The regulation and function of long non coding RNA in ischemic AKI: Role of GSTM3P1

摘要： 急性肾损伤(AKI)是一种主要的肾脏疾病，可由缺血、败血症、尿路梗阻引起。 还有肾毒素。在临床上，它与高死亡率有关，并可能进一步导致慢性肾脏疾病。 (CKD)。肾缺血是AKI的主要原因之一。它可以由大规模的心脏病发作、血管 功能障碍、心脏大手术或其他心血管疾病。取得进展的关键障碍之一是 如何提高AKI存活率，这与对AKI的调控认识有限密切相关。 肾小管细胞死亡和缺乏预防肾小管死亡的治疗。此应用程序的目标是 探讨以GSTM3P1为致病基因的长非编码RNA的致病功能及其调控 研究肾小管上皮细胞死亡的相关途径，寻找AKI治疗的新策略。 最近的研究发现，lncRNAs是包括AKI在内的肾脏疾病的关键新调节因子。我们的重点是 GSTM3P1是基于(1)我们确定GSTM3P1是与肾脏保护性microRNA相互作用的顶级lncRNA (MiRNA)(mir-489和mir-668)在RNA诱导的沉默复合体中，提示GSTM3P1是一种优秀的 举例研究miRNA和lncRNA之间的新调控机制；(2)我们的初步研究 提示GSTM3P1在缺血性AKI中的潜在诱导和强大的损伤作用 了解它的详细功能和调节机制可能会对AKI治疗的发展有很大帮助 (3)我们还发现了GSTM3P1对GSTM3的潜在抑制作用以及对GSTM3P1的理解 其潜在机制将为研究LncRNA和假基因的功能提供新的信息。我们的中央 假说认为GSTM3P1在肾脏缺血时被诱导，通过抑制肾脏而导致肾损伤 保护性因子，如mir-668和GSTM3。我们的目标是寻找新的治疗靶点(GSTM3P1， GSTM3)用于AKI治疗。我们将通过三个目标来检验这一假设。目的1：验证GSTM3P1的假设 在缺血AKI期间增加以引起肾小管损伤。AIM2：检验GSTM3P1相互作用的假设 含有mir-668，并导致mir-668腐烂，导致肾脏损伤。目的：验证GSTM3P1可以 通过抑制GSTM3诱导肾损伤。我们的预期结果包括：(1)确定GSTM3P1 和GSTM3作为AKI新的治疗靶点；(2)扩大对LncRNA在AKI中作用的认识；(3) 扩展了lncRNA和miRNA之间的调控知识；(4)扩展了蛋白质的知识 LncRNAs对基因表达的调控。我们的发现将对(1)AKI研究领域产生影响，通过阐明 LncRNA GSTM3P1的病理作用及其对mir-668和GSTM3的下游调控；以及(2)其他 新认识miRNA与lncRNA和蛋白质相互作用的医学研究领域 假基因中lncRNA对基因表达的调控。

Summary: Acute kidney injury (AKI) is a major renal disease that can be caused by ischemia, sepsis, urinary obstruction and nephrotoxins. It is associated with high mortality clinically and may further lead to chronic kidney diseases (CKD). Kidney ischemia is one of the leading causes of AKI. It can result from massive heart attack, blood vessel dysfunction, major cardiac surgery, or other cardiovascular diseases. One of the critical barriers to progress is how to improve the AKI survival rate, which is closely related to the limited understanding of the regulation of renal tubular cell death and lack of treatment to prevent renal tubular death. The goal of this application is to investigate the pathogenic function and regulation of long non-coding RNA (lncRNA) with GSTM3P1 as an example to study the related pathways in renal tubular cell death and to identify new strategies for AKI therapy. Recent studies identified lncRNAs as critical novel regulators of kidney diseases including AKI. Our focus on GSTM3P1 is based on (1) we identified GSTM3P1 as a top lncRNA to interact with renal protective microRNAs (miRNA) (mir-489 and mir-668) in RNA induced silencing complex, suggesting GSTM3P1 as an excellent example to study the novel regulation mechanism between miRNA and lncRNA; (2) our preliminary studies indicate potential induction and strong injurious effect of GSTM3P1 during ischemic AKI and the further understanding of its detailed function and regulation may significantly help AKI therapy development by using lncRNAs as targets; (3) we also found potential inhibition of GSTM3 by GSTM3P1 and the understanding of the underlying mechanism will provide new information for lncRNA and pseudogene function. Our central hypothesis is that GSTM3P1 is induced during kidney ischemia to cause kidney injury by inhibition of renal protective factors, such as mir-668 and GSTM3. Our objective is to identify new therapeutic targets (GSTM3P1, GSTM3) for AKI treatment. We will test the hypothesis by three aims. Aim1: Test the hypothesis that GSTM3P1 increases during ischemic AKI to induce renal tubular injury. Aim2: Test the hypothesis that GSTM3P1 interacts with mir-668 and causes mir-668 decay to induce kidney injury. Aim3: Test the hypothesis that GSTM3P1 can induce kidney injury through the inhibition of GSTM3. Our expect outcomes include: (1) identifying GSTM3P1 and GSTM3 as new therapeutic targets for AKI; (2) extending the knowledge of lncRNA function in AKI, (3) extending the knowledge of regulation between lncRNA and miRNA; (4) extending the knowledge of protein expression regulation by lncRNAs. Our findings will have impact on (1) the AKI research field by elucidating the pathological role of lncRNA GSTM3P1 and its downstream regulation of mir-668 and GSTM3; and (2) the other medical research fields for the novel understanding of interaction between miRNA and lncRNA and protein expression regulation by lncRNA from pseudogene.