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Neuroprotection and Retinal Ganglion Cell Death

神经保护和视网膜神经节细胞死亡

基本信息

批准号：
8002010
负责人：
RICHARD Harry MASLAND
金额：
$ 32.29万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2012-12-31
项目状态：
已结题

项目摘要

Neuroprotection and Retinal Ganglion Cell Death The overarching goal of the studies proposed in this application is to understand the specific apoptosis pathways that are triggered in RGC in glaucoma in order to identify targets for neuroprotection. In this application, we will build on a series of exciting new observations to test our hypothesis that calcineurin acts as a central control point in RGC death in glaucoma. In the aqueous outflow obstruction (Morrison) rat model of experimental glaucoma, we observe an increased lOP-related apoptotic cascade that involves dephosphorylation of proapoptotic Bad,release of cytochrome c (cytc) from the mitochondria, caspase activation and apoptotic retinal ganglion RGC loss. We hypothesize that these events are a consequence of aberrant calcineurin activation. Treatment of rats with surgically induced glaucoma with the calcineurin inhibitor, FK506 (tacrolimus, an FDA-approved immunosuppressant), leads to a dramatic neuroprotective response with blunting of the pBad dephosphorylation, cyt c release, RGC loss and axonal destruction. Moreover, in both rats with elevated IOP and the DBA/2J mouse model of glaucoma, we observe only in eyes with elevated IOP the appearance of a truncated form of calcineurin that lacks a key inhibitory domain, and is therefore constitutively active and proapoptotic. New preliminary data are consistent with calpain causing this abnormal cleavage event. These results suggest that calpain and calcineurin activation are critical early mediators of pressure-induced RGC death and that calcineurin activation is a potential nodal point in the control of RGC death in glaucoma. This hypothesis is tested in 3 aims: We propose to further evaluate the relationship between IOP and calpain and calcineurin activation and apoptosis of RGC to understand early events in IOP induced RGC death (aim 1). We will formally test the hypothesis thta the mechanism of action of FK506 is local inhibition of calcineurin (aim2). We will assess the role of calpain activation of calcineurin and of caspases, and determine whether calpain inhibition is neuroprotective in experimental glaucoma (aim 3). If further confirmed, these findings point towards a novel neuroprotective strategy with clinical applicability.

Neuroprotection and Retinal Ganglion Cell Death 本申请中提出的研究的总体目标是了解特定的细胞凋亡青光眼 RGC 中触发的通路，以确定神经保护的目标。在这个应用程序中，我们将建立一系列令人兴奋的新观察结果来检验我们的假设，即钙调神经磷酸酶的作用作为青光眼 RGC 死亡的中心控制点。在房水流出阻塞（莫里森）大鼠中在实验性青光眼模型中，我们观察到 IOP 相关的细胞凋亡级联增加，其中涉及促凋亡 Bad 的去磷酸化，线粒体中细胞色素 c (cytc) 的释放，半胱天冬酶激活和凋亡性视网膜神经节 RGC 损失。我们假设这些事件是一个结果 of aberrant calcineurin activation.用钙调神经磷酸酶治疗手术诱发的青光眼大鼠抑制剂 FK506（他克莫司，FDA 批准的免疫抑制剂）可产生显着的神经保护作用 pBad 去磷酸化、细胞色素 c 释放、RGC 损失和轴突破坏减弱的反应。此外，在眼压升高的大鼠和青光眼 DBA/2J 小鼠模型中，我们仅观察到眼压升高的眼睛出现截短形式的钙调神经磷酸酶，缺乏关键的抑制作用结构域，因此具有组成型活性和促凋亡作用。 New preliminary data are consistent with calpain causing this abnormal cleavage event.这些结果表明钙蛋白酶和钙调磷酸酶激活是压力引起的 RGC 死亡的关键早期介质，钙调磷酸酶激活是一种潜在的控制青光眼 RGC 死亡的节点。该假设通过 3 个目标进行检验：我们建议进一步评价眼压与钙蛋白酶、钙调神经磷酸酶激活及RGC凋亡的关系了解 IOP 引起的 RGC 死亡的早期事件（目标 1）。 We will formally test the hypothesis thta the FK506 的作用机制是局部抑制钙调神经磷酸酶 (aim2)。 We will assess the role of calpain 激活钙调神经磷酸酶和半胱天冬酶，并确定钙蛋白酶抑制是否具有神经保护作用 experimental glaucoma (aim 3).如果进一步得到证实，这些发现将指向一种新型的神经保护剂 strategy with clinical applicability.