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: 10334485
• 负责人: Jeremy A Lavine
• 金额: $ 22万
• 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/10334485
• 关键词: Adrenergic Antagonists; Adrenergic Receptor; Affect; 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; Genes; Genotype; Goals; Gold; Growth Factor Inhibition; Immunology; Inflammation; Inflammatory; Innate Immune System; Interleukin 6 Receptor; Interleukin-6; Laboratories; Lasers; Liquid substance; Lung; Measures; Mentors; Mentorship; Molecular Target; Mus; Natural Immunity; Ophthalmology; Pathogenesis; Patients; Persons; Phase; Phenotype; Physicians; Receptor Inhibition; Receptor Signaling; Reporter; Research; Research Institute; Research Personnel; Residencies; Resistance; Retina; Rheumatology; Role; Scientist; Signal Transduction; Specialist; Spider nevus; Surgeon; Techniques; Testing; Tissues; Training; Treatment Factor; Universities; Up-Regulation; Vascular Endothelial Growth Factors; Vision; Work; angiogenesis; base; beta-adrenergic receptor; career; career development; cell type; cellular targeting; cytokine; expectation; functional genomics; in vivo; individualized medicine; innovation; macrophage; 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.

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