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

• 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
• 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

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.

青光眼是导致不可逆性失明的主要原因之一，眼压降低会导致青光眼 (IOP) 是唯一经过验证的治疗方法，因为眼压升高是青光眼的关键危险因素，因此有几种动物模型。 已被开发用于研究视网膜对急性眼压的细胞、血管和电生理反应 虽然这些模型已经阐明了眼灌注和视网膜功能之间的关系。 以及响应急性 IOP 相关暴露而激活的许多细胞通路，有显着的影响 不同物种之间视神经结构和组成的差异，限制了这些发现的转化 该项目将首次研究眼压升高对活人眼睛的影响。 通过利用 Living Eye 项目开发的独特资源，该项目提供了实验访问权限。 在器官获取之前，对经研究同意的脑死亡器官捐献者体内进行人眼观察。 摘除，活眼项目提供了使用同一只眼睛进行细胞和组织的离体分析 我们的主要假设是急性眼压升高会导致视神经乳头变形。 (ONH)，这种变形驱动筛板 (LC) 内的机械敏感机制 视乳头周围巩膜启动 LC 病理性重塑，从而损伤视网膜神经节细胞的轴突 穿过这个机械动态区域将使用这些机械敏感路径来表征。 首次在人眼中进行空间转录组学以及免疫组织化学和蛋白质分析。 我们预测，眼压升高会引发促纤维化、炎症表型和转录组改变，从而导致 与 LC 内的结缔组织密度区域共定位，并与 体内测量的 IOP 引起的 ONH 变形是我们前所未有的测量结构的机会。 体内人类 ONH 的生物力学参数，并对细胞进行离体评估 相同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，这对于 青光眼视神经病的发生和进展。 人类 ONH 将严格评估动物模型用于研究机械转导的转化价值 以及定义 ONH 重塑的人类细胞和分子机制，以指导 开发旨在增强 ONH 对压力相关压力的恢复能力的治疗小说。

项目成果

Retinal electrophysiologic response to IOP elevation in living human eyes.

活体人眼对眼压升高的视网膜电生理反应。

• 发表时间: 2023-04
• 影响因子: 3.4
• 作者: Girkin, Christopher A;Garner, Mary Anne;Fazio, Massimo A;Clark, Mark E;Karuppanan, Udayakumar;Hubbard, Meredith G;Bianco, Gianfranco;Hubbard, Seth T;Fortune, Brad;Gross, Alecia K
• 通讯作者: Gross, Alecia K

Displacement of the Lamina Cribrosa With Acute Intraocular Pressure Increase in Brain-Dead Organ Donors.

脑死亡器官捐献者眼压急性升高导致筛板移位。

• 发表时间: 2023-12-01
• 影响因子: 4.4
• 作者: Girkin, Christopher A;Garner, Mary A;Gardiner, Stuart K;Clark, Mark E;Hubbard, Meredith;Karuppanan, Udayakumar;Bianco, Gianfranco;Bruno, Luigi;Fazio, Massimo A
• 通讯作者: Fazio, Massimo A