ENDOGENOUS NEUROPROTECTION IN GLAUCOMA

青光眼的内源性神经保护

• 批准号: 7761671
• 负责人: JEFFREY M GIDDAY
• 金额: $ 37.62万
• 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/7761671
• 关键词: Affect; Apoptotic; Blindness; Categories; Cell Death; Cell Survival; Cells; Cytoprotection; Exposure to; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glaucoma; Hypertension; Hypoxia; Individual; Injury; Ischemia; Knock-out; Mediating; Molecular; Molecular Profiling; Names; Nitric Oxide; Nitric Oxide Synthase; Operative Surgical Procedures; Pathway interactions; Phenotype; Phosphorylation; Physiologic Intraocular Pressure; Population; Prevention; 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

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(申请人提供)：青光眼在美国影响着数百万人，是全球第二大致盲原因。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对视网膜神经节细胞神经保护进行重点研究。在这方面，一种新的方法是通过预适应激活细胞内源性强大的生存机制。我们首次在啮齿类动物身上证明，短暂的非损伤性缺血或缺氧可促进视网膜免受缺血损伤的近乎完全的保护。我们现在在实验性青光眼的小鼠模型中表明，在高眼压之前，重复低氧预适应引起的长期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可诱导的和视网膜特异的基因敲除和转基因小鼠来开始阐明这种先天保护反应的机制基础，我们称之为青光眼耐受。具体目的1：阐明缺氧诱导转录因子HIF-11在介导青光眼耐受相关基因表达变化中的作用。假设：重复低氧预适应后的神经节细胞保护是由于HIF-11独特的表达谱导致血红素加氧酶-1和其他促进生存的HIF-11基因靶标的长期表达。具体目标2：确定一氧化氮如何调节重复低氧预适应促进青光眼耐受的能力。假设：通过重复低氧预适应激活构成一氧化氮合酶亚型，是通过促进HIF-11和CREB介导的细胞保护基因转录而诱导持久的细胞保护表型所必需的。具体目标3：建立低氧预适应诱导依赖蛋白激酶B的生存通路激活导致青光眼耐受的机制。假设：重复的低氧预适应促进PAKT的稳定，随后，几个抗凋亡效应分子的长时间磷酸化有助于青光眼耐受。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。青光眼中的神经节细胞死亡是导致数百万人严重视力丧失的原因。我们的工作提供了一种新的神经节细胞保护方法：应用应激刺激激活基因表达的内源性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产生一种针对高危青光眼人群的独特的预防和治疗策略。