Role of PAPP-A in Graves' Ophthalmopathy

项目摘要 Graves眼病（GO）是甲状腺外最严重的并发症， 自身免疫性格雷夫斯甲状腺机能亢进症其特征是眼眶脂肪体积增加和眼外 坚硬的骨性眼眶内的肌肉，这可能对眼睛功能产生有害后果。轨道 减压手术是用于严重GO的有效但侵入性的治疗。更好地了解 GO的病理机制可能会发现新的靶点来抑制GO的发展， 在出现任何临床表现之前，GO进展。 已经发现胰岛素样生长因子-I受体（IGF-IR）信号传导在促进GO中是必需的。 发病机制一种结合并阻断IGF-IR信号传导的单克隆抗体最近被FDA批准 治疗GO。然而，已经记录了不良事件，所有这些都可能是由于 IGF-IR：需要更好地了解IGF信号传导及其在眼眶组织中的调节，以充分理解 机制，避免/减少脱靶后果。一种方法是靶向IGF-IR的修饰剂 信号，而不是IGF-IR本身。我们建议把《行动纲领》A作为这样一个目标。 PAPP-A是一种新型的锌金属蛋白酶，可以通过切割 抑制性IGF结合蛋白，特别是IGFBP-4。相反，抑制PAPP-A表达或其 蛋白水解活性代表了降低IGF可用性的创新方法， IGF-IR信号传导。有趣的是，PAPP-A表达的最有效的刺激物是促炎性的。 细胞因子，其在来自GO患者的眼眶组织中增加。 我们假设PAPP-A是GO中IGF-R信号传导的关键调节剂。我们的具体目标是： 1)确定眼眶中的PAPP-A表达（基础和促炎性尼古丁诱导） 来自GO患者和对照受试者的成纤维细胞。 2)确定特异性抑制PAPP-A-的中和单克隆抗体的作用。 IGFBP-4介导的蛋白水解对IGF-I刺激的眼眶细胞增殖和分化的影响 来自GO患者的成纤维细胞。 我们有来自GO患者眶后脂肪的原代成纤维细胞， 通过培养和分析来确定可行性。初步结果支持PAPP-A在GO中的作用。我们 预期拟议实验的结果，最终可能导致一种新的靶向治疗， 患者GO

PROJECT SUMMARY Graves’ Ophthalmopathy (GO) is the most serious extra-thyroidal complication that develops in patients with autoimmune Graves’ hyperthyroidism. It is characterized by increased orbital fat volume and extra-ocular muscle within the unyielding bony orbit, which can have deleterious consequences on eye function. Orbital decompression surgery is an effective but invasive treatment used for severe GO. A better understanding of the pathological mechanisms underlying GO may identify novel targets to inhibit the development and progression of GO before any clinical manifestation. Insulin-like growth factor-I receptor (IGF-IR) signaling has been found to be essential in promoting GO pathogenesis. A monoclonal antibody that binds to and blocks IGF-IR signaling, was recently FDA-approved for treatment of GO. However, adverse events have been documented, all likely due to the ubiquitous nature of IGF-IR. A better understanding of IGF signaling and its regulation in orbital tissue is needed to fully understand mechanism and avoid/reduce off-target consequences. One approach would be to target modifiers of IGF-IR signaling, instead of the IGF-IR per se. We propose PAPP-A as such a target. PAPP-A is a novel zinc metalloprotease that can increase pericellular IGF bioavailability through cleavage of inhibitory IGF binding proteins, in particular IGFBP-4. Conversely, inhibition of PAPP-A expression or its proteolytic activity represents an innovative approach to decrease IGF availability with resultant attenuation of IGF-IR signaling. Interestingly, the most potent stimulators of PAPP-A expression are pro-inflammatory cytokines, which are increased in orbital tissue from GO patients. We hypothesize that PAPP-A is a key modulator of IGF-R signaling in GO. Our Specific Aims are to: 1) Determine PAPP-A expression (basal and pro-inflammatory cytokine-induced) in orbital fibroblasts from GO patients and control subjects. 2) Determine the effect of a neutralizing monoclonal antibody that specifically inhibits PAPP-A- mediated IGFBP-4 proteolysis on IGF-I stimulated proliferation and differentiation in orbital fibroblasts from GO patients. We have primary fibroblasts from retro-orbital fat of GO patients at early passage in-hand and the experience with culture and analyses to establish feasibility. Preliminary results support a role for PAPP-A in GO. We anticipate outcomes from the proposed experiments that could ultimately lead to a novel targeted therapy for patients with GO.