Biomolecular Analysis of Proteins in Visual Diseases

视觉疾病中蛋白质的生物分子分析

• 批准号: 8626867
• 负责人: ESTHER Elissa BISWAS-FISS
• 金额: $ 26.18万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2016-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626867
• 关键词: 11 cis Retinal; 220kDa rod outer segment rim protein; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Affect; Affinity; Alleles; Attenuated; Binding; Biochemical; Blindness; Cell Death; Cell Line; Clinical; Complement; Data; Development; Diagnosis; Disease; Functional disorder; Funding; Future; Genes; Genetic; Genetic Heterogeneity; Genotype; Goals; In Vitro; Indium; Individual; Isomerism; Knowledge; Laboratories; Lead; Length; Ligand Binding; Lipofuscin; Macular degeneration; Mammalian Cell; Membrane; Missense Mutation; Molecular; Mus; Mutation; Nucleotides; Open Reading Frames; Pathology; Patients; Phenotype; Photoreceptors; Physiological; Play; Property; Protein Analysis; Protein Conformation; Proteins; Public Health; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinitis Pigmentosa; Retinoids; Role; Severities; Specificity; Stargardt' s disease; Structure; Testing; Therapeutic; United States; Vision; Visual; Visual impairment; aging population; attenuation; base; clinical Diagnosis; clinical phenotype; cohort; cytotoxic; in vivo; mutant; outcome forecast; polypeptide; public health relevance; reconstitution; retinal rods; small molecule; stem cell therapy

PROJECT SUMMARY/ABSTRACT The ABCA4 gene is associated with a broad range of autosomal recessive retinal degenerations including Stargardt disease (STGD1), cone rod dystrophy (arCRD), retinitis pigmentosa (arRP) and fundus flavimaculatus (FFM). Disease-associated ABCA4 alleles show an extraordinary genetic heterogeneity, numbering over 700 mutations, and are found throughout the entire open reading frame. The wide spectrum of phenotypes and the corresponding dysfunctions of ABCA4 protein due to disease associated mutation(s) remains poorly understood. ABCA4 encodes a retina specific ATP binding cassette (ABC) transporter which is localized to the rod and cone photoreceptor outer segments discs. Defective ABCA4 transport of retinoids appears to contribute to the accumulation of cytotoxic lipofuscin ultimately leading to photoreceptor cell death and loss of central vision. Recent studies have suggested that ABCA4 may play a role in the translocation of 11-cis-, as well as, all-trans- retinal, adding to the complexity of this protein's mechanism of action. Currently, there are no therapeutics (small molecules or biologics) that target ABCA4, although gene and perhaps stem cell therapy hold great promise for some individuals. Molecular testing of ABCA4 is increasingly common in clinical diagnosis, yet biochemical and physiological correlations have not been made between the consequences of a given mutation in ABCA4 and the clinical development, progression and spectrum of retinal degenerations - limiting our ability to inform patients early in their diagnosis. The studies in this proposal seek to bridge the knowledge obtained from clinical genetics with the biochemical consequences of mutations in ABCA4 gene which influence macular degeneration so that more accurate prognoses and more targeted therapies may be developed in the near future.

项目摘要/摘要 ABCA4基因与多种常染色体隐性遗传性视网膜变性有关，包括 Stargardt病(STGD1)、视锥视杆细胞营养不良(ArCRD)、视网膜色素变性(ArRP)和眼底 黄斑天牛(FFM)与疾病相关的ABCA4等位基因表现出非凡的遗传异质性， 超过700个突变，并在整个开放阅读框架中发现。广谱的 疾病相关突变引起的ABCA4蛋白表型及相应功能障碍(S) 人们对此仍然知之甚少。 ABCA4编码视网膜特异性三磷酸腺苷结合盒(ABC)转运蛋白，定位于视杆细胞和视锥细胞 感光器外部节段的视盘。维甲酸的ABCA4转运缺陷似乎是导致 细胞毒性脂褐素的积聚最终导致感光细胞死亡和中央视力丧失。 最近的研究表明，ABCA4可能在11-顺式和全反式-11的易位中发挥作用。 视网膜，增加了这种蛋白质作用机制的复杂性。目前，还没有治疗方法 (小分子或生物制品)靶向ABCA4，尽管基因治疗和干细胞治疗效果很好 对某些人的承诺。ABCA4的分子检测在临床诊断中越来越常见，但 一种特定突变的后果之间还没有建立起生化和生理上的联系 ABCA4和视网膜退行性变的临床发展、进展和谱系-限制我们的 能够在诊断早期告知患者。这项建议中的研究试图在知识之间架起桥梁 从临床遗传学获得，具有ABCA4基因突变的生化后果 影响黄斑变性，以便更准确的预后和更有针对性的治疗 在不久的将来发展起来的。