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：
10665661
负责人：
Benjamin J Frankfort
金额：
$ 43.87万
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/10665661
关键词：
Abate Ablation Adult Affect Amacrine Cells Anatomy Animals Astrocytes Attention Autopsy Award Behavioral Biology Blindness Blood Vessels Blood capillaries Blood flow Brain Cell Hypoxia Cell physiology Cerebrospinal Fluid Circulation 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 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 Traction Transgenic Mice Transmission Electron Microscopy United States Variant Vision Visual 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.

项目摘要青光眼代表了多种复杂疾病，具有残留神经节细胞（RGC）的常见终点和视神经变性。有两个主要模型的青光眼发病机理存在 - 机械假设基于眼内压（IOP）和颅内压（ICP）和血管假设基于降低血液流向RGC和视神经的因素。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导致视网膜中的一系列微血管和低氧异常。这些异常不仅根据IOP和ICP级别和暴露持续时间不同，而且在其余细胞类型。特别是，我们对上游至关重要的RGC和无聚细胞（AC）感兴趣 RGC功能的调节剂。在此续签应用中，我们建议确定最早的差异 RGC，ACS和视网膜脉管系统对IOP和ICP变化的反应，并确定这些反应的基础的低氧机制。有三个具体目标：（1）确定视网膜毛细血管对IOP和/或ICP的变化的机理和差异敏感性； 2）描绘 IOP发生变化后，RGC和AC中发生的差异低氧反应，并检验假设 ACS缺氧引起RGC的生理功能障碍； 3）检验HIF1的假设 ICP诱导的RGC损伤需要低氧反应的主要调节剂。在这些目标中，我们将采用新颖的实验工具，使我们能够将IOP和ICP提升到可预测的特定水平持续时间，这使我们能够评估IOP/ICP变化的幅度和持续时间的影响。我们将还使用一种新技术来隔离和培养成人RGC和AC具有高保真度以探测差异两种细胞类型对缺氧和IOP损伤之前的反应。与一系列体内结合使用以及Mortem电生理，行为，解剖和转录组的RGC，ACS，以及野生型和转基因小鼠的视网膜脉管系统，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理的机械和血管假设，有可能识别统一的理论对青光眼的敏感性，可以指导未来的翻译诊断和治疗研究。