Synergy of ER stress and oxidative stress after TBI

描述（由申请人提供）：内质网（ER）的有效功能对于正常细胞功能是必不可少的，因为ER在维持细胞内Ca 2+稳态、蛋白质的正确折叠、翻译后修饰和新生蛋白质向不同目的地的运输中起重要作用。ER的任何破坏都会导致一组复杂的信号通路的激活，这些通路从ER传播到细胞质再到细胞核。这些统称为未折叠蛋白反应（UPR），其目的是补偿损伤并恢复正常的细胞内稳态。虽然有限和短暂的UPR是有益的，但长期或严重的UPR以及随后的ER应激导致细胞死亡。此外，CNS损伤导致氧化应激，这也是神经毒性的。我们推测，创伤性脑损伤（TBI）后，内质网应激和氧化应激是巧合的，相互加强双向和协同加重继发性脑损伤。使用啮齿动物模型的控制皮质撞击损伤，我们希望回答以下问题。(1)PERK介导的ER应激通路在TBI后的作用是什么？(2)在脑损伤后，内质网应激和氧化应激是否相关？特别是，如果ER应激介导的PERK和氧化应激调节NADPH氧化酶NOX 2相互影响？(3)敲除/抑制PERK通路eif 2、ATF 4和CHOP的单个限速蛋白对TBI后氧化应激和神经元损伤的影响是什么？相反，敲除/抑制NOX 2对TBI后ER应激和神经元损伤的影响是什么？长期目标是了解脑外伤后脑损伤中内质网应激和氧化应激的相互作用。

DESCRIPTION (provided by applicant): Efficient functioning of the Endoplasmic reticulum (ER) is indispensable for normal cellular functions as ER plays an important role in the maintenance of intracellular Ca2+ homeostasis, proper folding of proteins, post-translation modifications and transport of nascent proteins to different destinies. Any disruption of ER results in the activation of a complex set of signaling pathways that propagate from the ER to the cytosol to the nucleus. These are collectively known as unfolded protein response (UPR), which is aimed to compensate damage and to restore the normal cellular homeostasis. While limited and transient UPR is beneficial, prolonged or severe UPR, and the ensuing ER stress leads to cell death. Furthermore, CNS insults leads to oxidative stress which is also neurotoxic. We hypothesize that following traumatic brain injury (TBI), ER stress and oxidative stress are coincidental, potentiate each other bi-directionally and synergistically exacerbate the secondary brain damage. Using a rodent model of controlled cortical impact injury, we wish to answer the following questions. (1) What is the role of PERK-mediated ER stress pathway after TBI? (2) In the post-injury brain, are ER stress and oxidative stress connected? In particular, if ER stress mediated by PERK and oxidative stress modulated by NADPH oxidase NOX2 influence each other? (3) What is the effect of knocking-out/inhibiting individual rate-limiting proteins of PERK pathway eif2¿, ATF4 and CHOP on oxidative stress and neuronal damage after TBI? Conversely, what is the effect of knocking-out/inhibiting NOX2 on ER stress and neuronal damage after TBI? The long-term goal is to understand the mutual interplay of ER stress and oxidative stress in post-TBI brain damage.