The mechanotranscriptome of the optic nerve head following acute experimental ocular hypertension in living human eyes

活体人眼急性实验性高眼压后视神经乳头的机械转录组

基本信息

批准号：
10639434
负责人：
Massimo Antonio Fazio
金额：
$ 57.23万
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：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639434
关键词：
Acute Animal Model Animals Astrocytes Biomechanics Blindness Blood Vessels Brain Death Cells Connective Tissue Consent Data Development Electrophysiology (science)Evaluation Exhibits Eye Fibroblasts Functional disorder Glaucoma Histopathology Human Immunohistochemistry Individual Inflammatory Injury Ischemia Link Measurement Measures Mechanics Methods Microglia Modeling Molecular Neuroglia Ocular Hypertension Optic Disk Optic Nerve Organ Donor Organ Procurements Papillary Pathologic Pathway interactions Perfusion Phenotype Physiologic Intraocular Pressure Predisposition Protein Analysis Proteins Research Resources Retina Retinal Ganglion Cells Risk Risk Factors Science Sclera Stress Stretching Structure Study models Testing Therapeutic Intervention Time Tissues Transcript Translations Variant Weight-Bearing state axon injury cell type clinical care clinical imaging density design experimental study human disease imaging approach in vivo innovation insight mechanotransduction neural new therapeutic target novel therapeutics optic nerve disorder pressure promote resilience response retinal axon targeted treatment therapeutic development tissue culture transcriptome transcriptomics

项目摘要

Glaucoma is one of the leading causes of irreversible blindness for which the lowering of intraocular pressure (IOP) is the only proven treatment. Since elevated IOP is a critical risk factor for glaucoma, several animal models have been developed to study the cellular, vascular, and electrophysiologic responses of the retina to acute IOP elevation. While these models have elucidated the relationship between ocular perfusion and retinal function as well as many of the cellular pathways activated in response to acute IOP related exposure, there are significant differences in optic nerve structure and composition across species, limiting the translation of these findings to the human disease. This project will study the impact of IOP elevation in the living human eye for the first time by utilizing the unique resources developed by the Living Eye Project. This project provides experimental access to the human eye in vivo in research-consented brain-dead organ donors prior to organ procurement. Following enucleation, the Living Eye Project provides access to the same eyes for ex vivo analysis of cellular and tissue responses. Our principal hypothesis is that acute IOP elevation results in deformation of the optic nerve head (ONH), and this deformation drives mechanosensitive mechanisms within the lamina cribrosa (LC) and peripapillary sclera that initiate pathologic remodeling of the LC, which injures the axons of retinal ganglion cells traversing this mechanically dynamic region. These mechanosensitive pathways will be characterized using spatial transcriptomics for the first time in the human eye alongside immunohistochemistry and protein analysis. We predict that increased IOP initiates a profibrotic, inflammatory phenotype and transcriptomic alterations that regionally colocalize with the connective tissue density within the LC and are associated with the magnitude of IOP-induced deformation of the ONH measured in vivo. Our unprecedented opportunity to measure structural and biomechanical parameters of the human ONH in vivo and perform ex vivo evaluation of the cellular mechanobiology of the same tissues will provide the first direct experimental link between ONH mechanical strain and the molecular and cellular responses of ONH tissues that drive remodeling, which is critical to the development and progression of glaucomatous optic neuropathy. Defining this “mechanotranscriptome” in the human ONH will critically assess the translational value of animal models for studying mechanotransduction as well as define the human cellular and molecular mechanisms of ONH remodeling needed to guide the development of novel therapeutics designed to enhance the resilience of the ONH to pressure-related stress.

青光眼是不可逆失明的主要原因之一，其降低了眼内压（IOP）是唯一的经过验证的治疗方法。由于IOP升高是青光眼的关键危险因素，因此几种动物模型已经开发用于研究视网膜对急性IOP的细胞，血管和电生理反应海拔。尽管这些模型阐明了眼部灌注与残留功能之间的关系以及许多因急性IOP相关暴露而激活的细胞途径，也有明显的跨物种的视神经结构和组成的差异，将这些发现的翻译限制为人类疾病。该项目将首次研究IOP升高的影响通过使用Live Eye Project开发的独特资源。该项目提供实验访问在器官采购之前，在研究持续的脑死亡器官捐献者中，人类的眼睛是人类的。下列的封装，活眼镜项目可访问相同的眼睛，以进行细胞和组织的体内分析回答。我们的主要假设是急性IOP升高导致视神经头变形（ONH），这种变形驱动了层cribrosa（LC）内的机械敏感机制和启动LC的病理重塑的乳头核心巩膜，这损伤了残留神经节细胞的轴突穿越这个机械动态的区域。这些机械敏感途径将使用在人眼中首次与免疫组织化学和蛋白质分析同时，空间转录组学。我们预测，增加IOP会启动纤维化，炎症表型和转录组的变化，以此与LC内的结缔组织密度进行区域性共定位，并与 IOP诱导的体内测量的ONH变形。我们前所未有的衡量结构的机会人体内的人类onh和生物力学参数，并对细胞进行离体评估同一组织的机械生物学将提供ONH机械之间的第一个直接实验联系应变以及驱动重塑的ONH组织的分子和细胞反应，这对青光眼视力神经病的发展和进展。在人类ONH将批判性地评估动物模型的转化价值，以研究机械转传并定义了ONH重塑的人类细胞和分子机制，以指导新型疗法的开发旨在增强ONH对压力相关的应激的弹性。