Prevention of macular pathophysiology associated with F3 misfolding

预防与 F3 错误折叠相关的黄斑病理生理学

• 批准号: 10334408
• 负责人: John Douglas Hulleman
• 金额: $ 40.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334408
• 关键词: Affect; Age related macular degeneration; Age-Years; American; Blindness; Cell Culture Techniques; Cells; Characteristics; Complement 3a; Complement Activation; Complex; Confocal Microscopy; Data; Deposition; Developed Countries; Disease; Dose; Drusen; Enzyme-Linked Immunosorbent Assay; Event; Extracellular Protein; Functional disorder; Future; Generations; Genetic; Genetic Engineering; Goals; Golgi Apparatus; Health Care Costs; High Fat Diet; Human; IL-6 inhibitor; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Interleukins; Intervention; KDEL receptor; Knowledge; Late-Onset Disorder; Lipids; Macular degeneration; Measures; Mediating; Minerals; Modeling; Molecular; Mus; Mutation; Nonexudative age-related macular degeneration; Onset of illness; Outcome; Pathogenesis; Pathology; Patients; Persons; Phenotype; Pigment Epithelium; Play; Prevention; Production; Proteins; Research; Retina; Retinal Diseases; Retrieval; Role; S1-5 protein; Scaffolding Protein; Signal Transduction; Suggestion; Testing; Therapeutic; Up-Regulation; Vacuole; Vision; Vitamins; aged; base; cigarette smoke; cytokine; early onset; effective therapy; extracellular; genetic approach; genetic testing; in vivo; in vivo Model; insight; knock-down; macula; macular dystrophy; mouse model; mutant; neutralizing antibody; novel; novel therapeutics; prevent; protein aggregation; protein misfolding; scaffold

ABSTRACT Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in people greater than 60 years of age in industrialized countries. Worldwide, it is estimated that nearly 300 million people will have some form of AMD by 2040. Thus far, no effective treatment exists for halting dry AMD progression, the form which affects 90% of all AMD patients. The only suggestion for slowing this form of AMD is to take high-dose vitamin and mineral supplements daily. Emerging evidence suggests that mutations or alterations in fibulin-3 (F3), a secreted protein of unknown function, plays a prominent role in influencing the pathogenesis of macular degenerative diseases. One specific example is how an R345W mutation in F3 causes an early onset macular dystrophy called Malattia Leventinese (ML), which is characterized by complement activation, production of inflammatory cytokines, as well as sub-retinal pigment epithelium (RPE) deposits. However, in general, there is a lack of knowledge regarding how these macular degenerations develop. Furthermore, there are no effective treatments for either ML or the more prevalent disease, dry AMD. Therefore, there is an urgent need to develop a mechanistic understanding of the underlying causes of AMD-like diseases, such as ML, and to identify new therapies for them. In this proposal we plan to i) test genetic strategies directed at preventing the secretion of misfolded R345W F3 from RPE cells, ii) employ a novel, conditional approach to regulate inflammatory signaling downstream of R345W F3 misfolding, and iii) test whether WT F3 is also necessary for sub-RPE deposit formation. At the end of the study, we hope to have a better understanding of the molecular basis by which misfolded F3-facilitates inflammation and sub-RPE protein deposition, and to identify a number of therapeutically- tractable approaches for treating ML. The insight that we gain regarding how misfolded F3 is involved in triggering inflammation and sub-RPE deposits can likely be applied more broadly to prevalent retinal diseases such as dry AMD.

摘要 视网膜相关性黄斑变性（AMD）是人类不可逆失明的主要原因 在工业化国家超过60岁。据估计，在全球范围内， 到2040年，将有3亿人患有某种形式的AMD。到目前为止，还没有有效的治疗方法。 用于阻止干性AMD进展，这种形式影响90%的所有AMD患者。唯一的 减缓这种形式AMD的建议是服用高剂量的维生素和矿物质补充剂 日报新出现的证据表明，纤蛋白-3（F3）的突变或改变， 一种功能未知的蛋白质，在影响黄斑变性的发病机制中起着重要作用。 退化性疾病一个具体的例子是F3中的R345 W突变如何引起早期的 称为Malattia Leventinese（ML）的发作性黄斑营养不良，其特征在于 补体激活、炎性细胞因子的产生以及视网膜下色素 上皮（RPE）沉积。然而，总的来说，缺乏关于如何 这些黄斑变性发展。此外，对于这两种疾病都没有有效的治疗方法。 ML或更普遍的疾病，干性AMD。因此，迫切需要制定一个 对AMD样疾病（如ML）的根本原因的机械理解， 为他们寻找新的治疗方法。在这项提案中，我们计划i）测试针对以下方面的遗传策略： 防止从RPE细胞分泌错误折叠的R345 W F3，ii）使用新的条件性的 调节R345 W F3错误折叠下游炎症信号传导的方法，和iii）测试 WT F3是否也是RPE下存款形成所必需的。在研究结束时，我们 我希望能更好地理解错误折叠的F3-促进的分子基础 炎症和RPE下蛋白沉积，并确定一些治疗方法- 治疗ML的可行方法。我们获得的关于F3错误折叠程度的见解 参与触发炎症和RPE下沉积物可能会更广泛地应用于 常见的视网膜疾病，如干性AMD。