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Role of choroidal macrophages in regulating lipid homeostasis and immunosuppression of the RPE/choroid

脉络膜巨噬细胞在调节 RPE/脉络膜脂质稳态和免疫抑制中的作用

基本信息

批准号：
10313006
负责人：
Seth D Fortmann
金额：
$ 3.93万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10313006
关键词：
Adipose tissue Age Age related macular degeneration Age-Years Alzheimer&apos s Disease American Anatomy Anti-Inflammatory Agents Area Atherosclerosis Basement membrane Bioinformatics Blindness Blood Vessels Cells Cessation of life Choroid Choroidal Neovascularization Chronic Clinic Clinical Competence Data Deposition Disease Down-Regulation Drusen Ecosystem Elderly Enzyme-Linked Immunosorbent Assay Evaluation Excision Exudative age-related macular degeneration Eye FDA approved Fatty Liver Flow Cytometry Foundations Functional disorder Genes Genetic Polymorphism Goals Grant Health High Fat Diet Histologic Homeostasis Human Immune Immunohistochemistry Immunosuppression Individual Inflammation Inflammation Mediators Inflammatory Interleukin-1 beta Knockout Mice Lasers Lipid Binding Lipids Lipoproteins Location Maintenance Malignant Neoplasms Mediating Membrane Mentors Microglia Modeling Molecular Morphology Mus Myeloid Cells Neurodegenerative Disorders Nonexudative age-related macular degeneration Obesity Ophthalmologist Oral Pathogenesis Pathway interactions Patients Pericytes Peripheral Phagocytes Phagocytosis Pharmaceutical Preparations Phase I Clinical Trials Photoreceptors Physicians Play Population Primary Cell Cultures Relative Risks Research Research Proposals Retinal Diseases Risk Factors Role Safety Sampling Scientist Senile Plaques Signal Transduction Stains Structure of retinal pigment epithelium TNF gene TREM2 gene Techniques Testing Therapeutic Time Tissue Donors Tissues Training Tumor-associated macrophages Vision career density design disorder of macula of retina ex vivo imaging experience extracellular fovea centralis genetic risk factor human imaging imaging study immunoregulation in vivo imaging lipid metabolism macrophage macula neovascular neovascularization new therapeutic target novel p65 receptor binding relating to nervous system response responsible research conduct serial imaging single-cell RNA sequencing tissue repair transcriptome transcriptome sequencing transcriptomics translational study uptake

项目摘要

PROJECT SUMMARY Few therapeutic options exist for patients with age-related macular degeneration (AMD), and no FDA approved drugs are available for the most common subtype, dry AMD. Longitudinal imaging studies have identified the accumulation of drusen near the fovea as the single greatest anatomic risk factor for progression to severe disease, suggesting that loss of lipid homeostasis in the retinal pigmented epithelium (RPE) and choroid is a critical disease mechanism underlying AMD. Moreover, histologic and molecular studies have shown that inflammation of the macular RPE/choroid is an early, unifying feature of AMD. Yet, the molecular and cellular mechanisms responsible for the accumulation of lipid and inflammation in the RPE/choroid remain poorly understood. Using publicly available bulk and single-cell RNA-sequencing data from 150 human donors, we demonstrate that choroidal macrophages—a critical component of the choroidal ecosystem required for maintenance of the choriocapillaris and RPE function—are decreased and dysfunctional in the macular RPE/choroid in AMD. We detail novel transcriptomic observations related to the molecular underpinnings of choroidal macrophages in humans, demonstrating that they are robustly anti-inflammatory and express several key modules involved in lipid clearance. Of note is the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a liporeceptor that mediates lipid homeostasis and immunosuppression in a range of tissues and is lost in several diseases involving accumulation of extracellular material. Using choroidal tissue from mice, we employ a variety of techniques to validate key findings related to choroidal macrophages. We show that choroidal macrophages are important in maintaining lipid homeostasis in the choroid during times of chronic lipid challenge, as these cells expand and contain nearly all of the excess lipid after 9 weeks of high-fat diet. These findings led us to our core hypothesis that TREM2+ choroidal macrophages modulate lipid homeostasis in the RPE/choroid and suppress inflammation and choroidal neovascularization. We propose two Aims using TREM2 knock-out mice to interrogate the role of TREM2 signaling in choroidal macrophages with respect to lipid metabolism and immune and neovascular suppression in the RPE/choroid. We anticipate the findings from this proposal will expand our understanding of the role of choroidal macrophages in the choroidal ecosystem and will identify TREM2 as a novel drug target in AMD. The proposed training plan for the PI, Seth Fortmann, is sponsored by his mentor, Dr. Maria Grant MD. The overall goal of the training plan is to provide the PI with a strong scientific foundation for a successful career as a physician-scientist ophthalmologist. Included in the training plan are experiences that will help the PI: 1) gain competence in a variety of techniques including bioinformatics, flow cytometry, primary cell culture, and ex vivo imaging of human donor eyes; 2) develop hypothesis-driven research; 3) present data in an oral and written format; 4) effectively integrate research with the clinic; 5) collaborate with other scientists; and 6) responsibly conduct research.

