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：
10689806
负责人：
Seth D Fortmann
金额：
$ 4.97万
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/10689806
关键词：
Acceleration Adipose tissue Age Age Years Age related macular degeneration 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 Collaborations 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 Interleukin-1 beta Knockout Mice Lasers Lipid Binding Lipids Lipoproteins Location Macrophage 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 Retina Risk Factors Role Safety Sampling Scientist Senile Plaques Signal Transduction Stains Structure of retinal pigment epithelium TNF gene TREM2 gene Techniques Testing Therapeutic Tissue Donors Tissues Training Tumor-associated macrophages Vision Writing career chronic inflammatory disease density design disorder of macula of retina ex vivo imaging experience extracellular fovea centralis genetic risk factor health assessment human imaging imaging study immunoregulation in vivo imaging lipid metabolism macula neovascular neovascularization neural new therapeutic target novel p65 receptor binding 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.

项目概要年龄相关性黄斑变性 (AMD) 患者的治疗选择很少，而且 FDA 也没有已批准可用于最常见的药物亚型，即干 AMD 纵向成像研究。确定中央凹附近玻璃疣的积累是进展的单一最大的解剖学危险因素导致严重疾病，表明视网膜色素上皮 (RPE) 中脂质稳态的丧失和此外，组织学和分子研究表明，脉络膜是 AMD 的重要疾病机制。黄斑 RPE/脉络膜炎症是 AMD 的一个早期的、统一的特征，然而，这是分子和细胞的特征。负责 RPE/脉络膜中脂质积累和炎症的机制仍然很差使用来自 150 名人类捐赠者的公开批量和单细胞 RNA 测序数据，我们了解到。证明脉络膜巨噬细胞是脉络膜生态系统的重要组成部分脉络膜毛细血管和 RPE 功能的维持——在黄斑区减少且功能失调我们详细介绍了与 AMD 的分子基础相关的新转录组学观察。人类脉络膜巨噬细胞，证明它们具有强大的抗炎作用并表达多种参与脂质清除的关键模块值得注意的是骨髓上表达的触发受体的表达。 cells 2 (TREM2)，一种介导一系列组织中脂质稳态和免疫抑制的脂受体并在涉及细胞外物质积累的几种疾病中丢失，使用来自小鼠的脉络膜组织。我们采用多种技术来验证与脉络膜巨噬细胞相关的关键发现。脉络膜巨噬细胞在慢性脂质代谢过程中对维持脉络膜脂质稳态非常重要挑战，因为在高脂肪饮食 9 周后，这些细胞会扩张并含有几乎所有多余的脂质。研究结果使我们得出核心假设：TREM2+ 脉络膜巨噬细胞调节脂质稳态 RPE/脉络膜并抑制炎症和脉络膜新生血管形成我们提出使用 TREM2 的两个目标。基因敲除小鼠探究 TREM2 信号在脉络膜巨噬细胞中对脂质的作用 RPE/脉络膜中的代谢、免疫和新生血管抑制是我们预期的结果。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的作用的理解，并将确定 TREM2 为 AMD 的新药物靶点。 PI Seth Fortmann 的拟议培训计划由他的导师 Maria Grant MD 博士赞助。培训计划的总体目标是为 PI 的成功职业生涯提供坚实的科学基础作为一名医师科学家眼科医生，培训计划中包括对 PI 有帮助的经验：1) 获得各种技术的能力，包括生物信息学、流式细胞术、原代细胞培养和人类捐赠者眼睛的离体成像；2) 开展假设驱动的研究；3) 以口头和形式呈现数据；书面格式；4) 有效地将研究与临床结合起来；5) 与其他科学家合作；负责任地进行研究。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transthyretin proteoforms of intraocular origin in human subretinal fluid.

DOI：
10.1016/j.exer.2022.109163
发表时间：
2022-09
期刊：
EXPERIMENTAL EYE RESEARCH
影响因子：
3.4
作者：
Chen, Jianzhong;Cao, Dongfeng;Fortmann, Seth D.;Curcio, Christine A.;Feist, Richard M.;Crosson, Jason N.
通讯作者：
Crosson, Jason N.