Smad3 inhibitors for ophthalmic applications

用于眼科应用的 Smad3 抑制剂

• 批准号: 7895549
• 负责人: Ching Yuan
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895549
• 关键词: Amyloid Fibrils; Animal Model; Biological Assay; Bromides; Bulla; Burn injury; Cataract; Cells; Characteristics; Chemicals; Clinical Trials; Collagen; Collagen Type I; Cornea; Corneal Stromal Dystrophy; Corneal dystrophy; Cytokeratin; Debridement; Deposition; Disease; Epithelial; Epithelial Cells; Evaluation; Extracellular Matrix Proteins; Eye; FDA approved; Fibroblasts; Fibronectins; Fibrosis; Gel; Gelatinase A; Genes; Goals; Halofuginone; Inflammation; Injury; Interstitial Collagenase; Keratoplasty; Laser In Situ Keratomileusis; Matrix Metalloproteinases; Mechanics; Mediating; Metalloproteases; Morphology; Myofibroblast; Northern Blotting; Operative Surgical Procedures; Oryctolagus cuniculus; Pathway interactions; Patients; Phosphorylation; Play; Process; Recurrence; Reporter; Research; Role; Scleroderma; Signal Transduction; Skin; Smad Proteins; Smad protein; Smooth Muscle Actin Staining Method; Solid Neoplasm; Strabismus; Stress Fibers; Testing; Tissues; Topical application; Toxic effect; Trabeculectomy; Transforming Growth Factor-Beta Induced Protein IGH3; Transplantation; Visual Acuity; Western Blotting; Wound Healing; angiogenesis; antiangiogenesis therapy; clinically significant; conjunctiva; dosage; effective therapy; epithelial to mesenchymal transition; gene therapy; inhibitor/antagonist; insight; lens; melanoma; neovascularization; ocular surface; orbit muscle; prevent; promoter; public health relevance; research study

DESCRIPTION (provided by applicant): Smad3 plays a central role in the TGF?-mediated fibrosis with characteristic inflammation, proliferation and transformation of fibroblasts and epithelial-to- mesenchymal transition. Gene therapy and small chemicals targeting Smad3 signaling have shown great potentials for the successful fibrosis management. One potent synthetic compound that effectively inhibits the phosphorylation of Smad3 has already been approved by FDA to treat scleroderma and skin fibrosis disorders. In addition, with their anti-angiogenesis effects mediated via Smad3 inhibition, Smad3 inhibitors have also been tested in clinical trial as a neovascularization-suppressing agent for treating solid tumors such as melanoma. Since ocular tissues are vulnerable to fibrosis and neovascularization which can compromise the visual acuity, Smad3 inhibitors present new opportunities for treating above mentioned disorders in the eye. In this proposal, we plan to test two commercially available Smad3 inhibitors for their inhibitory effects on fibrosis and neovascularization. Furthermore, our preliminary study revealed that Smad3 is the key regulator for the expression of keratoepithelin. Keratoepithelin aggregates and leads to the abnormal amyloid fibril/amorphous deposits in certain types of stromal corneal dystrophies. Smad3 inhibitors may serve as suppressors for keratoepithelin expression and delay or prevent the recurrence of the abnormal deposits in corneal dystrophy patients. We will first investigate the expression of collagens, matrix metalloproteinases and keratoepithelin under Smad3 inhibitor treatment on corneal explant cultures. The fibrosis and neovascularization by alkaline burn, mechanical debridement and trabeculectomy surgery will be conducted on rabbit cornea and conjunctiva for the evaluation of Smad3 inhibitors. In addition, the anti-fibrosis potency of Smad3 inhibitors on lens and extraocular muscle injuries mimicking cataract and strabismus surgeries will be investigated in rabbits as well. The insights gained from this study are clinically significant and will greatly facilitate developing an effective treatment for fibrosis and neovascularization in ocular tissues. PUBLIC HEALTH RELEVANCE: The goal of this research is to test the Smad3 inhibitors for potential ophthalmic applications to treat fibrosis, neovascularizaiton and KE-related corneal dystrophies. Expression of fibrosis- and angiogenesis-related genes will be analyzed biochemically and by immunostainings in corneal explant cultures and animal models. Our results will provide insights for developing new treatments for these ocular conditions.

描述（由申请人提供）：SMAD3在TGF？介导的纤维化中起着核心作用，具有特征性的炎症，成纤维细胞的增殖和转化以及上皮到间质转变。基因疗法和针对SMAD3信号传导的小型化学物质对成功的纤维化管理表现出了巨大的潜力。 FDA已经批准了一种有效抑制SMAD3磷酸化的有效合成化合物，用于治疗硬皮病和皮肤纤维化障碍。此外，由于其通过SMAD3抑制介导的抗血管生成作用，SMAD3抑制剂也已在临床试验中被测试，作为一种治疗黑色素瘤等实体瘤的新生血管抑制剂。由于眼组织容易受到可能损害视力的纤维化和新血管形成，因此SMAD3抑制剂为治疗上述疾病的新机会提供了新的机会。在此提案中，我们计划测试两个市售的SMAD3抑制剂对纤维化和新血管形成的抑制作用。此外，我们的初步研究表明，SMAD3是角膜上皮素表达的关键调节剂。角膜上皮蛋白聚集体并导致某些类型的基质角膜营养不良的异常淀粉样蛋白原纤维/非晶沉积物。 SMAD3抑制剂可以作为角膜上皮表达的抑制剂，并延迟或防止角膜营养不良患者异常沉积物的复发。我们将首先研究在角膜外植体中Smad3抑制剂治疗下胶原蛋白，基质金属蛋白酶和角膜上皮素的表达。碱性燃烧，机械清创和小梁切除术手术的纤维化和新血管形成将在兔角膜和结膜上进行评估SMAD3抑制剂。此外，还将在兔子中研究SMAD3抑制剂在镜头和眼外肌肉损伤上的抗纤维化效力。从这项研究中获得的见解具有临床意义，将极大地促进对眼组织中纤维化和新血管形成的有效治疗方法。公共卫生相关性：这项研究的目的是测试SMAD3抑制剂的潜在眼科应用，以治疗纤维化，Neovascularizaiton和与KE相关的角膜营养不良。纤维化和血管生成相关基因的表达将通过生物化学和角膜外植体培养物和动物模型中的免疫染色进行分析。我们的结果将为这些眼部疾病开发新疗法提供见解。