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），也称为甲状腺相关的轨道病或眼科病是最多的常见的轨道病理。 TED是一种自身免疫性疾病，最多发生在一半的坟墓患者中疾病。在TED中，眼睛周围的组织发炎并最终重塑以引起蛋白质眼睛，眼睛周围肿胀，盖子位置的改变以及双视力。在最先进的情况下，扩展的组织压缩视神经，从而导致视力障碍。 TED的这些临床表现反映组织变化是由激活轨道成纤维细胞的自身抗体触发的，刺激了刺激的增殖充满脂质的脂肪细胞和形成疤痕的肌纤维细胞。轨道成纤维细胞也产生过量的细胞外基质由透明质酸和胶原蛋白组成，这进一步增加了大小和刚度轨道组织。目前无法治愈泰德。皮质类固醇，放射治疗和手术通常是常规的用于管理TED症状和体征。 Teprotumumab，一种胰岛素样生长因子1受体（IGF1R）阻断抗体已成为TED的第一种特异性疾病治疗方法。但是，批判知识限制我们对TED的理解的差距是自动抗体如何激活轨道成纤维细胞中的IGF1R信号传导促进眼科疾病。 IGF1R可以刺激增殖并增加肌纤维细胞的形成。主要的 TED中的抗原是甲状腺刺激的马酮受体（TSHR）。 IGF1R如何与TSHR和TED相互作用该疾病的自身抗体是一个基本尚未解决的问题。一种潜在的机制是通过芳基烃受体（AHR）。 AHR是结合合成和的配体激活转录因子天然衍生的芳族烃。 AHR控制细胞生长，发育和免疫的各个方面系统。证据表明，AHR在体内和体外阻止了TSHR和IGF1R信号传导。但是，机理尚不清楚，AHR是否调节TED中的这些途径尚不清楚。最大的开发TED的重要危险因素是吸烟。吸烟激活一种称为缺氧的转录因子诱导因子1α（HIF1A）。 AHR和HIF1A竞争控制细胞命运。吸烟可能会破坏HIF1A- AHR平衡，从而进一步增加IGF1R/TSHR信号。中央假设：AHR块 IGF1R/TSHR信号传导，这种相互作用的丧失是TED病理生理学的主要事件。目的 1：定义AHR阻断轨道成纤维细胞激活的分子途径。目标2：确定在阻断轨道中AHR时，香烟烟雾暴露在促进HIF1A和IGF1R信号中的作用成纤维细胞。目标3：评估AHR配体阻止TED自动抗体驱动的TSHR/IGF1R的能力信号。影响：我们的发现将表明AHR阻止了TED中的TSHR和IGF1R信号。完成具体目的将建立一种分子机制，吸烟加剧IGF1R/TSHR信号传导泰德。此外，实验应提供关键的证据，表明激活AHR途径是一种新颖，可行的治疗靶标。