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

青光眼是导致不可逆性失明的主要原因之一，而眼压的降低是导致青光眼的主要原因 (IOP)是唯一得到证实的治疗方法。由于高眼压是青光眼的关键危险因素，几种动物模型 已被用于研究视网膜对急性眼压的细胞、血管和电生理反应 立面。虽然这些模型已经阐明了眼睛血流和视网膜功能之间的关系，如 由于许多细胞通路在与急性眼压相关的暴露中被激活，因此有显著的 不同物种之间视神经结构和组成的差异，限制了这些发现的翻译 人类疾病。该项目将首次研究眼压升高对活人眼睛的影响。 通过利用活眼项目开发的独特资源。该项目提供了试验性的通道 对活体人眼的研究--在器官采购前征得脑死亡器官捐赠者的同意。跟随 眼球摘除，活眼计划为细胞和组织的体外分析提供了相同的眼睛 回应。我们的主要假设是急性眼压升高会导致视神经头变形。 (ONH)，这种变形驱动筛板(LC)和 启动LC病理性重塑的乳头周围巩膜，损伤视网膜神经节细胞的轴突 穿过这个机械动态区。这些机械敏感的途径将用 首次在人眼中进行空间转录，同时进行免疫组织化学和蛋白质分析。 我们预测，眼压升高会引发纤维变性、炎症表型和转录改变， 与LC内结缔组织密度呈区域性共定位，与结缔组织密度的大小相关 活体测量IOP诱导的ONH变形。我们前所未有的机会来衡量结构性 和生物力学参数，并进行细胞的体外评价 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 应变以及推动ONH组织重塑的分子和细胞反应，这对ONH组织的 青光眼视神经病变的发生发展。在《机械转录组》的定义中 人类ONH将批判性地评估用于研究机械转导的动物模型的翻译价值 以及确定人类ONH重塑的细胞和分子机制，以指导 开发新的治疗方法，旨在增强ONH对压力相关压力的弹性。

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.