MMP-9 based immune-driven mechanisms of neovascular AMD

项目摘要/摘要 年龄相关性黄斑变性(NvAMD)的新生血管“湿性”形式，由此新血管生长 在视网膜下，需要抗血管内皮生长因子眼部注射治疗，通常每隔1- 由于持续液体，患者剩余生命的3个月，可以通过以下方式可视化和量化 光学相干断层扫描(OCT)成像。最近的研究表明基质金属蛋白酶9 (MMP9)在视网膜供血免疫细胞(称为脉络膜)中表达，是形成过程中的中介。 和nvAMD的持久性。这一提议将阐明我们对这一新型免疫基础的理解 机制。MMP9高危基因患者的特征也将被评估，因为他们是 与nvAMD的标准治疗反应不完全相关。我们将确定基因调控 控制MMP9表达和确定免疫激活谱的区域 NvAMD。我们将使用基于人工智能(AI)的方法来关联可观察到的表型特征 NvAMD患者高危和低危MMP9基因的OCT和OCT血管成像研究 我们优秀的跨学科研究团队将合作使用最先进的基因组和 免疫学技术研究MMP9如何参与nvAMD和纤维化的机制。遗传学 将帮助对OCT图像进行基于人工智能和机器学习的分析，以了解与 最具挑战性的患者患有nvAMD。解开与MMP9相关的疾病机制 将揭示治疗干预的新靶点。该提案涵盖7个交叉领域中的5个 2021年11月1日，NEI在五年战略规划中提出了重点。这是下一个，必要的 NvAMD的里程碑，将有助于解决这一重大的社会经济健康负担。

PROJECT SUMMARY/ABSTRACT The neovascular ‘wet’ form of age-related macular degeneration (nvAMD), whereby new blood vessels grow under the retina, requires treatment with anti-vascular endothelial growth factor eye injections typically every 1- 3 months for the remainder of patients’ lives due to persistent fluid, which can be visualized and quantified by optical coherence tomography (OCT) imaging. Recent research has implicated matrix metalloproteinase 9 (MMP9), expressed in immune cells of the retinal blood supply (termed choroid), as a mediator in the formation and persistence of nvAMD. This proposal will elucidate our understanding of this novel immune-based mechanism. Characteristics of patients with high-risk genotype of MMP9 will also be assessed, as they are associated with incomplete response to standard therapies for nvAMD. We will identify genetic regulatory regions that control expression of MMP9 and determine the immunologic activation profiles in patients with nvAMD. We will use artificial intelligence (AI)-based approaches to associate phenotypic features observable on OCT and OCT-angiography with high- and low-risk MMP9 genotypes in patients with nvAMD. Our outstanding team of interdisciplinary researchers will collaborate to employ state-of-the-art genomic and immunologic techniques to study the mechanisms of how MMP9 is implicated in nvAMD and fibrosis. Genetics will aid AI- and machine learning-based analysis of OCT images to learn new features associated with the most challenging patients afflicted with nvAMD. Unraveling the disease mechanisms associated with MMP9 will reveal new targets for therapeutic intervention. This proposal encompasses 5 of the 7 cross-cutting areas of emphasis the NEI laid out in the 5-year Strategic Plan on November 1, 2021. This is the next, necessary milestone in nvAMD that will help to address this major socioeconomic health burden.