Axon Guidance Molecules and Optic Nerve Disease

轴突引导分子与视神经疾病

• 批准号: 7497727
• 负责人: DAVID W SRETAVAN
• 金额: $ 4.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497727
• 关键词: Adult; Affect; Age; Age-Months; Animals; Apoptosis; Axon; Axonal Transport; Behavior; Binding; Biological; Biological Assay; Blindness; Calcium; Cell Death; Cells; Cessation of life; Chronic; DBA/2 Mouse; Data; Depth; Development; Disease; Elevation; Embryo; Event; Exhibits; Exposure to; Family; Foundations; Functional disorder; Future; General Population; Genes; Glaucoma; Growth Cones; Health; In Situ Hybridization; Inbred DBA Mice; Lead; Link; Localized; Mechanics; Mediating; Molecular; Mouse Strains; Mus; Natural regeneration; Nervous System Part; Nervous system structure; Neuronal Injury; Neurons; Optic Disk; Optic Nerve; Optic Nerve Injuries; Pathogenesis; Pathology; Patients; Physiologic Intraocular Pressure; Physiological; Physiology; Play; Primates; Property; Reporting; Research; Retina; Retinal Ganglion Cells; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Site; Testing; Therapeutic; Thinking; Time; Tissues; Visual; Wit; Work; axon growth; axon guidance; disability; interest; neurodevelopment; neuronal cell body; nonhuman primate; optic nerve disorder; receptor; receptor binding; research study; response

The chronic and progressive loss of Retinal Ganglion Cells (RGC) and their axons is a hallmark of Glaucoma. Despite its well-appreciated link with elevated intraocular pressure (IOP), the sequence of molecular events that lead to RGC dysfunction and subsequent death is not clearly understood. Although increases in IOP may directly impact RGC cell bodies in the retina, a substantial body of evidence suggests that the site of primary damage may in fact be at the optic nerve head (ONH). It is thought that intrinsic tissue properties in the ONH makes it especially susceptible to mechanical damage, resulting in localized cellular and molecular changes that affect optic nerve axon physiology and survival. The identification of the direct molecular triggers of optic nerve axon dysfunction in glaucoma will significantly enhance our understanding of disease pathogenesis and may also potentially provide new important therapeutic avenues. Axon guidance molecules serve as key developmentalproteins that collectively exert major effects on RGC axons during formation of the optic nerve. Axon guidance molecules can directly activate intracellular signaling pathways in developing RGC axons to trigger cytoskeletal disassembly and the elimination of inappropriate axon branches. Recent work has reported that axon guidance molecules are also present in the adult nervous system particularly in settings of neuronal injury and pathology, where they may have previously unappreciated injurious functions on both neurons and axons. In our own work, we have found that specific guidance molecules reappear after optic nerve trauma and govern the ability of damaged adult RGC axons to regenerate. A possible functional role for axon guidance molecules in causing axon damage in more chronic and progressive forms of optic nerve injury, such as glaucoma, has not been explored. In this application, we propose a set of studies to test the notion that axon guidance molecule expression is up-regulated at the glaucomatous adult ONH region and that these axon guidance molecules are capable of eliciting significant physiological responses in adult RGC axons. These studies form the initial tests of a broader hypothesis that axon guidance molecules at the ONH trigger RGC axon dysfunction and are involved in the development or severity of glaucomatous damage. Our preliminary evidence shows that expression of specific axon guidance molecules are indeed up-regulated at the ONH of DBA/2J glaucomatous mice around the time of onset of axon damage. Furthermore, these molecules are capable of physiologically activating adult RGC axons, consistent with our specific hypothesis that guidance molecules may have a primary role in mediating axon damage in glaucoma.

视网膜神经节细胞（RGC）及其轴突的慢性和进行性损失是视网膜病变的标志。 青光眼尽管其与眼内压（IOP）升高的联系已被充分认识，但 导致RGC功能障碍和随后死亡的分子事件还不清楚。虽然 大量证据表明，IOP的增加可能直接影响视网膜中的RGC细胞体， 原发性损害的部位实际上可能在视神经头（ONH）。人们认为， ONH中的组织特性使其特别容易受到机械损伤，导致局部损伤。 影响视神经轴突生理和存活的细胞和分子变化。的识别 青光眼视神经轴突功能障碍的直接分子触发因素将显著增强我们的 了解疾病的发病机制，也可能潜在地提供新的重要的治疗途径。 轴突导向分子作为关键的发育蛋白， 视神经形成过程中的RGC轴突。轴突导向分子可以直接激活细胞内 信号通路在发展RGC轴突触发细胞骨架解体和消除 不适当的轴突分支最近的工作报道，轴突导向分子也存在于 成人神经系统，特别是在神经元损伤和病理的情况下，他们可能有 对神经元和轴突的先前未被认识到的损伤功能。在我们自己的工作中，我们发现 特定的引导分子在视神经损伤后重新出现， RGC轴突再生。轴突导向分子在引起神经元轴突损伤中可能的功能作用 还没有研究更慢性和进行性形式的视神经损伤，例如青光眼。 在这个应用中，我们提出了一系列研究来测试轴突导向分子 表达上调，在成人神经胶质瘤的ONH区域，这些轴突导向分子， 能够在成年RGC轴突中引发显著的生理反应。这些研究形成了最初的 测试了一个更广泛的假设，即ONH的轴突导向分子触发RGC轴突功能障碍， 与昏迷损害的发展或严重程度有关。我们的初步证据显示， 在DBA/2 J胶质瘤的ONH中，特异性轴突导向分子的表达确实上调， 在轴突损伤开始的时候。此外，这些分子能够在生理上 激活成人RGC轴突，这与我们的特定假设一致，即引导分子可能有一个 在介导青光眼轴突损伤中的主要作用。