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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.

青光眼是眼压降低导致不可逆失明的主要原因之一