Guidance Molecules in Retinal Axon Disease

我们的长期研究目标是了解视神经轴突对损伤和疾病反应的基本机制。本申请的总体目的是研究EphB 2和EphB 3（受体酪氨酸激酶的EphB家族的成员）在慢性视神经疾病（例如青光眼性神经病）的发展或进展中的潜在作用。总的来说，视神经病是一种主要的使人衰弱的疾病，在这个国家影响着300多万人，估计全世界有7000万人。增加对导致视力丧失的基本疾病机制的理解具有根本的重要性，并且与国家眼科研究所的使命直接相关。拟议的研究测试了EphB2和EphB3的假设，EphB2和EphB3是以前已知的在发育过程中的轴突指导作用的分子，在功能上参与视神经病中轴突缺失和视觉障碍的发展。该提案涉及这一假设的体内测试，调查在EphB2和EphB3不存在的情况下，激光诱导青光眼小鼠中RGC轴突损失的严重程度是否改变。在第二种青光眼小鼠模型DBA12J小鼠中进行了类似的研究，以加强研究结果与疾病机制的潜在相关性。这些研究的结果提供了外界信号如何影响视网膜神经节细胞轴突的正常健康，并可能导致神经节细胞的最终丧失的见解。鉴于参与EphB介导的信号传导的机制已被广泛研究，有机会利用我们对EphB生物学的理解来指导青光眼未来治疗策略的发展。

The long-term objective of our research is to understand the basic mechanisms underlying optic nerve axon response to injury and disease. The overall aim of the current application is to investigate the potential role of EphB2 and EphB3, members of the EphB family of receptor tyrosine kinases, in the development or progression of chronic optic nerve disease such as glaucomatous neuropathy. As a whole, optic neuropathies are a major debilitating disease that affects more than three million individuals in this country, and an estimated seventy million worldwide. An increased understanding of the basic disease mechanisms leading to vision loss is of fundamental importance and is directly relevant to the mission of the National Eye Institute. The proposed studies test the hypothesis that EphB2 and EphB3, molecules previously known for their axon guidance role during development, are functionally involved in the development of axon loss and visual disability in optic neuropathies. The proposal involves in vivo tests of this hypothesis investigating whether the severity of RGC axon loss in mice with laser-induced glaucoma is altered in the absence of EphB2 and EphB3. This is supplemented by similar studies in a second mouse model of glaucoma, the DBAl2J mouse, in order to strengthen the potential relevance of the study results to disease mechanisms. The results from these studies provide inSight into how extrinsic signals can affect the normal health of retinal ganglion cell axons and can lead to the eventual loss of ganglion cells. Given that the mechanisms involved in EphB mediated signaling have been extensively studied, there is an opportunity to utilize our understanding of EphB biology to guide the development of future therapeutic strategies for glaucoma.