MMP-9 based immune-driven mechanisms of neovascular AMD

基于MMP-9的新生血管性AMD的免疫驱动机制

• 批准号: 10719958
• 负责人: Jon C.D. Houtman
• 金额: $ 54.04万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719958
• 关键词: 3-Dimensional; Address; Affect; Age related macular degeneration; Angiography; Antigen-Presenting Cells; Area; Artificial Intelligence; Bite; Blindness; Blood Vessels; Blood specimen; Cell Culture Techniques; Cells; Cellular biology; Characteristics; Choroid; Choroidal Neovascularization; Clinic; Collaborations; Complement Factor H; Data; Dendritic Cells; Disease; Elderly; Epitope Mapping; Epitopes; Exudative age-related macular degeneration; Eye; Fibrosis; Frequencies; Gelatinase B; Gene Expression; Genes; Genetic; Genomics; Genotype; Helper-Inducer T-Lymphocyte; Human; Image; Image Analysis; Immune; Immune response; Immunologic Techniques; Immunology; Individual; Inflammatory; Injections; Learning; Liquid substance; Longitudinal cohort; Machine Learning; Mediating; Mediator; Mutation; Nucleic Acid Regulatory Sequences; Optical Coherence Tomography; Pathway interactions; Patients; Peptides; Phenotype; Physiological; Play; Proteins; Research; Research Personnel; Retina; Risk; Signal Transduction; Societies; Strategic Planning; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Tissues; Training; Treatment Factor; Treatment Protocols; Validation; Variant; Vascular Endothelial Growth Factors; Vascular blood supply; Vision; Visual Acuity; Visualization; Weaning; antigen-specific T cells; automated algorithm; chemokine; cohort; cytokine; experience; genetic variant; genomic locus; health economics; high risk; immune activation; immunomodulatory therapies; improved; inhibitor; innovation; multidisciplinary; neovascular; new therapeutic target; novel; novel therapeutic intervention; polarized cell; preservation; profiles in patients; response; retinal imaging; retinal prosthesis; risk variant; single-cell RNA sequencing; socioeconomics; translational impact; treatment response

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.

项目总结/摘要 新生血管“湿性”型年龄相关性黄斑变性（nvAMD），即新血管生长 在视网膜下，需要用抗血管内皮生长因子眼部注射治疗，通常每隔1- 由于持续性液体，患者的剩余生命中持续3个月，可通过以下方式进行可视化和量化： 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 基质金属蛋白酶9（MMP 9），在视网膜血液供应（称为脉络膜）的免疫细胞中表达，作为形成 和nvAMD的持久性。这项提议将阐明我们对这种新的基于免疫的 机制还将评估具有MMP 9的高风险基因型的患者的特征，因为它们是 与对nvAMD标准治疗的不完全应答相关。我们将确定基因调节 控制MMP 9表达并决定免疫激活特征的区域 nvAMD。我们将使用基于人工智能（AI）的方法将可观察到的表型特征 nvAMD患者中高风险和低风险MMP 9基因型的OCT和OCT血管造影。 我们杰出的跨学科研究团队将合作采用最先进的基因组和 免疫学技术来研究MMP 9如何参与nvAMD和纤维化的机制。遗传学 将有助于对OCT图像进行基于AI和机器学习的分析，以学习与 最具挑战性的nvAMD患者。揭示与MMP 9相关的疾病机制 将揭示治疗干预的新靶点。本提案涵盖7个交叉领域中的5个 NEI在2021年11月1日的五年战略计划中提出了重点。这是下一个，必要的 这是nvAMD的一个里程碑，将有助于解决这一重大的社会经济健康负担。