Optic nerve regeneration: translational studies

视神经再生：转化研究

• 批准号: 8620787
• 负责人: LARRY Ira BENOWITZ
• 金额: $ 15.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620787
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenylate Cyclase; Area; Axon; Back; Binding; Binding Proteins; Biological Models; Blindness; Brain; Cell surface; Cells; Cicatrix; Clinical; Complement; Cyclic AMP; Data; Degenerative Disorder; Dependovirus; Dominant-Negative Mutation; Dose; Enzymes; Eye; Future; Genes; Glaucoma; Growth; Growth Cones; Growth Factor; Growth Inhibitors; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Left; Length; Life; Mediating; Methods; Midbrain structure; Monomeric GTP-Binding Proteins; Mus; Myelin; Natural regeneration; Nerve; Neuraxis; Neuroglia; Neurons; Optic Chiasm; Optic Nerve; Optic Nerve Injuries; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Proteins; Reagent; Research; Retinal Ganglion Cells; Signal Pathway; Signal Transduction; Small Interfering RNA; Stream; Synapses; Tars; Testing; Time; Translating; Virus; Vision; Vision Disorders; Visual; analog; axon growth; axon regeneration; clinical application; comparative efficacy; diencephalon; gene therapy; inhibitor/antagonist; injured; nerve injury; neural circuit; oncomodulin; optic nerve regeneration; public health relevance; receptor; recombinase; repaired; response; ribosyltransferase; translational study; treatment effect

Summary The optic nerve cannot regenerate if injured, leaving victims of traumatic or ischemic nerve damage or degen- erative diseases such as glaucoma with permanent visual losses. We have recently identified ways to partially reverse this situation by activating the intrinsic growth state of retinal ganglion cells (RGCs), the projection neu- rons of the eye. When exposed to oncomodulin (Ocm), a growth factors produced by inflammatory cells, RGCs lacking the pten gene and having elevated levels of cAMP are able to regenerate injured axons through the en- tire optic nerve, across the optic chiasm, and into appropriate target areas, where they form synapses and par- tially restore visual responses. We now propose to develop ways to translate these findings into methods that are suitable for clinical application. We will develop and test adeno-associated viruses to express Ocm, elevate intracellular levels of cAMP, and counteract cell-intrinsic and cell-extrinsic inhibitors of axon growth. These studies will increase our ability to augment regeneration in the optic nerve, potentially helping many victims of traumatic or degenerative visual disorders. The methods and reagents developed here may also be useful for restoring neural circuits in other parts of the CNS. !! ! !

摘要 如果视神经受伤，就不能再生，导致创伤性或缺血性神经损伤或变性- 永久性视力丧失的疾病，如青光眼。我们最近找到了部分 通过激活视网膜神经节细胞(RGC)的固有生长状态，即投射神经元，来逆转这种情况。 眼睛的隆隆。当接触到肿瘤素(OCM)时，这是一种由炎症细胞、RGCs产生的生长因子 缺乏PTEN基因和cAMP水平升高的人能够通过EN-2再生受损的轴突。 疲劳视神经，穿过视交叉，进入适当的靶区，在那里它们形成突触和PAR- 最终恢复视觉反应。我们现在建议开发一些方法来将这些发现转化为 均适合临床应用。我们将开发和测试腺相关病毒来表达OCM，提升 细胞内cAMP水平，并抵消细胞内和细胞外的轴突生长抑制因子。这些 研究将增加我们增强视神经再生的能力，潜在地帮助许多 外伤性或退化性视力障碍。这里开发的方法和试剂也可能对 恢复中枢神经其他部分的神经回路。 ！！ 好了！ 好了！