Brain and eye pressure-induced optic nerve and retinal degeneration

脑和眼压引起的视神经和视网膜变性

基本信息

批准号：
10475612
负责人：
Benjamin J Frankfort
金额：
$ 42.55万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475612
关键词：
Abate Ablation Adult Affect Amacrine Cells Anatomy Animals Astrocytes Attention Autopsy Award Behavioral Biology Blindness Blood Circulation Blood Vessels Blood capillaries Blood flow Brain Cell Hypoxia Cell physiology Cerebrospinal Fluid Clinical Treatment Complex Contrast Sensitivity Custom Data Dependence Disease Elderly Electrophysiology (science)Electroretinography Energy Metabolism Equilibrium Excision Eye Functional disorder Funding Future Gene Expression Genes Genetic Transcription Glaucoma Hyperactivity Hypoxia Immunohistochemistry Individual Infusion procedures Injury Intracranial Hypertension Intracranial Pressure Intraocular pressure test Laboratories Link Mechanics Microspheres Modeling Modification Mus Nerve Degeneration Neurodegenerative Disorders Optic Disk Optic Nerve Optical Coherence Tomography Oxygen Pathogenesis Patients Pattern Phenotype Physiologic Intraocular Pressure Physiological Physiology Population Predisposition Publishing Research Retina Retinal Degeneration Retinal Ganglion Cells Risk Factors Role Series Structure Techniques Testing Therapeutic Studies Time Tissues Transgenic Mice Transmission Electron Microscopy United States Variant Vision Visual base cell injury cell type decubitus ulcer experimental study hypoxia inducible factor 1 in vivo interest mechanical force multi-electrode arrays novel optic nerve disorder preference pressure prevent response theories tool transcriptomics translational diagnostics translational therapeutics

项目摘要

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.

项目概要青光眼代表了许多复杂的疾病，其共同终点是视网膜神经节细胞（RGC）青光眼发病机制存在两种主要模型——机械性模型。假设，基于眼压 (IOP) 和颅内压 (ICP) 的相互作用，以及血管假说，该假说基于减少流向 RGC 和视神经的血流量的因素。我们实验室的初步结果表明，机械因素的实验操作，例如小鼠的 IOP 和 ICP 会导致视网膜出现一系列微血管和缺氧异常。异常似乎不仅根据 IOP 和 ICP 水平以及暴露持续时间而不同，而且在视网膜之间也存在差异。我们特别对 RGC 和无长突细胞 (AC) 感兴趣，它们是关键的上游细胞。在这个更新申请中，我们建议确定最早的差异。 RGC、AC 和视网膜脉管系统对 IOP 和 ICP 变化的反应，并确定这些反应背后的缺氧机制有三个具体目标：（1）确定视网膜毛细血管丛对 IOP 和/或 ICP 变化的机制和不同敏感性 2) 描述； IOP 变化后 RGC 和 AC 中发生的差异性缺氧反应，并检验假设 AC 缺氧会导致 RGC 生理功能障碍；3) 检验 HIF1α 的假设；缺氧反应的主要调节因子是 ICP 引起的 RGC 损伤所必需的。将采用新颖的实验工具，使我们能够将 IOP 和 ICP 提高到特定的可预测水平持续时间，这使我们能够评估 IOP/ICP 变化的幅度和持续时间的影响。还使用新技术以高保真度分离和培养成人 RGC 和 AC，以探究差异两种细胞类型对缺氧和之前的 IOP 损伤的反应与一系列体内实验结合使用。以及 RGC、AC 的死后电生理、行为、解剖和转录组评估以及野生型和转基因小鼠的视网膜血管系统，我们将确定 IOP 和 ICP 变化，并评估缺氧和缺氧反应的改变如何改变这些我们的研究将提供影响 RGC/AC 功能障碍和生存之间的重要联系。青光眼发病机制的机械和血管假说，有可能确定一个统一的理论对青光眼的易感性可以指导未来的转化诊断和治疗研究。