Vasculogenesis in Thyroid Eye Disease

甲状腺眼病的血管发生

• 批准号: 9360548
• 负责人: LEO A KIM
• 金额: $ 24.63万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360548
• 关键词: Acute; Affect; Alternative Therapies; Area; Autoimmune Process; Blindness; Blood; Blood Vessels; Chronic; Clinical; Cornea; Data; Deposition; Diplopia; Edema; Environment; Etiology; Exhibits; Exophthalmos; Extravasation; Eye; Eyelid structure; Fatty acid glycerol esters; Graves' Disease; Human; Immune system; Incidence; Infection; Inflammation; Inflammatory; Intercellular Fluid; Knowledge; Laboratories; Lead; Light; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic vessel; Mediator of activation protein; Modeling; Molecular; Mus; Muscle; Ocular orbit; Optic Nerve; Oxazolone; Pathology; Patients; Phenotype; Physicians; Play; Production; Regulation; Reporting; Research; Rest; Role; Secondary to; Site; Specimen; Steroids; Surgical Decompression; Swelling; Testing; Thyroid Gland; Thyroid Hormones; Tissues; Vision; Woman; angiogenesis; base; bevacizumab; blood vessel development; bone; improved; lipid biosynthesis; men; mouse model; novel; orbit muscle; standard care; systemic autoimmune disease; thyroid associated ophthalmopathies; vasculogenesis

Vasculogenesis in Thyroid Eye Disease PROJECT SUMMARY In Graves disease, the body's immune system attacks the thyroid gland, causing abnormal levels of thyroid hormone production. For reasons that are unknown, one of the primary sites of the pathology that occurs in Graves disease is the orbit, including the muscles that move the eyes and the orbital fat. Additionally, the inflammation associated with this condition leads to extraocular muscle enlargement and adipogenesis, which results in proptosis and eyelid edema. Graves eye disease, also called thyroid eye disease (TED), is a potentially sight-threatening condition in which approximately 10-20 percent of patients with this systemic autoimmune disorder will develop severe inflammation in the eye sockets that can lead to disabling double vision or irreversible vision loss. Currently, there are no specific treatments for TED beyond steroids and/or surgical decompression of the orbits, which involves breaking of the bones surrounding the orbit. To date, research has centered on identifying what makes the orbit a unique, vulnerable environment for this systemic condition, as other areas in the body with fat deposits fail to exhibit similar inflammatory changes. Previous studies suggest that under normal conditions, orbital tissues have blood vessels, but there is an absence of lymphatic vessels within the orbital fat surrounding the eye. In contrast, other fat deposits within the body contain both blood and lymphatic vessels. Based on this, we hypothesize that the orbital inflammation and edema that occurs in TED may be caused by the inability to drain fluid from the interstitial space, as there are no lymphatic vessels within the orbital tissue. While TED is most often characterized by chronic inflammation, episodes of acute inflammation that may be vision threatening can occur. Preliminary data from our laboratory demonstrates that blood vessel proliferation and new lymphatic channel formation occurs within the orbit during the acute inflammatory episodes in TED. Thus, we believe that regulation of blood and lymphatic vessel formation within the orbit could ameliorate the effects of acute orbital inflammation. To test this, we propose to determine the novel molecular mechanisms underlying the formation of blood and lymphatic vessels within the human orbit (Aim 1) and to investigate whether the regulation of new blood vessel formation and/or promotion of lymphangiogensis can reduce the orbital edema phenotype observed in an oxazolone mouse model of acute orbital inflammation developed in our laboratory (Aim 2). At the conclusion of these studies, we will have expanded our knowledge of the molecular mechanisms underlying vasculogenesis within the orbit by identifying potential targets responsible for the regulation of orbital vasculogenesis. It is hoped that the identification of these novel targets could lead to alternative therapies for the treatment of the acute inflammation that occurs in TED.

甲状腺眼病的血管发生 项目摘要 在格雷夫斯病中，身体的免疫系统攻击甲状腺，导致甲状腺激素水平异常。 荷尔蒙分泌由于未知的原因，发生在心脏病患者中的病理学的主要部位之一， 格雷夫斯病是眼眶，包括移动眼睛的肌肉和眼眶脂肪。另夕h 与这种疾病相关的炎症导致眼外肌增大和脂肪形成， 导致眼球突出和眼睑水肿。Graves眼病，也称为甲状腺眼病（TED），是一种 潜在的视力威胁状况，其中大约10- 20%的全身性患者 自身免疫性疾病会在眼窝中产生严重的炎症， 视力或不可逆的视力丧失。目前，除了类固醇和/或类固醇外，还没有针对TED的特定治疗方法。 眼眶减压手术，包括眼眶周围骨头的断裂。到目前为止， 研究的重点是确定是什么使轨道成为一个独特的，脆弱的环境，为这个系统 这种情况下，因为身体其他部位的脂肪沉积未能表现出类似的炎症变化。先前 研究表明，在正常情况下，眼眶组织有血管，但没有血管。 眼睛周围的眶脂肪内的淋巴管。相反，体内的其他脂肪沉积 同时含有血管和淋巴管。基于此，我们假设眼眶炎症和 在TED中发生的水肿可能是由于不能从间质空间排出液体引起的，因为存在 眼眶组织内没有淋巴管虽然TED最常见的特征是慢性炎症， 可能发生威胁视力的急性炎症发作。我们实验室的初步数据 表明血管增生和新的淋巴管形成发生在眼眶内 在TED的急性炎症发作期间。因此，我们认为，血液和淋巴管的调节 眶内成形术可减轻急性眶炎的影响。为了验证这一点，我们建议 确定血管和淋巴管形成的新分子机制， 人类眼眶（目的1），并研究是否调节新血管的形成和/或促进 的淋巴管生成可以减少在恶唑酮小鼠模型中观察到的眼眶水肿表型。 急性眼眶炎症在我们的实验室发展（目的2）。在这些研究结束时，我们将拥有 扩大了我们对眼眶内血管发生的分子机制的认识， 确定负责调节眼眶血管发生的潜在靶点。希望广大 这些新靶点的鉴定可能导致治疗急性 TED中发生的炎症