The role of beta2-adrenergic receptor and interleukin-6 signaling in macrophage-driven choroidal neovascularization

β2-肾上腺素受体和白细胞介素6信号在巨噬细胞驱动的脉络膜新生血管中的作用

• 批准号: 10557138
• 负责人: Jeremy A Lavine
• 金额: $ 15.57万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557138
• 关键词: Adrenergic Antagonists; Adrenergic Receptor; Affect; Angiogenesis Inhibitors; Angiogenesis Pathway; Anti-Inflammatory Agents; Area; Award; Basic Science; Bioinformatics; Biology; Blindness; Cancer Center; Cardiovascular system; Cells; Cellular biology; Choroidal Neovascularization; Clinical; Collaborations; Data; Development Plans; Disease; Doctor of Philosophy; Educational process of instructing; Endothelial Cells; Exudative age-related macular degeneration; Eye; Fellowship; Flow Cytometry; Foundations; Funding; Future; Gene Expression Profile; Genotype; Goals; Growth Factor Inhibition; Immunology; Inflammation; Inflammatory; Innate Immune System; Interleukin 6 Receptor; Interleukin-6; Laboratories; Lasers; Liquid substance; Lung; Macrophage; Measures; Mentors; Mentorship; Molecular Target; Mus; Natural Immunity; Neomycin resistance gene; Ophthalmology; Pathogenesis; Patients; Persons; Phase; Phenotype; Physicians; Productivity; Receptor Inhibition; Receptor Signaling; Reporter; Research; Research Institute; Research Personnel; Residencies; Resistance; Retina; Rheumatology; Role; Scientist; Signal Transduction; Sorting; Specialist; Spider nevus; Surgeon; Techniques; Testing; Tissues; Training; Treatment Factor; Universities; Up-Regulation; Vascular Endothelial Growth Factors; Vision; Work; angiogenesis; antagonist; beta-adrenergic receptor; career; career development; cell type; cellular targeting; clinical training; cytokine; expectation; functional genomics; in vivo; individualized medicine; innovation; monocyte; mouse model; new therapeutic target; novel; professor; programs; receptor; receptor expression; recruit; response; skills; standard of care; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY: Candidate and Career Development Plan: Dr. Lavine is a vitreoretinal surgeon, physician-scientist, and Assistant Professor of Ophthalmology at Northwestern University. Dr. Lavine had a successful PhD, laying his strong scientific foundation, and has successfully balanced clinical duties with productive, basic science research in ophthalmology for the past 8 years of clinical training. His long-term career goal is to identify novel cellular and molecular targets of the innate immune system for anti-angiogenic therapy in order to move vitreoretinal specialists past the anti-vascular endothelial growth factor (VEGF) era and into individualized medicine. To accomplish this, his immediate goal is to develop his career as a funded, independent physician-scientist with expertise in the intersection of inflammation and angiogenesis. This K08 award will help achieve these goals by developing Dr. Lavine’s scientific and professional skills in advanced immunology and bio-informatics. Dr. Lavine and his co-mentors, Dr. Perlman and Dr. Quaggin, have developed a detailed strategy to achieve these objectives through carefully planned course work, didactics, laboratory techniques, and collaborations at Northwestern University. The current proposal will lay the foundation for future R01-level proposals on the intersection between innate immunity and angiogenesis in choroidal neovascularization (CNV). Research Plan: Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in the developed world, and is treated solely by inhibiting VEGF. Although highly effective, 15% of patients still lose vision despite maximal anti-VEGF therapy. Evidence suggests a role for pro-angiogenic macrophages in nAMD pathogenesis, but currently there are no therapies to specifically target these cells. Interleukin-6 (IL-6), a pro- inflammatory cytokine known to be produced by macrophages, correlates with nAMD activity and is necessary for laser-induced CNV, a mouse model of nAMD. Our preliminary data demonstrate that beta2-adrenergic receptor (AR) inhibition decreases laser-induced CNV area by reducing IL-6 levels in macrophages. Our central hypothesis is that beta2-AR signaling influences macrophage differentiation, promotes a pro-angiogenic macrophage phenotype, increases IL-6 levels, and activates angiogenesis by activating the IL-6 receptor directly on endothelial cells to increase CNV area. To test this hypothesis, we formulated the following specific aims: 1) Determine the retinal/choroidal cell type(s) that express interleukin-6 in response to beta2-AR antagonism 2) Identify the cell type that produces IL-6 and the cell type that responds to IL-6 to increase laser-induced CNV. 3) Delineate how beta2-AR and IL-6 deficiency regulate the transcriptional profile of macrophages during CNV. Completion of these aims will determine the cell types that respond to beta2-AR antagonism, produce IL-6, and respond to IL-6 to increase CNV area. These data will set the stage for anti-IL-6 therapy for nAMD. Furthermore, we will delineate how beta2-AR inhibition influences the transcriptomic profile of macrophages in the CNV milieu, which will identify new anti-inflammatory and anti-angiogenic therapeutic targets.

