Molecular Mechanisms underlying vision impairment after TBI

 描述(由申请人提供)：创伤性脑损伤(TBI)每年在美国影响约170万人。超过47%的受伤人口患有非表浅性眼部损伤，其中很大一部分人面临失明风险。颅脑损伤诱发的增重 视力问题包括双眼视觉功能障碍、光敏感、畏光和视觉 场缺陷。这些通常与由于视网膜神经节细胞(RGC)损伤而导致的急性和慢性PERG反应不足有关。这些伤害的病理生理学还不是很清楚，但对我们士兵和退伍军人的日常生活活动产生了负面影响。我们假设，通过抑制Brn3a-硫水化(Brn3a-SSH)可以改善或防止脑损伤依赖的RGC严重死亡以及随后的PERG缺陷和视力障碍，Brn3a-SSH是导致Brn3a降解和失活的关键机制。这一假说是基于我们最近发表的数据，该数据显示CBS高度富含RGC，而我们令人信服的初步数据表明，TBI导致RGC死亡增加，同时通过与E3连接酶Siah的相互作用降解硫化的Brn3a。在CBS杂合子小鼠(CBS+/-)或给予Brn3a硫化突变体(Brn3a-C406S)后，TBI诱导的RGC细胞死亡明显减少。我们概述了三个特定的目的来检验上述假说：目的1检验TBI通过调节CBS表达和细胞内H2S水平导致Brn3a-硫酸盐水合的假说。目的2：验证Brn3a-硫酸盐水合作用触发脑损伤后RGC死亡的假说。目的3：验证减少Brn3a-硫酸盐水合作用挽救脑损伤引起的RGC功能和结构改变的假说。实现这些目标将有助于更清楚地理解Brn3a-硫酸盐水合作用导致脑损伤后RGC丢失的机制(S)。鉴于Brn3a的失活对脑损伤后RGC丢失的诱导，防止Brn3a-硫酸盐水合将具有深远的翻译意义。

 DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) affects about 1.7 million people in the US per year. More than 47% of total injured population had non-superficial eye injuries and a large subset of this population is under the risk of blindness. TBI-induced increase in visual problems includes binocular vision dysfunction, light sensitivity, photophobia and visual field defects. These are often associated with deficiency in both acute and chronic PERG responses due to damage to retinal ganglion cells (RGC). The pathophysiology of these injuries is not well understood but impacts negatively the daily living activities of our soldiers and veterans. We hypothesize that TBI-dependent severe RGC death and subsequent deficiency in PERG and vision disturbances can be ameliorated or prevented by inhibiting Brn3a-sulfhydration (Brn3a-SSH), the key mechanism responsible for degradation and inactivation of Brn3a. The hypothesis is based on our recently published data showing that CBS is highly enriched in RGC and our compelling preliminary data showing that TBI leads to increased RGC death concomitant with degradation of sulfhydrated Brn3a through its interaction with an E3 ligase Siah. In CBS heterozygous mice (cbs+/-) or administration of sulfhydration mutant of Brn3a, (Brn3a-C406S), TBI-induced RGC cell death was reduced significantly. We outline three Specific Aims to test the above hypotheses: Aim 1 Test the hypothesis that TBI leads to Brn3a-sulfhydration via modulation of CBS expression and intracellular H2S levels. Aim 2: Test the hypothesis that Brn3a-sulfhydration triggers RGC death following TBI. Aim 3: Test the hypothesis that reducing Brn3a-sulfhydration rescues TBI-induced functional and structural alterations in RGC. Accomplishing these aims will lead to a clearer understanding of the mechanism(s) by which Brn3a- sulfhydration contributes to induction of RGC loss following TBI. Given the impact of inactivation of Brn3a on induction of RGC loss after TBI, preventing Brn3a-sulfhydration will have far-reaching translational implications.