Regulation of Retroocular Connective Tissue

眼后结缔组织的调节

• 批准号: 8716758
• 负责人: TERRY J SMITH
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716758
• 关键词: Accounting; Address; Anatomic Sites; Antibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bone Marrow; Build-it; CD34 gene; CXCL12 gene; CXCR4 gene; Cells; Clinical Trials; Connective Tissue; Deposition; Disease; Disease model; Drug Targeting; Enzymes; Exhibits; Eye; Family; Fibroblasts; Fibrosis; Funding; Generations; Glycosaminoglycans; Hematopoietic stem cells; Human; Hyaluronan; IL8 gene; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-6; Mediating; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Mus; Normal tissue morphology; Ocular orbit; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Population; Process; Production; Protein Isoforms; Recruitment Activity; Regulation; Role; Site; Syndrome; T-Lymphocyte; TNF gene; Testing; Thyroid Gland; Thyroid stimulating immunoglobulins; Thyrotropin Receptor; Tissue Expansion; Tissues; Translating; Vision; Work; base; chemokine; chemokine receptor; cytokine; design; effective therapy; hyaluronan synthase 1; in vitro testing; insight; knock-down; novel; response; retroocular; therapeutic target; thyroid associated ophthalmopathies; trafficking; translational study

DESCRIPTION (provided by applicant): The overall objective of this proposal is to understand the role of orbital fibroblasts in the pathogenesis of thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves' disease (GD). In its most severe forms, TAO can threaten sight. There are currently no specific and effective therapies for TAO. Thus devising new treatments for TAO represents an important unmet need. Central components of TAO are localized inflammation and abnormal deposition of hyaluronan (HA). Cytokines produced by infiltrating T cells and orbital fibroblasts are thought to drive the pathogenesis of TAO. HA is synthesized by a family of three hyaluronan synthase (HAS) isoforms. Short chain HA, a product of multiple HAS isoforms, is highly inflammatory. CD34+ fibrocytes are circulating bone marrow derived hematopoietic stem cells. They express the chemokine receptor, CXCR4 and migrate to tissue injury in response to CXCL12. We have found that TAO orbital tissue comprises two discrete cell populations, including CD34+ and CD34- fibroblasts. Moreover, fibrocytes are recruited uniquely to the TAO orbit where they appear to give rise to CD34+ fibroblasts. In contrast, healthy orbital tissue contains only CD34- fibroblasts. Unexpectedly we found that fibrocytes and orbit-infiltrating CD34+ fibroblasts express thyrotropin receptor (TSHR), the central autoantigen in GD. When activated by GD-specific thyroid stimulating immunoglobulins (TSI) or with TSH, fibrocytes express high levels of inflammatory cytokines that are implicated in the pathogenesis of TAO. We have generated a new conceptual model of TAO based on two testable hypotheses. Hypothesis 1: recruitment of fibrocytes to the TAO orbit accounts for the two divergent populations of CD34+ and CD34- fibroblasts. CD34+ fibroblasts derive from fibrocyte precursors. They express TSHR and respond to TSH and TSI, accounting for the cytokines that drive TAO. On the other hand, CD34- fibroblasts over-express CXCL12 in TAO and thus orchestrate CD34+ fibrocyte recruitment to the orbit. Hypothesis 2: TAO orbit-infiltrating CD34+ fibroblasts uniquely express HAS1 enzyme and produce excessive highly inflammatory short-chain HA. To test these hypotheses, we now propose the following specific aims. Specific Aim 1: determine the mechanisms underlying TSHR-mediated cytokine production in fibrocytes and in orbit-infiltrating CD34+ fibroblasts and determine the mechanism for CXCL12 over-expression in TAO orbital tissue that may underlie fibrocyte recruitment. Specific Aim 2: define the mechanisms involved in the unique anatomic-site and disease-specific expression and induction by IL-1¿ of HAS1 and the production of short-chain HA by TAO orbital fibroblasts. Our results, we believe, support a new and potentially paradigm-shifting model for TAO. The proposed studies represent logical extensions of our preliminary findings. They should directly impact the field of TAO by defining potentially attractive therapeutic targets which can be tested in vitro and can be translated into clinical trials involving patients with this vexing disease.

描述（由申请人提供）：本提案的总体目标是了解眼眶成纤维细胞在甲状腺相关眼病（TAO）发病机制中的作用，甲状腺相关眼病是格雷夫斯病（GD）最严重形式的眼部表现。 TAO 会威胁视力。目前尚无针对 TAO 的特异性和有效疗法，因此，针对 TAO 设计新的治疗方法代表了未满足的重要需求。透明质酸 (HA) 被认为是由浸润性 T 细胞和眼眶成纤维细胞产生的细胞因子，由三个透明质酸合酶 (HAS) 亚型家族合成，是多种 HAS 亚型的产物。 CD34+ 纤维细胞是循环骨髓来源的造血干细胞，它们表达趋化因子受体。 CXCR4 并响应 CXCL12 迁移到组织损伤中。我们发现 TAO 眼眶组织包含两个离散的细胞群，包括 CD34+ 和 CD34- 成纤维细胞。相反，健康的眼眶组织仅含有 CD34- 成纤维细胞，我们意外地发现纤维细胞和眼眶浸润细胞。 CD34+ 成纤维细胞表达促甲状腺素受体 (TSHR)，这是 GD 中的中心自身抗原。当被 GD 特异性促甲状腺免疫球蛋白 (TSI) 或 TSH 激活时，纤维细胞会表达高水平的炎症细胞因子，这些细胞因子与 TAO 的发病机制有关。基于两个可检验假设 1 的新 TAO 概念模型：将纤维细胞募集到 TAO 轨道可解释两个不同的群体。 CD34+ 和 CD34- 成纤维细胞源自纤维细胞前体，它们表达 TSHR 并响应 TSH 和 TSI，从而驱动 TAO。另一方面，CD34- 成纤维细胞在 TAO 中过度表达 CXCL12，从而协调 CD34+。假设 2：TAO 眼眶浸润 CD34+成纤维细胞独特地表达 HAS1 酶并产生过量的高炎症性短链 HA。为了检验这些假设，我们现在提出以下具体目标 1：确定纤维细胞和眼眶浸润 CD34+ 成纤维细胞中 TSHR 介导的细胞因子产生的机制。并确定 TAO 眼眶组织中 CXCL12 过度表达的机制，该机制可能是纤维细胞募集的基础。 具体目标 2：定义独特的机制。 IL-1 的解剖部位和疾病特异性表达和诱导¿我们相信，我们的研究结果支持了 TAO 的新的、潜在的范式转变模型，它们代表了我们初步研究结果的逻辑扩展，它们应该直接影响该领域。通过定义潜在有吸引力的治疗靶点，可以对 TAO 进行研究，这些靶点可以在体外进行测试，并可以转化为涉及患有这种令人烦恼的疾病的患者的临床试验。