LncRNA FosDT mediates ischemic brain damage

 描述（由申请人提供）：导致继发性神经元死亡的机制以及卒中后的神经功能障碍尚未完全了解。最近的研究表明，脑缺血迅速改变了各种类型的非编码RNA（ncRNA）的表达谱。这一观察结果对中风后结果具有重要的功能意义，因为ncRNA目前被认为是哺乳动物中转录和翻译的控制器。特别是，我们最近的研究表明，几个长的非编码RNA（lncRNA; lincRNA）的表达，作为支架之间的染色质修饰蛋白（CMP），转录因子，组蛋白和DNA。在本提案中，作为测试案例，我们希望分析一种名为Fos下游转录物（FosDT; MRAK 159688）的此类lncRNA的作用，其在缺血性脑中高度上调。基于初步数据，我们假设（1）FosDT表达增加有助于卒中后继发性脑损伤和神经功能障碍。(2)FosDT的作用机制是通过其与CMPs Sin 3A和coREST的相互作用，从而调节缺血性脑中REST介导的GRIA 2和NFKB 2的抑制。FosDT敲低通过去抑制这些阻止缺血性神经元死亡的REST抑制基因来保护缺血后的脑。目的1：利用FosDT siRNA介导的FosDT基因敲低，探讨FosDT基因在脑卒中后继发性脑损伤和神经功能障碍中的作用。目的2是评估FosDT介导的缺血性脑损伤的机制是否与REST介导的GRIA 2和NFKB 2的抑制相互作用。总的来说，本项目将评估中风后诱导的lncRNA在缺血后脑损伤中的意义以及在缺血后传播lncRNA作用的下游机制。据我们所知，这些是第一个提出的研究，以评估lncRNA在缺血后脑损伤中的作用。长期目标是优先考虑实验，以决定是否值得探索这类新的RNA作为中风治疗剂。

 DESCRIPTION (provided by applicant): The mechanisms that contribute to the secondary neuronal death and thereby the neurological dysfunction following stroke are not completely understood. Recent studies showed that cerebral ischemia rapidly alters the expression profiles of various classes of noncoding RNAs (ncRNAs). This observation has significant functional implications to post-stroke outcome as ncRNAs are currently considered as controllers of transcription and translation in mammals. In particular, our recent studies showed that expression of several long noncoding RNAs (lncRNAs; lincRNAs) that serve as scaffolding between chromatin-modifying proteins (CMPs), transcription factors, histones and DNA. In the present proposal, as a test case we wish to analyze the role of one such lncRNA named Fos Downstream Transcript (FosDT; MRAK159688), which is highly up-regulated in the ischemic brain. Based on the preliminary data, we hypothesize that (1) Increased FosDT expression contributes to post-stroke secondary brain damage and neurological dysfunction. (2) Mechanism of FosDT action is by its interaction with CMPs Sin3A and coREST and thereby modulating the REST-mediated suppression of GRIA2 and NFKB2 in the ischemic brain. FosDT knockdown protects brain after ischemia by de-repressing these REST-suppressed genes that prevent ischemic neuronal death. Aim 1 is to evaluate the functional significance of FosDT in promoting secondary brain damage and neurological dysfunction following experimental stroke using FosDT siRNA-mediated knockdown. Aim 2 is to evaluate if the mechanism of FosDT-mediated ischemic brain damage is by interaction with the REST-mediated repression of GRIA2 and NFKB2. Overall, this project will evaluate the significance of an lncRNA induced after stroke in post-ischemic brain damage and the downstream mechanisms that propagate the actions of the lncRNA after ischemia. These are the first proposed studies to our knowledge to evaluate the role of an lncRNA in post-ischemic brain damage. The long- term goal is to prioritize the experiments to decide if it is worth exploring this new class of RNAs as stroke therapeutics.