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

总结： 急性肾损伤（acute kidney injury，阿基）是一种主要的肾脏疾病，可由缺血、脓毒症、尿路梗阻等引起 和肾毒素。它与临床上的高死亡率相关，并可能进一步导致慢性肾脏疾病 （CKD）。肾缺血是阿基的主要原因之一。它可能是由于严重的心脏病发作，血管 功能障碍、重大心脏手术或其他心血管疾病。进步的关键障碍之一是 如何提高阿基的存活率，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 以GSTM 3 P1为靶基因，探讨长链非编码RNA（lncRNA）的致病功能及其调控， 例如，研究肾小管细胞死亡的相关途径，并确定阿基治疗的新策略。 最近的研究将lncRNA确定为包括阿基在内的肾脏疾病的关键新型调节因子。我们专注于 GSTM 3 P1是基于（1）我们鉴定GSTM 3 P1作为与肾保护microRNA相互作用的顶级lncRNA 在RNA诱导的沉默复合物中，GSTM 3 P1与miRNA（mir-489和mir-668）的表达相关，表明GSTM 3 P1是一种极好的沉默复合物。 为进一步研究miRNA与lncRNA之间的调控机制提供了一个范例;（2）我们的初步研究 表明GSTM 3 P1在缺血性阿基期间的潜在诱导和强损伤作用，并且进一步 了解其详细的功能和调节可能会显着帮助阿基治疗的发展， （3）我们还发现GSTM 3 P1对GSTM 3有潜在的抑制作用，并且我们对GSTM 3的作用机制的理解是， 其潜在机制将为lncRNA和假基因的功能提供新的信息。我们的中央 假设GSTM 3 P1在肾缺血过程中被诱导，通过抑制肾缺血引起肾损伤。 保护因子，如mir-668和GSTM 3。我们的目标是确定新的治疗靶点（GSTM 3 P1， GSTM 3）用于阿基治疗。我们将通过三个目标来检验这个假设。目的1：检验GSTM 3 P1 在缺血性阿基期间增加以诱导肾小管损伤。目的2：检验GSTM 3 P1相互作用的假设 并导致mir-668衰变以诱导肾损伤。目的3：检验GSTM 3 P1可以 通过抑制GSTM 3诱导肾损伤。我们的预期结果包括：（1）GSTM 3 P1 和GSTM 3作为阿基的新治疗靶点;（2）扩展阿基中lncRNA功能的知识，（3） 扩展了lncRNA和miRNA调控的知识;（4）扩展了蛋白质调控的知识 通过lncRNA的表达调节。我们的研究结果将对（1）阿基研究领域产生影响， lncRNA GSTM 3 P1的病理作用及其对mir-668和GSTM 3的下游调节;和（2）其他 对miRNA和lncRNA与蛋白质之间相互作用的新理解的医学研究领域 通过来自假基因的lncRNA调控表达。

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.