Aryl Hydrocarbon Receptor Ligands and Thyroid Eye Disease

芳基烃受体配体与甲状腺眼病

• 批准号: 9053494
• 负责人: RICHARD P. PHIPPS
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053494
• 关键词: Adherence; Adipocytes; Adrenal Cortex Hormones; Adverse effects; Affect; Animal Model; Antibodies; Aryl Hydrocarbon Receptor; Attenuated; Autoimmune Diseases; Binding; Blindness; C-terminal; Carboxylic Acids; Cell physiology; Cells; Chronic; Cicatrix; Collagen; Complement; Connective Tissue; Data; Diplopia; Disease; Dominant Negative Receptor; Drug Targeting; Effector Cell; Esters; Etiology; Event; Evidence based treatment; Exophthalmos; External Beam Radiation Therapy; Extracellular Matrix; Eye; Family; Fibroblasts; Foundations; Goals; Graves' Disease; Health; Human; Hyaluronan; Immune; In Vitro; Individual; Indoles; Inflammation; Inflammatory; Knowledge; Ligands; Measures; Mediating; Molecular Chaperones; Morbidity - disease rate; Myofibroblast; Ocular orbit; Operative Surgical Procedures; Pain; Patients; Phosphorylation; Plasmids; Production; Property; Proteins; Radiation; Radiosurgery; Repression; Research Project Grants; Signal Transduction; Small Interfering RNA; Smooth Muscle Actin Staining Method; Subfamily lentivirinae; Surface; System; T-Lymphocyte; Testing; Therapeutic; Thiazoles; Thyrotropin Receptor; Tissues; Transforming Growth Factor beta; Translating; Vision; activating transcription factor; aryl hydrocarbon receptor ligand; base; cellular targeting; clinically relevant; genetic approach; innovation; interstitial; novel therapeutics; pressure; small molecule; thyroid associated ophthalmopathies; transcription factor; translational study

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that binds diverse synthetic and natural compounds. We recently discovered that treating human orbital fibroblasts with AhR ligands not only impairs TGFb-driven myofibroblast formation, but also inhibits expression of the GPI-anchored protein, Thy1. This finding is important because human orbital fibroblasts are heterogeneous and can be divided into two subsets based on their surface expression of Thy1. Orbital fibroblasts expressing Thy1 (Thy1+) have the potential to form myofibroblasts, unlike cells lacking Thy1. And, the conversion of activated orbital fibroblasts to form scar-producing myofibroblasts is a key sight-threatening and incurable pathological feature of Thyroid Eye Disease (TED). Myofibroblasts produce excessive amounts of alpha-smooth muscle actin, collagen and hyaluronan leading to a stiff, fibrotic orbit. TED occurs in more than half of patients with Graves' Disease. Chronic orbital inflammation in TED leads to extensive tissue remodeling causing pain, proptosis, and even blindness. Current treatments for TED such as corticosteroids, external beam radiation and surgery are aimed at the consequences of disease, rather than the etiology, and cause unwanted side effects including post-surgical morbidity. Our long-term goal is to understand the mechanisms underlying TED leading to mechanism-based therapies. As there is no good animal model of TED, our translational studies use primary human orbital fibroblasts that accurately reproduce the events in the TED orbit. Identification of molecules that blunt TED myofibroblasts is a pressing need, and AhR ligands (e.g. ITE, FICZ) are a promising class of small molecules for potential use in TED. Goals: Establish the therapeutic value and the fundamental mechanisms whereby AhR ligands attenuate myofibroblast formation and extracellular matrix accumulation in TED. We will also discover the underlying mechanisms whereby AhR ligands repress Thy1 expression and determine if Thy1 repression is required for the anti-scarring properties of AhR ligands. Organizing Hypothesis: AhR ligands attenuate human orbital myofibroblast production and connective tissue remodeling in TED. Specific Aim 1: Test the prediction that key small molecule AhR ligands block human orbital fibroblast-to-myofibroblast differentiation. Specific Aim 2: Determine the mechanisms whereby AhR ligands block human orbital fibroblast-to-myofibroblast differentiation. Specific Aim 3: Investigate how AhR ligands mediate orbital myofibroblast formation by regulating Thy1 expression. Significance: Discovering that AhR ligands have therapeutic value in treating TED is a major advance, establishing new candidate drugs and targets for TED therapies. We will identify the mechanisms underlying Thy1 expression, myofibroblast formation and extracellular matrix accumulation in TED, and translate this knowledge into clinically relevant and innovative approaches to attenuate or even cure orbital remodeling and scarring in TED.

描述（由申请人提供）：芳烃受体（AhR）是一种配体激活的转录因子，可结合多种合成和天然化合物。我们最近发现，用 AhR 配体处理人眼眶成纤维细胞不仅会损害 TGFb 驱动的肌成纤维细胞形成，而且还会抑制 GPI 锚定蛋白 Thy1 的表达。这一发现很重要，因为人类眼眶成纤维细胞具有异质性，可以根据 Thy1 的表面表达分为两个亚群。与缺乏 Thy1 的细胞不同，表达 Thy1 (Thy1+) 的眼眶成纤维细胞有可能形成肌成纤维细胞。而且，激活的眼眶成纤维细胞转化为产生疤痕的肌成纤维细胞是甲状腺眼病（TED）威胁视力且无法治愈的关键病理特征。肌成纤维细胞产生过量的α-平滑肌肌动蛋白、胶原蛋白和透明质酸，导致眼眶僵硬、纤维化。超过一半的格雷夫斯病患者会出现 TED。 TED 中的慢性眼眶炎症会导致广泛的组织重塑，导致疼痛、眼球突出，甚至失明。目前的 TED 治疗方法，如皮质类固醇、外照射和手术，都是针对疾病的后果，而不是病因，并会导致不良副作用，包括术后发病率。我们的长期目标是了解 TED 的潜在机制，从而实现基于机制的治疗。由于没有好的 TED 动物模型，我们的转化研究使用原代人眼眶成纤维细胞来准确重现 TED 轨道中的事件。迫切需要鉴定能够钝化 TED 肌成纤维细胞的分子，而 AhR 配体（例如 ITE、FICZ）是一类有望用于 TED 的小分子。目标：确定 AhR 配体在 TED 中减弱肌成纤维细胞形成和细胞外基质积累的治疗价值和基本机制。我们还将发现 AhR 配体抑制 Thy1 表达的潜在机制，并确定 AhR 配体的抗疤痕特性是否需要 Thy1 抑制。组织假设：AhR 配体减弱 TED 中人眼眶肌成纤维细胞的产生和结缔组织重塑。具体目标 1：测试关键小分子 AhR 配体阻断人眼眶成纤维细胞向肌成纤维细胞分化的预测。具体目标 2：确定 AhR 配体阻止人眼眶成纤维细胞向肌成纤维细胞分化的机制。具体目标 3：研究 AhR 配体如何通过调节 Thy1 表达来介导眼眶肌成纤维细胞形成。意义：发现 AhR 配体在治疗 TED 中具有治疗价值是一项重大进展，为 TED 疗法建立了新的候选药物和靶点。我们将确定 TED 中 Thy1 表达、肌成纤维细胞形成和细胞外基质积累的机制，并将这些知识转化为临床相关的创新方法，以减轻甚至治愈 TED 中的眼眶重塑和疤痕形成。