Molecular regulation of fibroblast activation in Thyroid Eye Disease

甲状腺眼病成纤维细胞活化的分子调控

基本信息

批准号：
10674812
负责人：
Collynn Fremont Woeller
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674812
关键词：
Adipocytes Adrenal Cortex Hormones Antigens Aromatic Hydrocarbons Aryl Hydrocarbon Receptor Attenuated Autoantibodies Autoimmune Diseases Automobile Driving Binding Blindness Blocking Antibodies Cell Fate Control Cell Proliferation Cells Cicatrix Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Culture Techniques Data Development Diplopia Disease Equilibrium Event Extracellular Matrix Eye Eye diseases Fibroblasts Functional disorder Genes Genetic Transcription Goals Graves&apos Disease HIF1A gene Hormone Receptor Hyaluronan IGF1 gene Immune system In Vitro Individual Inflammatory Insulin-Like-Growth Factor I Receptor Knowledge Ligands Lipids Mediating Mediator Modeling Molecular Myofibroblast Ocular orbit Operative Surgical Procedures Optic Nerve Orbital Diseases Pain Pathologic Pathology Pathway interactions Patients Plasma Positioning Attribute Production Proliferating Proteomics Radiation therapy Receptor Signaling Regulation Risk Factors Role Signal Induction Signal Transduction Signs and Symptoms Small Interfering RNA Smoke Smoking Swelling Symptoms Technology Testing Therapeutic Thyroid Gland Thyrotropin Receptor Time Tissue Expansion Tissues Visual impairment Work aryl hydrocarbon receptor ligand cell growth cigarette smoke cytokine experimental study exposure to cigarette smoke hypoxia inducible factor 1 in vivo modifiable risk mutant novel receptor receptor expression therapeutic target three dimensional cell culture thyroid associated ophthalmopathies transcription factor transcriptome sequencing

项目摘要

Thyroid eye disease (TED), also referred to as thyroid-associated orbitopathy or ophthalmopathy is the most common orbital pathology. TED is an autoimmune disease that occurs in up to half of patients with Graves’ disease. In TED, the tissues surrounding the eye become inflamed and ultimately remodel to cause protrusion of the eyes, swelling around the eyes, alteration of lid position, and double vision. In the most advanced cases, the expanded tissues compress the optic nerve, causing vision impairment. These clinical manifestations of TED reflect tissue changes triggered by autoantibodies that activate orbital fibroblasts that stimulate proliferation of lipid-laden adipocytes and scar-forming myofibroblasts. Orbital fibroblasts also produce excessive amounts of extracellular matrix composed of hyaluronan and collagen, which further increases the size and stiffness of orbital tissue. There is presently no cure for TED; corticosteroids, radiation therapy, and surgery are routinely used to manage TED symptoms and signs. Teprotumumab, an insulin-like growth factor 1 receptor (IGF1R) blocking antibody has emerged as the first disease-specific treatment for TED. However, a critical knowledge gap that limits our understanding of TED is how autoantibodies activate IGF1R signaling in orbital fibroblasts to promote eye disease. IGF1R can stimulate proliferation and increase myofibroblast formation. The predominant antigen in TED is the thyroid stimulating hormone receptor (TSHR). How IGF1R interacts with TSHR and TED autoantibodies in the disease is a fundamental and unresolved question. One potential mechanism is through the aryl hydrocarbon receptor (AHR). The AHR is a ligand-activated transcription factor that binds synthetic and naturally derived aromatic hydrocarbons. The AHR controls aspects of cell growth, development and the immune system. Evidence suggests that AHR blocks TSHR and IGF1R signaling in vivo and in vitro. However, the mechanism(s) are unclear and whether the AHR regulates these pathways in TED is unknown. One of the most significant risk factors for developing TED is smoking. Smoking activates a transcription factor called hypoxia inducible factor 1 alpha (HIF1a). AHR and HIF1a compete to control cell fate. Smoking may disrupt the HIF1a- AHR balance thereby further increasing IGF1R/TSHR signaling. Central Hypotheses: The AHR blocks IGF1R/TSHR signaling, and loss of this interaction is a primary event in the pathophysiology of TED. Aim 1: Define the molecular pathway(s) by which the AHR blocks orbital fibroblast activation. Aim 2: Determine the role of cigarette smoke exposure in promoting HIF1a and IGF1R signaling while blocking AHR in orbital fibroblasts. Aim 3: Evaluate the ability of the AHR ligands to block TED autoantibody driven TSHR/IGF1R signaling. Impact: Our findings will show that AHR blocks TSHR and IGF1R signaling in TED. Accomplishing the specific aims will establish a molecular mechanism whereby smoking exacerbates IGF1R/TSHR signaling in TED. Further, the experiments should provide critical evidence that activating the AHR pathway is a novel and viable therapeutic target for treating TED.