项目概要： 候选人和职业发展计划：Lavine博士是一名玻璃体视网膜外科医生，内科医生，科学家， 西北大学眼科学助理教授。拉文博士有一个成功的博士学位，奠定了他 强大的科学基础，并成功地平衡了临床职责与生产，基础科学研究 在过去8年的临床培训中，他的长期职业目标是识别新的细胞， 抗血管生成治疗的先天免疫系统的分子靶点， 专家过去的抗血管内皮生长因子（VEGF）的时代，并进入个性化的药物。到 完成这一目标，他的直接目标是发展他的职业生涯作为一个资助，独立的医生，科学家与 在炎症和血管生成的交叉点的专业知识。K 08奖将通过以下方式帮助实现这些目标： 发展Lavine博士在高级免疫学和生物信息学方面的科学和专业技能。拉文医生 和他的共同导师，帕尔曼博士和奎金博士，已经制定了一个详细的战略，以实现这些目标。 通过精心策划的课程工作，教学法，实验室技术和合作， 西北大学。目前的提案将为未来的R 01级提案奠定基础， 先天免疫和脉络膜新生血管形成（CNV）中血管生成之间的交叉。 研究计划：新生血管性年龄相关性黄斑变性（nAMD）是致盲的主要原因， 发达国家，并且仅通过抑制VEGF来治疗。虽然非常有效，但仍有15%的患者 尽管有最大的抗VEGF治疗，有证据表明促血管生成巨噬细胞在nAMD中的作用 发病机制，但目前还没有专门针对这些细胞的治疗方法。白细胞介素-6（IL-6），一种前 已知由巨噬细胞产生的炎性细胞因子与nAMD活性相关， 激光诱导的CNV，nAMD的小鼠模型。我们的初步数据表明，β 2-肾上腺素能 受体（AR）抑制通过降低巨噬细胞中的IL-6水平来降低激光诱导的CNV面积。我们的中央 假设β 2-AR信号传导影响巨噬细胞分化，促进促血管生成， 巨噬细胞表型，增加IL-6水平，并通过直接激活IL-6受体来激活血管生成 增加CNV面积。为了验证这一假设，我们制定了以下具体目标： 1)确定对β 2-AR拮抗反应表达白细胞介素-6的视网膜/脉络膜细胞类型 2)确定产生IL-6的细胞类型和响应IL-6以增加激光诱导的CNV的细胞类型。 3)描述β 2-AR和IL-6缺乏如何调节CNV期间巨噬细胞的转录谱。 这些目标的完成将确定响应β 2-AR拮抗作用、产生IL-6和 对IL-6产生应答以增加CNV面积。这些数据将为nAMD的抗IL-6治疗奠定基础。此外，委员会认为， 我们将描述β 2-AR抑制如何影响CNV环境中巨噬细胞的转录组学特征， 这将确定新的抗炎和抗血管生成治疗靶点。