PARP-1在LPS诱导的大鼠心肌细胞炎症反应中的作用机制的研究

发布时间：2019-01-24 20:20

【摘要】：二磷酸腺苷聚合酶1(PARP-1),即多聚ADP核糖转移和合成酶,为PARP家族最早发现的成员,在许多细胞功能中起到重要的作用,例如DNA损伤修复,基因转录调节,物质的胞内运输,染色质修饰,有丝分裂体的形成和细胞死亡等。PARP-1的过度活化可以导致能量的耗竭和细胞凋亡,但是近期的研究表明PARP-1在一些局部或者系统性的炎症中起到有害的作用。在脊椎动物的炎症反应中,微生物入侵宿主,首先被天然免疫系统通过种系编码的模式识别受体(PRRs)识别,其中TLRs(Toll-like receptors)在识别特定模式的微生物组分中起到至关重要的作用。在过去的几年里,LPS/TLR4信号通路有了很多研究。TLR4(Toll-like receptor 4)识别脂多糖LPS后,招募下游信号分子,引发一系列的信号级联反应,最终活化转录因子NF-κB,诱导一些促炎因子的表达。NF-κB是在炎症反应中起到中枢作用的转录因子。在炎症失调过程中,PARP-1能够作为NF-κB的共激活子,共同调节相关基因的表达。但是PARP-1的酶活性在NF-κB转录活化中的重要性仍然存在争议。关于PARP-1在基因表达的调节上的研究主要集中在转录水平的调控机制,最近的一项研究提出,PARP-1对炎症基因表达的调控可能存在转录后水平的调节作用。在我们的研究中,我们选取了大鼠的心肌细胞来研究PARP-1在LPS导致的炎症反应中的作用机制。研究在LPS导致的炎症反应中,PARP-1的活性变化以及这种变化对信号通路及炎症因子表达的影响。我们的研究表明,PARP-1在LPS导致的炎症反应中活性上调,并且与NF-κB共同作用,调节炎症因子IL-6、MCP-1的表达。另外还证明PARP-1在炎症因子MCP-1的转录后mRNA的稳定性上起到一定的调节作用。我们的工作进一步探讨了PARP-1在LPS信号转导通路中的作用机制,并揭示了PARP-1在炎症因子MCP-1 mRNA的稳定性上的调节作用,为深入理解PARP-1在炎症中的调节机制提供了新的路径,希望能为心肌疾病的诊断治疗提供一种有效的方法。
[Abstract]:Adenosine diphosphate polymerase 1 (PARP-1), a poly-ADP ribose transfer and synthase, is the earliest member of the PARP family and plays an important role in many cellular functions, such as DNA damage repair and gene transcription regulation. Intracellular transport of substances, chromatin modification, mitotic formation and cell death, etc. Excessive activation of PARP-1 can lead to energy depletion and cell apoptosis. But recent studies have shown that PARP-1 can play a deleterious role in some local or systemic inflammation. In vertebrate inflammation, microbes invade the host and are first recognized by the innate immune system through a pattern-recognition receptor (PRRs) encoded by the species. TLRs (Toll-like receptors) plays an important role in the identification of microbial components in specific patterns. In the past few years, LPS/TLR4 signaling pathway has been studied. After TLR4 (Toll-like receptor 4) recognizes lipopolysaccharide LPS, it recruits downstream signal molecules, triggers a series of signal cascade reactions, and finally activates the transcription factor NF- 魏 B. NF- 魏 B is a transcription factor that plays a central role in inflammatory response. In the process of inflammation disorder, PARP-1 can act as co-activator of NF- 魏 B and regulate the expression of related genes. However, the importance of PARP-1 activity in NF- 魏 B transcriptional activation remains controversial. The regulation of PARP-1 gene expression is mainly focused on the regulation mechanism of transcription level. A recent study suggested that the regulation of inflammatory gene expression by PARP-1 may have the regulation of posttranscriptional level. In our study, we selected rat cardiomyocytes to study the role of PARP-1 in the inflammatory response induced by LPS. To study the changes of PARP-1 activity in inflammatory response induced by LPS and its effect on signal pathway and inflammatory factor expression. Our results show that PARP-1 is up-regulated in the inflammatory response induced by LPS and works with NF- 魏 B to regulate the expression of the inflammatory factor IL-6,MCP-1. It is also demonstrated that PARP-1 plays a role in regulating the posttranscriptional mRNA stability of the inflammatory factor MCP-1. Our work further explored the role of PARP-1 in the LPS signal transduction pathway and revealed the regulatory role of PARP-1 in the stability of the inflammatory factor MCP-1 mRNA. It provides a new way to understand the regulatory mechanism of PARP-1 in inflammation and provides an effective method for the diagnosis and treatment of myocardial diseases.
【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2011
【分类号】：R363

【共引文献】