甲状腺眼病（TED），也称为甲状腺相关性眼病或眼病，是最常见的眼病。常见的眼眶病理学是一种自身免疫性疾病，多达一半的格雷夫斯病患者会发生这种疾病。在 TED 疾病中，眼睛周围的组织发炎并最终重塑导致突出。在最严重的情况下，眼睛周围肿胀、眼睑位置改变和复视。扩张的组织压迫视神经，导致视力障碍。反映由自身抗体触发的组织变化，这些自身抗体激活眼眶成纤维细胞，刺激增殖眼眶成纤维细胞还会产生过量的脂质脂肪细胞和形成疤痕的肌成纤维细胞。由透明质酸和胶原蛋白组成的细胞外基质，进一步增加了细胞的尺寸和硬度目前 TED 无法治愈，放射治疗和手术是常规治疗。用于治疗 TED 症状和体征。 Teprotumumab 是一种胰岛素样生长因子 1 受体 (IGF1R)。阻断抗体已成为 TED 的第一种疾病特异性治疗方法。限制我们对 TED 理解的差距是自身抗体如何激活眼眶成纤维细胞中的 IGF1R 信号促进眼部疾病。 IGF1R 可刺激增殖并增加肌成纤维细胞的形成。 TED 中的抗原是促甲状腺激素受体 (TSHR)。IGF1R 如何与 TSHR 和 TED 相互作用。该疾病中的自身抗体是一个基本且尚未解决的问题，一个潜在的机制是通过。芳基烃受体 (AHR) 是一种配体激活的转录因子，可结合合成的和天然衍生的芳香烃控制细胞生长、发育和免疫系统的各个方面。有证据表明，AHR 在体内和体外均可阻断 TSHR 和 IGF1R 信号传导。机制尚不清楚，AHR 是否调节 TED 中的这些途径也是未知的。发生 TED 的重要危险因素是吸烟会激活一种称为缺氧的转录因子。诱导因子 1 α (HIF1a) 与 HIF1a 竞争控制细胞命运。 AHR 平衡进一步增加 IGF1R/TSHR 信号传导中心假设：AHR 阻断。 IGF1R/TSHR 信号传导以及这种相互作用的丧失是 TED Aim 病理生理学的主要事件。 1：定义 AHR 阻断眼眶成纤维细胞激活的分子途径。目标 2：确定香烟烟雾暴露在促进 HIF1a 和 IGF1R 信号传导同时阻断眼眶 AHR 中的作用目标 3：评估 AHR 配体阻断 TED 自身抗体驱动的 TSHR/IGF1R 的能力。影响：我们的研究结果表明，AHR 会阻断 TED 中的 TSHR 和 IGF1R 信号传导。具体目标是建立一种分子机制，通过吸烟使 IGF1R/TSHR 信号恶化此外，这些实验应该提供关键证据，证明激活 AHR 途径是一种新颖且有效的方法。治疗 TED 的可行治疗靶点。