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.

家长补助金（R01 EY027785；资助期2/1/2018 - 1/31-2023）标题为“预防黄斑变性” 与 F3 错误折叠相关的病理生理学”。年龄相关性黄斑变性 (AMD) 是主要原因。 全世界工业化国家 60 岁以上人群出现不可逆转的失明。 据估计，到 2040 年，近 3 亿人将患有某种形式的 AMD。迄今为止，尚无有效的治疗方法 存在用于阻止干性 AMD 进展，这种形式影响了 90% 的 AMD 患者。 减缓这种疾病的方法是每天服用高剂量的维生素和矿物质补充剂。 表明 fibulin-3 (F3)（一种功能未知的分泌蛋白）的突变或改变在 一个具体的例子是 R345W 在影响黄斑变性疾病的发病机制中的作用。 F3 突变会导致早发性黄斑营养不良，称为 Malatia Leventinese (ML)，其特征是 通过补体激活和炎性细胞因子以及视网膜下色素上皮的产生 此外，F3 中的 D49A 突变与患者发生 AMD 相关。 然而，总的来说，人们对这些黄斑如何发生缺乏了解。 变性的发展以及它们如何受到 F3 的影响此外，还没有有效的治疗方法。 无论是针对 ML 还是更常见的疾病（干性 AMD），都迫切需要开发一种新的治疗方法。 从机制上了解 AMD 类疾病（例如 ML）的根本原因，并识别新的 为他们提供治疗。 本次家长资助中提出的研究将；i) 测试旨在防止错误折叠分泌的策略。 来自细胞的 F3 并评估其后果，ii) 采用一种新颖的、有条件的方法来调节 F3 错误折叠下游的炎症信号转导，以及 iii) 测试 WT F3 是否是亚 RPE 所必需的 最终，在完成这些研究后，我们希望能够更好地了解沉积物的形成。 错误折叠的 F3 促进炎症和亚 RPE 蛋白沉积的分子基础，并鉴定 我们获得了一些治疗 ML 的可治疗方法。 错误折叠的 F3 参与引发炎症，亚 RPE 沉积物可能更广泛地应用于 流行的视网膜疾病，例如干性 AMD。 该资助的目标 1 提出了这样的想法：F3 折叠和/或分泌的治疗定向调节可能 作为治疗 ML 和 F3 错误折叠引起的其他疾病的根本原因的一种方法。 专注于为更深入地了解 F3 突变如何导致 眼部疾病，如 AMD 和 ML，并操纵细胞质量控制机制来预防 F3- 相关疾病。