Role of PAPP-A in Graves' Ophthalmopathy

PAPP-A 在格雷夫斯眼病中的作用

• 批准号: 10651452
• 负责人: Cheryl A. Conover
• 金额: $ 7.95万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10651452
• 关键词: Adverse event; Autoimmune; Binding; Biological Availability; Clinical; Clinical Trials; Complication; Development; Enzymes; Exophthalmos; Eye; FDA approved; Fatty acid glycerol esters; Fibroblasts; Hand; Hyperthyroidism; Inflammatory; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Insulin-Like-Growth Factor I Receptor; Mediating; Metalloproteases; Monoclonal Antibodies; Nature; Ocular orbit; Outcome; Pathogenesis; Pathologic; Patients; Pregnancy-Associated Plasma Protein-A; Proliferating; Proteolysis; Receptor Signaling; Regulation; Role; Signal Transduction; Surgical Decompression; Testing; Tissues; Work; Zinc; attenuation; cytokine; experience; experimental study; innovation; lipid biosynthesis; neutralizing monoclonal antibodies; new therapeutic target; novel; orbit muscle; overexpression; prevent; thyroid associated ophthalmopathies

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.

项目概要 格雷夫斯眼病 (GO) 是患有以下疾病的患者出现的最严重的甲状腺外并发症 自身免疫性格雷夫斯甲状腺功能亢进症的特点是眼眶脂肪量增加和眼外脂肪增多。 坚硬的骨性眼眶内的肌肉，这会对眼眶功能产生有害影响。 减压手术是一种有效但侵入性的治疗方法，用于治疗严重 GO。 GO 的病理机制可能会识别新的靶点来抑制 GO 的发展和 在任何临床表现之前发生 GO 进展。 已发现胰岛素样生长因子-I 受体 (IGF-IR) 信号传导对于促进 GO 至关重要 一种结合并阻断 IGF-IR 信号传导的单克隆抗体最近获得 FDA 批准。 然而，不良事件已被记录，这很可能是由于 GO 的普遍存在所致。 为了充分理解 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。 一种方法是针对 IGF-IR 的修饰剂。 我们建议将 PAPP-A 作为这样的靶点。 PAPP-A 是一种新型锌金属蛋白酶，可通过裂解 抑制性IGF结合蛋白，特别是IGFBP-4，抑制PAPP-A或其表达。 蛋白水解活性代表了一种降低 IGF 可用性的创新方法，从而减弱 IGF-IR 信号传导表明，PAPP-A 表达最有效的刺激物是促炎性的。 GO 患者的眼眶组织中细胞因子增加。 我们追求 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 PAPP-A 的表达（基础和促炎细胞因子诱导的） 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效果 介导 IGFBP-4 蛋白水解对 IGF-I 刺激的眼眶增殖和分化 来自 GO 患者的成纤维细胞。 我们手头上有早期传代的来自 GO 患者眼眶后脂肪的原代成纤维细胞和经验 初步结果支持 PAPP-A 在 GO 中的作用。 预测所提出的实验的结果，这些结果可能最终导致一种新的靶向治疗 GO 患者。