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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眶病或眼病，是最常见的眼病。常见的眼眶病变TED是一种自身免疫性疾病，发生在高达一半的Graves'患者中。疾病在TED中，眼睛周围的组织发炎，最终重塑，导致突出眼周肿胀、眼睑位置改变和复视。在最严重的病例中，膨胀的组织压迫视神经，导致视力受损。TED的这些临床表现反映了自身抗体引发的组织变化，这些抗体激活了眼眶成纤维细胞，载脂脂肪细胞和瘢痕形成肌成纤维细胞。眼眶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，这进一步增加了细胞的大小和硬度。眼眶组织目前还没有治愈TED的方法;皮质类固醇、放射治疗和手术是常规的治疗方法。用于管理TED症状和体征。Teprotumumab，一种胰岛素样生长因子1受体（IGF 1 R）阻断抗体已经成为TED的第一种疾病特异性治疗方法。然而，一个关键的知识限制我们对TED理解的一个缺口是自身抗体如何激活眼眶成纤维细胞中的IGF 1 R信号，促进眼部疾病。IGF 1 R可刺激增殖并增加肌成纤维细胞形成。的主要 TED中的抗原是促甲状腺激素受体（TSHR）。IGF 1 R如何与TSHR和TED相互作用自身抗体在疾病中的作用是一个基本的和未解决的问题。一个潜在的机制是通过芳香烃受体（AHR）。AHR是一种配体激活的转录因子，其结合合成和天然芳烃。AHR控制细胞生长、发育和免疫的各个方面。系统有证据表明，AHR阻断TSHR和IGF 1 R信号在体内和体外。但机制尚不清楚，AHR是否调节TED中的这些途径尚不清楚。一个最导致TED的重要危险因素是吸烟。吸烟会激活一种叫做缺氧的转录因子诱导因子1 α（HIF 1a）。AHR和HIF 1a竞争控制细胞命运。吸烟可能会破坏HIF 1a- AHR平衡，从而进一步增加IGF 1 R/TSHR信号传导。中心假设：AHR阻滞 IGF 1 R/TSHR信号传导和这种相互作用的丧失是TED病理生理学中的主要事件。目的 1：定义AHR阻断眼眶成纤维细胞活化的分子途径。目标2：确定香烟烟雾暴露在促进HIF 1a和IGF 1 R信号传导同时阻断眼眶AHR中的作用成纤维细胞目的3：评价AHR配体阻断TED自身抗体驱动的TSHR/IGF 1 R的能力发信号。影响：我们的研究结果将表明，AHR在TED中阻断TSHR和IGF 1 R信号传导。完成具体的目标是建立一个分子机制，吸烟加剧IGF 1 R/TSHR信号转导， Ted.此外，这些实验应该提供关键的证据，即激活AHR途径是一种新的，可行的治疗靶点