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）：芳基烃受体（AHR）是结合多种合成和天然化合物的配体激活转录因子。我们最近发现，用AHR配体治疗人轨道成纤维细胞不仅会损害TGFB驱动的肌纤维细胞的形成，而且还抑制了GPI锚定蛋白的表达，Thy1。这一发现很重要，因为人轨道成纤维细胞是异质的，并且可以根据其表面表达Thy1分为两个子集。表达Thy1（Thy1+）的轨道成纤维细胞具有形成肌纤维细胞的潜力，这与缺乏THY1的细胞不同。而且，活化的轨道成纤维细胞的转化以形成产生疤痕的肌纤维细胞，是甲状腺眼病（TED）的关键视力危险和无法治愈的病理特征。肌成纤维细胞产生过多的α-光滑肌肉肌动蛋白，胶原蛋白和透明质酸，导致僵硬的纤维化轨道。 TED发生在一半以上的坟墓疾病患者中。 TED中的慢性轨道炎症会导致广泛的组织重塑，导致疼痛，伴甚至失明。当前对TED的治疗方法，例如皮质类固醇，外束辐射和手术旨在旨在疾病的后果，而不是病因，并引起不必要的副作用，包括手术后发病率。我们的长期目标是了解TED的基本机制，从而导致基于机制的疗法。由于没有良好的TED动物模型，我们的翻译研究使用了原代人轨道成纤维细胞，可准确再现TED轨道中的事件。鉴定钝的肌纤维细胞是一种紧迫的需求，而AHR配体（例如ITE，FICZ）是一类有希望的小分子，用于TED。目标：建立治疗价值和基本机制，通过这些机制，AHR配体减弱了TED中的肌纤维细胞形成和细胞外基质的积累。我们还将发现AHR配体抑制Thy1表达的基本机制，并确定AHR配体的抗施加特性是否需要Thy1抑制。组织假设：AHR配体减弱了TED中人类轨道成肌纤维细胞的产生和结缔组织重塑。特定目标1：测试关键小分子AHR配体阻断人轨道成纤维细胞与肌纤维细胞分化的预测。特定目标2：确定AHR配体阻止人轨道成纤维细胞与肌纤维细胞分化的机制。特定目标3：研究AHR配体如何通过调节Thy1表达来介导轨道肌纤维细胞形成。意义：发现AHR配体在治疗TED方面具有治疗价值，这是一个重大进展，建立了新的候选药物和TED疗法的靶标。我们将确定THY1表达，肌纤维细胞形成和细胞外基质在TED中的积累的机制，并将这些知识转化为临床相关和创新的方法，以减轻甚至治愈轨道重塑和固定在TED中。