Treatment of BIGH3-related Corneal Dystrophies with Meptides

用肽治疗 BIGH3 相关角膜营养不良

• 批准号: 7176987
• 负责人: Ching Yuan
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176987
• 关键词: Adhesions; Alzheimer' s Disease; Amyloid; Amyloid Fibrils; Animal Model; Animals; Antibodies; Biological Assay; Biological Availability; Biotin; Cells; Cicatrix; Cornea; Corneal Diseases; Corneal Injury; Corneal Opacity; Corneal Stroma; Corneal dystrophy; Data; Delayed Hypersensitivity; Deposition; Disease; Electron Microscopy; Enzyme-Linked Immunosorbent Assay; Epithelial; Fluorescein; Fluorescein-5-isothiocyanate; Fluoresceins; Fluorescence; Foundations; Future; Gene Mutation; Genes; Human; Immune response; In Vitro; Inflammation; Inherited; Invasive; Keratoplasty; Kinetics; Knowledge; Label; Learning; Link; Mass Spectrum Analysis; Measures; Mediating; Methylation; Missense Mutation; Modification; Molecular Genetics; Morbidity - disease rate; Mus; Necrosis; Ocular Pathology; Organ Culture Techniques; Pain; Peptides; Phenotype; Proteins; Recombinant Proteins; Recurrence; Research Personnel; Simulate; System; TGFBI gene; Testing; Therapeutic; Therapeutic Effect; Thioflavin T; Tissues; Toxic effect; Transforming Growth Factor-Beta Induced Protein IGH3; Vertebral column; Wound Healing; amino group; amyloid fibril formation; amyloid formation; concept; corneal epithelium; cytotoxicity; dosage; genetic analysis; mutant; novel; prevent; programs; protein aggregation; protein misfolding; resazurin; research study; size; success; synthetic peptide

DESCRIPTION: BIGH3-related corneal dystrophies are a group of potentially blinding inherited corneal disorders that have been attributed to more than 30 missense mutations of BIGH3 gene in 5q3l of humans. These dystrophies are characterized by stromal amyloid and/or non-amyloid deposits, and painful recurrent corneal erosions due to poor epithelial adhesions. Corneal transplantation or phototherapeutic keratectomy (PTK) is often needed to remove corneal opacities and scars. These therapeutic options offer only temporary relief and cannot prevent recurrences, thereby necessitating other non-invasive yet effective, alternative treatments In this proposal, we intend to employ novel synthetic peptides, known as Meptides (N-methylated peptide), to prevent the abnormal amyloid fibril aggregations in BIGHS-related corneal dystrophies. The therapeutic potential of meptides has been demonstrated in Alzheimer's disease. Meptides with their relatively small size and sequence-specific inhibition of amyloidogenic region offer greater advantages over other therapeutic options such as amyloid-specific antibody or nonspecific amyloid-interfering compounds. We have identified and synthesized two meptides specifically targeting one of the amyloidogenic regions of BIGH3. Our preliminary studies with Thioflavin T fluorescence assay and electron microscopy demonstrated that these meptides successfully suppressed amyloid fibril formation in vitro. We will further modify the compositions of meptides for optimal inhibition of amyloid aggregations and investigate their bioavailability, potential toxicities and immune response in corneal tissues with cultured corneal cells, organ cultures and animal models. The knowledge thus learned from meptide-mediated perturbation of protein aggregations should facilitate further understanding of the abnormal protein aggregations in BIGHS-related corneal dystrophies and serve as a foundation for developing future therapies for BIGHS-related corneal dystrophies and other conformational diseases related to protein misfolding.

描述：BIGH3相关的角膜营养不良是一群潜在的遗传性角膜疾病，归因于5q3l人类中的Bigh3基因的30多个错义突变。这些营养不良的特征是基质淀粉样蛋白和/或非淀粉样蛋白沉积物，以及由于上皮粘附不良而引起的疼痛复发性角膜侵蚀。通常需要角膜移植或光质角膜切除术（PTK）来清除角膜泥泞和疤痕。这些治疗方法仅提供暂时的缓解，无法防止复发，从而在该提案中需要其他无侵袭性但有效的替代治疗方法，我们打算采用新型的合成肽，即称为Meptides（N-甲基化肽），以防止异常淀粉样纤维纤维聚集在Bighs-Cornelected Cornelected Cornealelected Corneal rystrophies中。在阿尔茨海默氏病中已经证明了米普蒂德斯的治疗潜力。其大小相对较小和序列特异性抑制淀粉样区的MEPTIDES比其他治疗选择具有更大的优势，例如淀粉样蛋白特异性抗体或非特异性淀粉样蛋白互换化合物。 我们已经确定并合成了两个特异性针对Bigh3淀粉样蛋白生成区之一的MEPTIDE。我们对硫非类T荧光测定法和电子显微镜的初步研究表明，这些MEPTIDE在体外成功抑制了淀粉样蛋白纤维形成。我们将进一步修改MEPTIDES的组成，以最佳地抑制淀粉样蛋白聚集，并研究其生物利用度，潜在毒性和具有培养的角膜细胞，器官培养和动物模型的角膜组织中的生物利用度，潜在的毒性和免疫反应。因此，从Meptide介导的蛋白质聚集的扰动中学到的知识应有助于进一步理解与Bighs相关的角膜营养不良中的异常蛋白质聚集，并为发展与蛋白质失误相关的与Bighs相关的构象疾病的未来治疗提供基础。