Transient Receptor Potential Channels and Neurodegeneration in Glaucoma

描述（由申请人提供）：我们的长期目标是了解青光眼中神经变性的机制并找到减轻它的新方法。青光眼中的视力丧失涉及通过两种广泛的变性程序选择性丧失视网膜神经节细胞（RGC）神经元：在视投射中，影响RGC轴突，以及在视网膜中，影响RGC树突，突触和细胞体。变性是由于对眼内压（IOP）的敏感性引起的，但降低IOP的方案并不总是减缓进展。因此，在神经元水平进行干预需要更好地了解RGC通路如何响应IOP相关的应激源，以及这种响应是否包括对抗功能丧失的机制。我们在这个项目中的目标是集中在表征一个这样的机制，涉及TRPV 1（瞬时受体电位香草素-1）受体。我们的中心假设是TRPV 1通过增强对IOP相关应激的兴奋性活动来对抗RGC变性。在其他系统中，增加TRPV 1在神经元膜保持细胞骨架的完整性，并增强突触兴奋，通过提高钙离子活性，以应对压力。我们提出了一个类似的作用TRPV 1在RGCs中，已经建立了TRPV 1作为一个强大的Ca 2+通道在RGCs，激活时，增加兴奋和影响他们的生存。我们将使用急性（微珠闭塞）和慢性（DBA 2 J）小鼠模型来测试我们的假设，我们已经绘制了关键的RGC退行性结局指标。对于目标1，我们将应用急性模型的TRPV 1基因敲除小鼠，以确定TRPV 1依赖的轴突和视网膜的结果和他们的进展RGC变性。对于目标2，我们将在急性和慢性模型中比较TRPV 1表达和定位的IOP依赖性变化，并将这些变化与RGC亚细胞区室联系起来，以确定TRPV 1作用的结构相关性。对于目标3，我们将在两种模型中测量IOP的变化如何影响TRPV 1对RGC兴奋的贡献，并确定调节TRPV 1敏感性是否促进存活。这些新的研究将利用我们完成的TRPV 1研究和已经到位的独特工具箱来阐明一种新的级联反应，这种级联反应可以对抗和减缓与青光眼相关的压力诱导的功能丧失。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanisms of neurodegeneration in glaucoma and find new ways to abate it. Vision loss in glaucoma involves selective loss of retinal ganglion cell (RGC) neurons through two broad degenerative programs: in the optic projection, affecting RGC axons, and in the retina, affecting RGC dendrites, synapses and cell bodies. Degeneration arises from sensitivity to intraocular pressure (IOP), but IOP-lowering regimens do not always slow progression. Thus, to intervene at the neuronal level requires a better understanding of how the RGC pathway responds to IOP-related stressors and whether this response includes mechanisms to counter loss of function. Our objective in this project is focused on characterizing one such mechanism involving the TRPV1 (transient receptor potential vanilloid-1) receptor. Our central hypothesis is that TRPV1 counters RGC degeneration by enhancing excitatory activity in response to IOP- related stress. In other systems, increased TRPV1 at the neuronal membrane maintains cytoskeletal integrity and augments synaptic excitation by enhancing Ca2+ activity in response to stress. We propose a similar role for TRPV1 in RGCs, having established TRPV1 as a robust Ca2+ channel in RGCs that, when activated, increases excitation and influences their survival. We will test our hypothesis using both acute (microbead occlusion) and chronic (DBA2J) mouse models for which we have mapped key RGC degenerative outcome measures. For Aim 1, we will apply the acute model to a TRPV1 knock-out mouse to identify TRPV1- dependent axonal and retinal outcomes and their progression in RGC degeneration. For Aim 2, we will compare in the acute and chronic models IOP-dependent changes in TRPV1 expression and localization and link these changes to RGC subcellular compartments to identify structural correlates of TRPV1's action. For Aim 3 we will measure in both models how changes in IOP influence TRPV1's contribution to RGC excitation and determine if modulating TRPV1 sensitivity promotes survival. These new studies will capitalize on our completed studies of TRPV1 and a unique toolbox already in place to illuminate a novel cascade that could counter and slow stress-induced loss of function associated with glaucoma.