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

• 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
• 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

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 和视神经退化青光眼发病机制存在两种主要模型-机械性 基于眼内压（IOP）和颅内压（ICP）相互作用的假设，以及 血管假说，其基于减少流向RGCs和视神经的血流的因素。 我们实验室的初步结果表明，机械因素的实验操作， 小鼠的IOP和ICP导致视网膜中的一系列微血管和缺氧异常。这些 异常似乎不仅根据IOP和ICP水平和暴露时间而不同，而且视网膜病变之间也存在差异。 细胞类型。特别是，我们感兴趣的是RGC和无长突细胞（AC），这是关键的上游 RGC功能的调节器。在此续期申请中，我们建议确定最早的差异 RGC、AC和视网膜血管系统对IOP和ICP变化的反应，并确定 这些反应背后的缺氧机制。具体目标有三：（1）确定 视网膜毛细血管丛对IOP和/或ICP变化的机制和鉴别敏感性; 2）描绘 眼压变化后RGCs和AC中发生的不同缺氧反应，并检验这一假设 AC中的缺氧导致RGC中的生理功能障碍;和3）为了检验HIF 1 α抑制的假设， 缺氧反应的主要调节因子，是ICP诱导的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IOP和ICP升高到可预测的水平， 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。我们将 并采用新的技术高保真分离培养成人RGCs和AC， 两种细胞类型对缺氧和先前IOP损伤的反应。与一系列体内 以及RGC，AC， 以及野生型和转基因小鼠的视网膜血管，我们将确定 IOP和ICP变化，并评估缺氧和缺氧反应如何改变这些变化 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，可能确定一个统一的理论， 青光眼的易感性，可以指导未来的转化诊断和治疗研究。