ENDOGENOUS NEUROPROTECTION IN GLAUCOMA

青光眼的内源性神经保护

基本信息

批准号：
8035338
负责人：
JEFFREY M GIDDAY
金额：
$ 36.12万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035338
关键词：
Affect Apoptotic Blindness CREB1 gene Categories Cell Death Cell Survival Cells Cytoprotection Exposure to Gene Expression Gene Targeting Genes Genetic Transcription Glaucoma Hypertension Hypoxia Individual Injury Ischemia Knockout Mice Mediating Molecular Molecular Profiling Names Nitric Oxide Nitric Oxide Synthase Operative Surgical Procedures Pathway interactions Phenotype Phosphorylation Physiologic Intraocular Pressure Population Prevention strategy Principal Investigator Protein Isoforms Proto-Oncogene Proteins c-akt Research Retina Retinal Ganglion Cells Rodent Role Stimulus Strategic Planning Stress Transgenic Mice Work base ganglion cell heme oxygenase-1 high risk mouse model neuroprotection new therapeutic target novel strategies optic nerve disorder preconditioning prevent programs response transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Glaucoma affects millions in the US and is the second leading cause of blindness worldwide. While surgical and pharmacologic approaches to reduce intraocular pressure can be beneficial, a recently convened NEI strategic planning group explicitly recommended focused research on retinal ganglion cell neuroprotection. One novel approach in this regard is the activation, by preconditioning, of robustly powerful survival mechanisms endogenous to the cell. We were the first to demonstrate in rodents that brief exposures to noninjurious ischemia or hypoxia promote near complete protection of the retina from ischemic injury. We now show in a mouse model of experimental glaucoma that long-lasting phenotypic changes induced by repetitive preconditioning with hypoxia, prior to intraocular hypertension, can prevent ganglion cell death. Studies proposed herein will utilize inducible and retina-specific knockout and transgenic mice to begin to elucidate the mechanistic basis of this innate protective response we have termed glaucoma tolerance. Specific Aim 1: Elucidate the role of the hypoxia-inducible transcription factor HIF-11 in mediating changes in gene expression responsible for glaucoma tolerance. Hypothesis: Ganglion cell protection following repetitive hypoxic preconditioning results from a unique expression profile for HIF-11 that leads to the long-lasting expression of heme oxygenase-1 and other survival-promoting HIF-11 gene targets. Specific Aim 2: Determine how nitric oxide modulates the ability of repetitive hypoxic preconditioning to promote glaucoma tolerance. Hypothesis: Activation of the constitutive nitric oxide synthase isoforms by repetitive hypoxic preconditioning is necessary for induction of a long-lasting cytoprotective phenotype by facilitating HIF-11-mediated and CREB-mediated transcription of cytoprotective genes. Specific Aim 3: Establish the mechanisms whereby glaucoma tolerance is achieved as a result of hypoxic preconditioning-induced activation of pAkt (protein kinase B)-dependent survival pathways. Hypothesis: Repetitive hypoxic preconditioning promotes pAkt stabilization and, subsequently, the prolonged phosphorylation of several anti-apoptotic effectors that contribute to glaucoma tolerance. The endogenous mechanisms of ganglion cell protection identified in this research program may provide novel therapeutic targets for preventing or reducing optic neuropathy in glaucoma. Ganglion cell death in glaucoma is responsible for devastating vision loss in millions of individuals. Our work provides a new approach to ganglion cell protection: Applying stress stimuli that activate endogenous mechanisms of gene expression to promote ganglion cell survival. Elucidation of the molecular basis of these innate cytoprotective pathways will yield a unique category of prevention and treatment strategies for the high-risk glaucoma population.

描述（由申请人提供）：青光眼影响美国数百万人，是全球第二大失明原因。虽然降低眼压的手术和药物方法可能是有益的，但最近召开的 NEI 战略规划小组明确建议重点研究视网膜神经节细胞神经保护。在这方面的一种新方法是通过预处理激活细胞内源性的强大生存机制。我们是第一个在啮齿动物中证明短暂暴露于非伤害性缺血或缺氧可以促进视网膜近乎完全保护免受缺血性损伤的人。我们现在在实验性青光眼小鼠模型中表明，在高眼压之前反复缺氧预处理诱导的持久表型变化可以防止神经节细胞死亡。本文提出的研究将利用诱导型和视网膜特异性敲除小鼠和转基因小鼠来开始阐明这种先天保护反应的机制基础，我们将其称为青光眼耐受性。具体目标 1：阐明缺氧诱导转录因子 HIF-11 在介导青光眼耐受性基因表达变化中的作用。假设：重复缺氧预处理后的神经节细胞保护源于 HIF-11 独特的表达谱，该表达谱导致血红素加氧酶-1 和其他促进存活的 HIF-11 基因靶标的持久表达。具体目标 2：确定一氧化氮如何调节重复低氧预处理的能力，以促进青光眼耐受。假设：通过重复缺氧预处理激活组成型一氧化氮合酶亚型对于通过促进 HIF-11 介导和 CREB 介导的细胞保护基因转录来诱导持久的细胞保护表型是必要的。具体目标 3：建立因缺氧预处理诱导 pAkt（蛋白激酶 B）依赖性生存途径激活而实现青光眼耐受的机制。假设：重复缺氧预处理可促进 pAkt 稳定，并随后促进几种有助于青光眼耐受的抗凋亡效应物的长期磷酸化。本研究项目中确定的神经节细胞保护的内源性机制可能为预防或减少青光眼视神经病变提供新的治疗靶点。青光眼中的神经节细胞死亡导致数百万人严重视力丧失。我们的工作提供了一种保护神经节细胞的新方法：应用应激刺激激活基因表达的内源机制，以促进神经节细胞存活。阐明这些先天细胞保护途径的分子基础将为高危青光眼人群产生一类独特的预防和治疗策略。