Supplement to Promote Diversity in Health-Related Research - Prevention of macular pathophysiology...Parent Grant

促进健康相关研究多样性的补充 - 预防黄斑病理生理学......家长补助金

• 批准号: 10164525
• 负责人: John Douglas Hulleman
• 金额: $ 4.39万
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164525
• 关键词: Address; Affect; Age related macular degeneration; Age-Years; Blindness; Cells; Complement Activation; Deposition; Developed Countries; Development; Disease; Dose; Drusen; Functional disorder; Funding; Grant; Health; Inflammation; Inflammatory; Knowledge; Lead; Macular degeneration; Minerals; Molecular; Mutation; Nonexudative age-related macular degeneration; Pathogenesis; Patients; Pigment Epithelium; Play; Prevention; Prevention Research; Production; Proteins; Quality Control; Regulation; Research; Retinal Diseases; Role; S1-5 protein; Signal Transduction; Suggestion; Testing; Therapeutic; Vitamins; cytokine; early onset; effective therapy; insight; macula; macular dystrophy; novel; novel therapeutics; parent grant; prevent

The parent grant (R01 EY027785; funding period 2/1/2018 - 1/31-2023) is titled “Prevention of Macular Pathophysiology Associated with F3 Misfolding”. 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 the disease 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 and production of inflammatory cytokines, as well as sub-retinal pigment epithelium (RPE) deposits. Furthermore, a D49A mutation in F3 has been associated with development of AMD in patients with cuticular drusen. In general however, there is a lack of knowledge regarding how these macular degenerations develop and how they might be influenced by F3. 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. The research proposed in this parent grant will; i) test strategies directed at preventing the secretion of misfolded F3 from cells and evaluate the consequences thereof, ii) employ a novel, conditional approach to regulate inflammatory signaling downstream of F3 misfolding, and iii) test whether WT F3 is necessary for sub-RPE deposit formation. Ultimately, at completion of these studies, 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. Aim 1 of the grant addresses the idea that therapeutically directed regulation of F3 folding and/or secretion may serve as a way to treat the underlying cause of ML and other diseases caused by F3 misfolding. DaNae will be focused on making contributions towards developing a deeper understanding of how mutations in F3 lead to ocular disease, such as AMD and ML, and manipulating cellular quality control mechanisms to prevent F3- associated disease.

父母赠款（R01 EY027785； 2/1/2018-1/31-2023）的标题为“预防黄斑 与F3错误折叠相关的病理生理学”。与年龄相关的黄斑变性（AMD）是主要原因 工业化国家大于60岁的人的不可逆转的失明。在世界范围内 据估计，到2040年，将近3亿人将拥有某种形式的AMD。 存在停止干燥AMD进展的情况，这种形式影响了所有AMD患者的90％。唯一的建议 减慢这种疾病的形式是每天服用高剂量的维生素和矿物质补充剂。新兴证据 表明Fibulin-3（F3）的突变或变化是一种未知功能的分泌蛋白 在影响黄斑退行性疾病的发病机理中的作用。一个具体的例子是R345W F3中的突变导致早期发作的黄斑营养不良，称为Malattia Leventinese（ML），其特征是 通过完成激活和产生炎症细胞因子以及下属色素上皮 （RPE）沉积物。此外，F3中的D49A突变与患者的AMD发展有关 与可爱的drusen。但是，总的来说，缺乏关于这些黄斑如何的知识 退化的发展及其如何受F3的影响。此外，没有有效的治疗方法 对于ML或更普遍的疾病，干燥AMD。因此，迫切需要开发 对AMD样疾病（例如ML）的基本原因的机械理解，并确定新的原因 他们的疗法。 这项父母赠款提出的研究将； i）旨在防止分泌错误的测试策略 来自细胞的F3并评估其后果，ii）员工一种新型的条件方法来调节 F3错误折叠的下游炎症信号传导，iii）测试WT F3是否需要sub-rpe 存款形成。最终，完成这些研究后，我们希望对 分子基础错误折叠的F3栖息地注射和亚RPE蛋白沉积，并确定 许多可用于治疗ML的历史可获得的方法。我们对如何获得的见解 错误折叠的F3参与触发注入，并可能更广泛地应用子RPE沉积物 普遍的残留疾病，例如干燥AMD。 赠款的目的1解决了以下想法：F3折叠和/或分泌的热定向调节 作为治疗ML和其他因F3错误折叠引起的其他疾病的根本原因的方式。达纳会 专注于为更深入地了解F3中的突变如何导致 眼部疾病，例如AMD和ML，以及操纵细胞质量控制机制，以防止F3- 相关疾病。