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

家长基金(R01 EY027785；资助期2018年2月1日-2018年1月31日-2023年1月31日)题为“黄斑预防” 与F3错误折叠有关的病理生理学“。老年性黄斑变性(AMD)是主要原因 在工业化国家，60岁以上人群的失明是不可逆转的。在世界范围内，它是 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，还没有有效的治疗方法 存在阻止干性AMD进展的方法，这种形式影响了90%的AMD患者。唯一的建议是 减缓这种形式的疾病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 提示纤维蛋白-3(F3)的突变或改变，一种功能未知的分泌蛋白，在 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R345W如何 F3基因突变会导致早发性黄斑营养不良症，称为马拉提氏症(ML)，其特征是 通过激活补体和产生炎症细胞因子，以及视网膜下色素上皮 (RPE)存款。此外，F3中的d49a突变与患者AMD的发生有关。 有角质软骨膜。然而，总的来说，缺乏关于这些黄斑是如何形成的知识 退化的发展以及他们可能如何受到F3的影响。此外，目前还没有有效的治疗方法 对于ML或更流行的疾病，干性AMD。因此，迫切需要开发一种 从机制上理解类似AMD的疾病的根本原因，如ML，并确定新的 为他们提供治疗。 在这项父母拨款中提出的研究将：i)测试旨在防止错误折叠分泌的策略 F3并评估其后果，ii)使用一种新的、有条件的方法来调节 F3错误折叠下游的炎症信号，以及III)检测WT F3是否是亚RPE所必需的 成矿作用。最终，当这些研究完成后，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 一些治疗上容易处理的方法治疗ML。我们所获得的关于如何 错误折叠的F3与引发炎症有关，亚RPE沉积可能更广泛地应用于 常见的视网膜疾病，如干性黄斑变性。 赠款的目标1解决了通过治疗指导调节F3折叠和/或分泌的想法 作为一种治疗ML和其他由F3错误折叠引起的疾病的潜在原因的方法。丹妮会是 专注于为更深入地理解F3突变如何导致 眼部疾病，如AMD和ML，以及操纵细胞质量控制机制以预防F3- 相关疾病。

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.