Brain and eye pressure-induced optic nerve and retinal degeneration

项目摘要 青光眼是一种以视网膜神经节细胞(RGC)为共同终点的复杂疾病 和视神经退化。存在两种主要的青光眼发病模式-机械性青光眼 基于眼压和颅内压相互作用的假说，以及 血管假说，其基础是减少流向视网膜神经节细胞和视神经的血液。 我们实验室的初步结果表明，对机械因素的实验操纵 小鼠的眼压和颅内压会导致视网膜的一系列微血管和缺氧性异常。这些 异常情况似乎不仅根据眼压、颅内压水平和暴露时间而有所不同，而且在视网膜之间也不同。 单元类型。特别是，我们对RGC和无长突细胞(ACS)感兴趣，它们是关键的上游细胞 研资局职能的调节者。在此续期申请中，我们建议确定最早的差额 视网膜神经节细胞、急性冠脉综合征和视网膜血管系统对眼压和颅内压变化的反应，并确定 这些反应背后的低氧机制。有三个具体目标：(1)确定 视网膜毛细血管丛对眼压和/或颅内压变化的机制和不同的易感性；2)勾画 视网膜神经节细胞和急性冠脉综合征在眼压改变后出现的不同缺氧反应，并检验假设 急性冠脉综合征中的缺氧导致视网膜神经节细胞的生理功能障碍；以及3)检验假设HIF1， 缺氧反应的主要调节因子，是肝内胆汁淤积物所致的RGC损伤所必需的。在这些目标中，我们 将采用新的实验工具，使我们能够将眼压和颅内压提高到特定的可预测水平 持续时间，这使我们能够评估眼压/颅内压变化幅度和持续时间的影响。我们会 此外，还采用了一种新的技术来分离和培养成年视网膜节细胞和AC，以探讨其差异 两种细胞对低氧和前期眼压损伤的反应。与一系列体内的 以及对视网膜神经节细胞、急性冠脉综合征、 以及野生型和转基因小鼠的视网膜血管系统，我们将确定 眼压和颅内压的变化，并评估低氧和低氧反应的改变如何改变这些 对影响RGC/AC功能障碍和生存的贡献。我们的研究将提供一个重要的联系 青光眼发病机制的机械和血管假说，潜在地确定了一个统一的理论 对青光眼的易感性可以指导未来的转化性诊断和治疗研究。

Project Summary Glaucoma represents a number of complex diseases with a common endpoint of retinal ganglion cell (RGC) and optic nerve degeneration. Two major models of glaucoma pathogenesis exist – the mechanical hypothesis, which is based on the interaction of intraocular pressure (IOP) and intracranial pressure (ICP), and the vascular hypothesis, which is based on factors that reduce blood flow to RGCs and the optic nerve. Preliminary results from our laboratory suggest that experimental manipulations of mechanical factors such as IOP and ICP in mice result in a range of microvascular and hypoxic abnormalities in the retina. These abnormalities appear to differ not only according IOP and ICP level and exposure duration, but among retinal cell types. In particular, we are interested in RGCs and amacrine cells (ACs), which are critical upstream regulators of RGC function. In this renewal application, we propose to identify the earliest differential responses of RGCs, ACs, and the retinal vasculature to IOP and ICP variation, and to determine the impact of the hypoxic mechanisms that underlie these responses. There are three specific aims: (1) determine the mechanism and differential susceptibilities of retinal capillary plexi to changes in IOP and/or ICP; 2) delineate the differential hypoxic responses that occur in RGCs and ACs after changes in IOP, and test the hypothesis that hypoxia in ACs causes physiologic dysfunction in RGCs; and 3) to test the hypothesis that HIF1, the primary regulator of the hypoxic response, is required for ICP-induced RGC injury. Throughout these Aims, we will employ novel experimental tools that enable us to elevate IOP and ICP to predictable levels for specific durations, which allow us to assess the effects of both magnitude and duration of IOP/ICP change. We will also use a new technique to isolate and culture adult RGCs and AC with high fidelity to probe the differential responses of both cell types to hypoxia and preceding IOP injury. Used in conjunction with a series of in vivo and post mortem electrophysiologic, behavioral, anatomic, and transcriptomic assessments of RGCs, ACs, and the retinal vasculature in both wild type and transgenic mice, we will determine the relative contributions of IOP and ICP change, and assess how alteration of hypoxia and the hypoxic response modifies these contributions to impact RGC/AC dysfunction and survival. Our research will provide an important link between mechanical and vascular hypotheses of glaucoma pathogenesis, potentially identifying a unified theory for susceptibility to glaucoma that can guide future translational diagnostic and therapeutic studies.