Role of gasderminD in ganglion cell dysfunction and injury

在原发性青光眼中，高眼压（OHT）应激触发神经毒性级联反应，导致选择性青光眼。 视网膜神经节细胞（RGC）死亡。然而，青光眼中将机械性、非缺血性应激转化为RGC功能障碍、损伤和死亡的分子机制仍然存在高度争议。我们发现 不同强度和持续时间的OHT应激急性激活神经元NLRP 1/NLRP 3炎性小体， 其在体内释放白细胞介素-1 β细胞因子并触发RGCs中GasderminD孔形成。 这个项目是基于我们激动人心的初步数据，其中炎性小体阻断抑制GsdmD 在急性OHT和慢性OHT中激活并预防OHT攻击的RGC的功能障碍和损失 （青光眼）模型。我们设计这个项目是为了验证我们的新假设，即代谢和生理 在OHT损伤中，RGCs的功能障碍导致其损失，这是通过激活GsdmD孔来促进的。 线粒体和质膜。如果我们的假设是正确的， 视网膜可以防止青光眼中RGC的功能下降和丢失。

In primary glaucoma, ocular hypertension (OHT) stress triggers a neurotoxic cascade leading to selective death of retinal ganglion cells (RGC). However, the molecular mechanism transforming mechanical, non-ischemic stress into RGC dysfunction, injury and death in glaucoma remains highly debated. We discovered that OHT stress of various intensity and duration acutely activates neuronal NLRP1/NLRP3 inflammasomes that release of interleukin-1β cytokine and trigger GasderminD pore formation in RGCs in vivo. This project is premised on our exciting preliminary data where inflammasome blockade suppressed GsdmD activation and prevented dysfunction and loss of OHT-challenged RGCs in both acute OHT and chronic OHT (glaucoma) models. We designed this project to test our new hypothesis that metabolic and physiological dysfunction of RGCs leading to their loss in OHT injury is facilitated by activation of GsdmD pores in mitochondria and plasma membranes. If our hypothesis is correct, modulation of inflammasome pathway in the retina would prevent functional decline and loss of RGC in glaucoma.