Molecular Mechanisms underlying vision impairment after TBI

TBI 后视力障碍的分子机制

• 批准号: 9420719
• 负责人: Nilkantha Sen
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9420719
• 关键词: Activities of Daily Living; Acute; Affect; Alpha Cell; American; Attenuated; Axonal Transport; Binding; Binocular Vision; Blindness; Brain Injuries; CASP3 gene; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Chronic; Cystathionine beta-Synthase; Cysteine; DNA Binding Domain; Data; Defect; Detection; Enzymes; Eye Injuries; Functional disorder; Genetic Transcription; Goals; Hydrogen Sulfide; Impairment; In Situ Nick-End Labeling; Individual; Injury; Intervention; Laboratories; Measures; Modeling; Molecular; Molecular Target; Monitor; Morbidity - disease rate; Mus; Neuronal Differentiation; Neurons; Outcome; Oxidative Stress; Pattern; Photophobia; Population; Process; Protein Analysis; Proteins; Publishing; Research; Retina; Retinal; Retinal Ganglion Cells; Risk; Route; Scotoma; Soldier; Stress; Stroke; Synapses; Testing; Therapeutic Intervention; Transcriptional Activation; Traumatic Brain Injury; Up-Regulation; Veterans; Vision; Visual; Visual Fields; Visual impairment; axonal degeneration; base; gene synthesis; hypoxia inducible factor 1; injured; mitochondrial dysfunction; mortality; mouse model; mutant; nervous system disorder; novel; overexpression; particle; prevent; promoter; public health relevance; response; small hairpin RNA; sulfhydration; tool; transcription factor; ubiquitin-protein ligase

 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.

 描述（由申请人提供）：创伤性脑损伤（TBI）每年影响美国约170万人。超过47%的总受伤人口有非浅表性眼损伤，这一人群的一个大的子集是失明的风险。TBI诱导增加 包括双眼视觉功能障碍、光敏感、恐惧症和视觉障碍。 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反应的缺乏有关。这些损伤的病理生理学尚不清楚，但对我们的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TBI依赖性严重RGC死亡和随后的PERG缺陷和视力障碍可以通过抑制Brn 3a-巯基化（Brn 3a-SSH）来改善或预防，Brn 3a-巯基化是负责Brn 3a降解和失活的关键机制。该假设是基于我们最近发表的数据，显示CBS高度富集RGC，以及我们令人信服的初步数据，显示TBI导致RGC死亡增加，伴随着通过其与E3连接酶Siah的相互作用而降解的巯基化Brn 3a。在CBS杂合子小鼠（cbs+/-）或Brn 3a的硫水合突变体（Brn 3a-C406 S）的给药中，TBI诱导的RGC细胞死亡显著减少。我们概述了三个具体目的来测试上述假设：目的1测试TBI通过调节CBS表达和细胞内H2S水平导致Brn 3a-硫水合的假设。目的2：检验Brn 3a-硫水合作用在TBI后触发RGC死亡的假设。目的3：测试减少Brn 3a-硫水合作用拯救TBI诱导的RGC功能和结构改变的假设。实现这些目标将导致更清楚地理解Brn 3a-硫水合作用有助于诱导TBI后RGC损失的机制。鉴于Brn 3a失活对TBI后诱导RGC损失的影响，防止Brn 3a-硫水合作用将具有深远的翻译意义。