制移植完全逆转 1 型糖尿病的因素之一。因此，开发新方法来预防 β 细胞自身免疫损伤或其移植后复发可能会在该领域取得重大进展。 Lisofylline (LSF) 是一种抗炎化合物，已被证明可以阻断 IL-12 信号传导，并且 LSF 可以减少分离的大鼠 β 细胞中 IL-1 诱导的 β 功能障碍。 LSF 可以部分通过维持 β 细胞中正常的线粒体功能来预防细胞因子引起的损伤。此外，数据表明 LSF 可以显着减少 NOD 小鼠自发的 1 型糖尿病发展。然而，LSF在临床上的应用有限，因为它的半衰期很短，几乎没有口服生物利用度，而且是一种相对较弱的药物，体外需要20μM浓度才能看到这些效果。目前的试点提案将使用集中的组合化学设计来开发更有效、更具选择性和口服生物可利用的抗炎剂，其活性范围与 LSF 相同。目标#1是设计和合成该库并评估可能口服稳定的药物。目标 #2 是使用我们开发的 β 细胞保护测定和 IL-12 信号传导测定来筛选具有潜在口服稳定性和吸收性的候选药物。目标 #3 将在 NOD 小鼠中测试 2 种先导化合物，以确定它们在预防 1 型糖尿病发展中的作用。将进行功能和组织学研究。该提案的最终目标是确定一种主要口服候选药物，用于进一步详细的体外和体内开发，用于预防 1 型糖尿病的 1/2 期临床试验。这种相同的化合物还应该有助于在胰岛细胞移植后维持β细胞功能。