ENDOGENOUS NEUROPROTECTION IN GLAUCOMA

青光眼的内源性神经保护

• 批准号: 7351622
• 负责人: JEFFREY M GIDDAY
• 金额: $ 37.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351622
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Accounting; Acute; Address; Affect; Apoptotic; Blindness; CREB1 gene; Categories; Cell Death; Cell Survival; Cells; Cyclic AMP-Responsive DNA-Binding Protein; Cytoprotection; Documentation; Erythropoietin; Exhibits; Experimental Models; Exposure to; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glaucoma; Goals; Hypertension; Hypoxia; Individual; Injury; Ischemia; Knock-out; Knowledge; Laboratories; Mediating; Molecular; Molecular Genetics; Molecular Profiling; Mus; Mutant Strains Mice; NOS1 protein, human; Neuraxis; Nitric Oxide; Nitric Oxide Synthase; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Physiologic Intraocular Pressure; Population; Prevention; Protein Isoforms; Proto-Oncogene Proteins c-akt; Publishing; Research; Retina; Retinal; Retinal Ganglion Cells; Risk; Rodent; Role; Signal Pathway; Stimulus; Strategic Planning; Stress; Thioredoxin; Tissues; Transcription Coactivator; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Week; Work; base; ganglion cell; heme oxygenase-1; human NOS3 protein; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; mouse model; neuroprotection; novel; novel strategies; novel therapeutics; optic nerve disorder; preconditioning; prevent; programs; progressive neurodegeneration; protective effect; response; retinal ischemia; therapeutic target; transcription factor; zinc-protoporphyrin-9

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）：青光眼在美国影响数百万人，是全球第二大致盲原因。虽然手术和药物方法降低眼压可能是有益的，但最近召集的NEI战略规划小组明确建议重点研究视网膜神经节细胞的神经保护。在这方面，一种新的方法是通过预处理激活细胞内源性的强大的生存机制。我们是第一个在啮齿动物中证明短暂暴露于非损伤性缺血或缺氧可促进视网膜免受缺血性损伤的几乎完全保护。我们现在在实验性青光眼小鼠模型中表明，在眼内高压之前，由缺氧反复预处理引起的长期表型改变可以防止神经节细胞死亡。本文提出的研究将利用诱导和视网膜特异性敲除和转基因小鼠来开始阐明这种我们称之为青光眼耐受性的先天保护反应的机制基础。特异性目的1：阐明缺氧诱导的转录因子HIF-11在青光眼耐受基因表达变化中的介导作用。假设：重复缺氧预处理后的神经节细胞保护来自HIF-11的独特表达谱，导致血红素加氧酶-1和其他促进生存的HIF-11基因靶点的持久表达。具体目标2：确定一氧化氮如何调节重复缺氧预处理促进青光眼耐受性的能力。假设：通过重复缺氧预处理激活组成型一氧化氮合酶同工型是通过促进hif -11介导和creb介导的细胞保护基因转录诱导持久细胞保护表型所必需的。具体目标3：建立青光眼耐受是缺氧预处理诱导的pAkt（蛋白激酶B）依赖生存途径激活的结果。假设：重复缺氧预处理促进pAkt的稳定，随后，几个抗凋亡效应物的磷酸化延长，有助于青光眼耐受性。本研究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。青光眼的神经节细胞死亡是造成数百万人视力丧失的主要原因。我们的工作为神经节细胞保护提供了一种新的途径：应用应激刺激激活内源性基因表达机制来促进神经节细胞的存活。阐明这些先天细胞保护途径的分子基础将为青光眼高危人群提供一种独特的预防和治疗策略。