Neurotrophins and Retinal Ganglion Cell Regeneration

神经营养因子和视网膜神经节细胞再生

• 批准号: 8320222
• 负责人: Rosa E. Blanco
• 金额: $ 11.14万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320222
• 关键词: Adult; Affect; Axon; Biological Assay; Biological Models; Brain-Derived Neurotrophic Factor; Cell Death; Cell Survival; Collaborations; Development; Disease; Educational workshop; Electron Microscopy; Goals; Grant; Injury; Knowledge; Learning; Lesion; Link; Mammals; Measures; Mediating; Memory; Methods; Molecular; Natural regeneration; Neuraxis; Neurons; Optic Nerve; Optics; Pathway interactions; Pattern; Peer Review; Photic Stimulation; Polymers; Process; Publications; Rana; Recovery; Research; Retinal; Retinal Ganglion Cells; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Speed; Staging; Staining method; Stains; Synapses; Techniques; Tectum Mesencephali; Testing; Therapeutic; United States National Institutes of Health; Visual; Visual system structure; Work; abstracting; axon growth; axon regeneration; ganglion cell; implantation; improved; in vivo; inhibitor/antagonist; neurotrophic factor; optic nerve regeneration; prevent; public health relevance; retinotectal; retinotopic; synaptogenesis

DESCRIPTION (provided by applicant): Abstract After lesioning the frog optic nerve, regeneration occurs and retinal ganglion cells (RGCs) reconnect to their targets. Even so, approximately 50% of the retinal ganglion cells die, compared to mammals where almost all do so. Application of neurotrophins such as brain-derived neurotrophic factor (BDNF) can largely prevent this cell death. However, although these factors are known to have potent effects on axonal growth, branching and synapse formation during development, very little is known about how they will affect regrowing axons during regeneration and reconnection to the target. Before neurotrophins can be used therapeutically to increase ganglion cell survival it is important that these potential effects on target reconnection are understood. The following aims should help in that understanding, and will contribute to our long-term goal of elucidating the molecular requirements for achieving complete and accurate regeneration of the optic pathway. In the first aim, we will test the hypothesis that axonally-applied BDNF increases the speed of axonal regeneration. This will be tested using assays of axonal growth with immunohistochemical markers, and by investigating whether blockers of the Erk and PI3K signaling pathways slow axonal regeneration. In the second aim, we will test the hypothesis that BDNF is synthesized in the tectum, and that increasing tectal BDNF levels promotes RGC branching and synapse formation and modulates the refinement of the retinotopic projection during regeneration. In the third aim, we will investigate how the levels and patterns of visual activity affect the synthesis of BDNF by regenerating frog RGCs, and whether these changes in BDNF synthesis in RGCs in turn affect the refinement of the regenerating retinal projection. This research will help our understanding of the molecular pathways involved in the regrowth and reconnection of regenerating nerve cells in the central nervous system. PUBLIC HEALTH RELEVANCE: Relevance This research will help our understanding of the molecular pathways involved in the regrowth and reconnection of regenerating nerve cells in the central nervous system. This basic knowledge will increase our understanding of the molecular mechanisms involved in the formation and modulation of synaptic connections during regeneration. It will also have the potential to contribute towards improved therapeutic methods to promote recovery after injury and disease.

描述（由申请人提供）：摘要使青蛙视神经，再生发生，视网膜神经节细胞（RGC）重新连接到其靶标。即便如此，与几乎全部这样做的哺乳动物相比，大约50％的视网膜神经节细胞死亡。神经营养蛋白（例如脑源性神经营养因子（BDNF））的应用可以在很大程度上预防这种细胞死亡。但是，尽管已知这些因素对轴突生长，分支和突触在发育过程中产生有效的影响，但对于它们在再生和重新连接期间如何影响轴突将如何影响它们将如何影响轴突。在神经营养蛋白可以治疗以增加神经节细胞的存活之前，重要的是要了解这些潜在的对目标重新连接的影响。以下目标应有助于这种理解，并将有助于我们阐明分子需求以实现光学途径的完整和准确再生的长期目标。在第一个目的中，我们将测试轴突应用的BDNF增加轴突再生速度的假设。这将使用带有免疫组织化学标记的轴突生长的测定法进行测试，并通过研究ERK和PI3K信号通路的阻滞剂是否慢轴突再生。在第二个目的中，我们将检验以下假设：BDNF在tectum中合成，并且增加的直肠BDNF水平会促进RGC分支和突触形成，并调节再生过程中视网膜预测的完善。在第三个目标中，我们将研究视觉活动的水平和模式如何通过再生青蛙RGC来影响BDNF的综合，以及RGC中BDNF合成中的这些变化反过来又影响了重生视网膜预测的细化。这项研究将有助于我们理解中枢神经系统中涉及和重新连接的分子途径。 公共卫生相关性：相关性这项研究将有助于我们理解中枢神经系统中再生神经细胞的再生和重新连接所涉及的分子途径。这些基本知识将增加我们对再生过程中突触连接形成和调节所涉及的分子机制的理解。它还有潜力有助于改善治疗方法，以促进受伤和疾病后的康复。