Transient Receptor Potential Channels and Neurodegeneration in Glaucoma

青光眼的瞬时受体电位通道和神经变性

基本信息

批准号：
8708867
负责人：
David J. Calkins
金额：
$ 39.31万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2016-04-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708867
关键词：
Abate Acute Address Affect Animals Axon Biological Preservation Blindness Cell membrane Cells Chronic Dendrites Disease Event Exposure to Glaucoma Goals Injury Intervention Investigational Therapies Knock-out Knockout Mice Learning Length Link Maps Measures Membrane Microspheres Modeling Mus Nerve Nerve Degeneration Neuroglia Neurons Optic Nerve Optics Outcome Outcome Measure Pathologic Processes Pathway interactions Physiologic Intraocular Pressure Regimen Research Retina Retinal Retinal Degeneration Retinal Ganglion Cells Role Site Stress Synapses System Testing Therapeutic Up-Regulation Vanilloid Work axonal degeneration base density desensitization experience innovation loss of function mouse model neuronal cell body novel novel strategies pressure programs receptor research study response stressor therapeutic target vanilloid receptor subtype 1

项目摘要

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.

描述（由申请人提供）：我们的长期目标是了解青光眼中神经退行性的机制，并找到减轻它的新方法。青光眼中的视力丧失涉及通过两个广泛的退化程序选择性丧失视网膜神经节细胞（RGC）神经元的选择性丧失：在光学投影中，影响RGC轴突，在视网膜中影响RGC树突，突触和细胞体。退化是由对眼内压（IOP）的敏感性引起的，但是降低IOP的方案并不总是会缓慢进展。因此，要在神经元水平上进行干预需要更好地理解RGC途径如何响应与IOP相关的压力源，以及该反应是否包括应对功能丧失的机制。我们在该项目中的目标集中在表征涉及TRPV1（瞬态受体电势Vanilloid-1）受体的一种此类机制。我们的中心假设是，TRPV1通过响应IOP相关的应力来增强兴奋活动来对抗RGC变性。在其他系统中，神经元膜上的TRPV1增加可通过响应压力来增强Ca2+活性来维持细胞骨架完整性并增强突触激发。我们提出了TRPV1在RGC中的类似作用，在RGC中将TRPV1建立为强大的Ca2+通道后，我们会增加激活时会增加激发并影响其存活。我们将使用急性（Microbead闭塞）和慢性（DBA2J）小鼠模型来检验我们的假设，为此我们绘制了关键的RGC退行性结果指标。对于AIM 1，我们将将急性模型应用于TRPV1敲除小鼠，以识别TRPV1依赖性轴突和视网膜结果及其在RGC变性中的进展。对于AIM 2，我们将在TRPV1表达和本地化的急性和慢性模型IOP依赖性变化中进行比较，并将这些更改与RGC亚细胞隔室联系起来，以识别TRPV1动作的结构相关性。对于AIM 3，我们将在两个模型中衡量IOP的变化如何影响TRPV1对RGC激发的贡献，并确定调节TRPV1敏感性是否促进生存。这些新的研究将利用我们对TRPV1的完整研究，以及已经建立了一个独特的工具箱，以照亮一种可以反击并缓慢应激引起的与青光眼相关的功能丧失的新型级联。