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.

父母补助金（R 01 EY 027785;资助期2/1/2018 - 1/31-2023）的标题是“预防黄斑病变”。 与F3错误折叠相关的病理生理学”。视网膜相关性黄斑变性（AMD）是 在工业化国家，60岁以上的人患上不可逆转的失明。在世界范围内， 据估计，到2040年，将有近3亿人患有某种形式的AMD。到目前为止，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。唯一的建议是 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。新出现的证据 这表明，fibulin-3（F3）的突变或改变，一种功能未知的分泌蛋白， 在影响黄斑变性疾病发病机制中的作用。一个具体的例子是R345 W F3中的突变导致称为Malattia Leventinese（ML）的早发性黄斑营养不良，其特征在于 通过补体激活和炎性细胞因子的产生，以及视网膜下色素上皮 (RPE)存款此外，F3中的D49 A突变与患者中AMD的发展相关。 表皮玻璃疣然而，一般来说，缺乏关于这些黄斑病变如何发生的知识。 退化的发展以及它们如何受到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，并确定新的 治疗他们。 这项研究提出的父母补助金将：i）测试策略，旨在防止分泌错误折叠的 ii）采用一种新的、有条件的方法来调节 iii）测试WT F3对于亚RPE是否是必需的， 存款形成。最后，在完成这些研究后，我们希望能更好地了解 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 许多治疗ML的治疗方法。我们所获得的关于 错误折叠的F3参与触发炎症，并且RPE下沉积物可能更广泛地应用于 常见的视网膜疾病，例如干性AMD。 该授权的目的1提出了这样的想法，即F3折叠和/或分泌的治疗性定向调节可以 作为治疗ML和由F3错误折叠引起的其他疾病的根本原因的方法。DaNae将是 致力于为更深入地了解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，以防止F3- 相关疾病。