项目总结对于老年性黄斑变性(AMD)患者，几乎没有治疗选择，也没有FDA 批准的药物可用于最常见的亚型，干性AMD。纵向成像研究已经确定黄斑中心凹附近的玻璃体积聚是进展的单一最大解剖危险因素。严重疾病，提示视网膜色素上皮(RPE)和脉络膜是AMD的重要发病机制。此外，组织学和分子研究表明黄斑RPE/脉络膜炎症是AMD的早期统一特征。然而，分子和细胞 RPE/脉络膜中脂质堆积和炎症的机制仍不清楚明白了。使用公开的来自150名人类捐赠者的批量和单细胞RNA测序数据，我们证明脉络膜巨噬细胞-脉络膜生态系统的关键组成部分脉络膜毛细血管和RPE功能的维持-黄斑减少和功能障碍 AMD的RPE/脉络膜。我们详细描述了与分子基础相关的新的转录学观察。人类的脉络膜巨噬细胞，表明它们具有强大的抗炎作用，并表达几种参与脂质清除的关键模块。值得注意的是髓系上表达的触发受体的表达细胞2(TREM2)，一种脂类受体，在一系列组织中介导脂质稳态和免疫抑制并在几种涉及细胞外物质堆积的疾病中丢失。利用老鼠的脉络膜组织，我们使用各种技术来验证与脉络膜巨噬细胞相关的关键发现。我们证明了脉络膜巨噬细胞在慢性脂溢性疾病期间维持脉络膜脂类平衡中的重要作用挑战，因为这些细胞在9周的高脂肪饮食后膨胀并包含几乎所有多余的脂肪。这些我们的核心假设是TREM2+脉络膜巨噬细胞调节脂质稳态。 RPE/脉络膜，抑制炎症和脉络膜新生血管。我们提出了使用TREM2的两个目标基因敲除小鼠询问TREM2信号在脉络膜巨噬细胞中对脂质的作用 RPE/脉络膜的新陈代谢、免疫和新生血管抑制。我们期待着由此得出的结论。该提案将扩大我们对脉络膜巨噬细胞在脉络膜生态系统中作用的理解，并将确定TREM2为治疗AMD的新药物靶点。建议的私家侦探赛斯·福特曼的培训计划由他的导师玛丽亚·格兰特博士赞助。培训计划的总体目标是为PI职业生涯的成功提供坚实的科学基础作为一名内科科学家眼科医生。培训计划中包括有助于PI的经验：1) 掌握各种技术，包括生物信息学、流式细胞术、原代细胞培养和人体供眼的体外成像；2)发展假设驱动的研究；3)以口头和书面形式；4)有效地将研究与临床相结合；5)与其他科学家合作；6) 负责任地开展研究。