miRNA-Regulation of Dendritic Cell Function

免疫系统具有独特的能力来检测和应对广泛的有害威胁，包括细菌、病毒、寄生虫和癌症。然而，并不是所有的免疫反应都是平等的，为了有效，免疫反应必须根据威胁的类型进行调整。快速反应的先天免疫系统通过产生分泌介质和通过改变称为病原体特异性分化的细胞表型来创造病原体定制的微环境，从而为病原体控制奠定了基础。树突状细胞(DC)是免疫系统先天手臂的一部分，是微环境的关键调节者，整合环境刺激以进行相应的分化，并将病原体特异性信息传递给免疫系统的其他组成部分。另一方面，病原体寻求调节或逃避免疫反应，以促进传播。直接与微生物相互作用的细胞，如DC，面临着立即对病原体做出反应并绕过逃避机制的挑战。我们假设，DC中基因表达的转录后调节调节DC的激活及其诱导病原体特异性免疫反应的能力。蛋白质的表达可以通过microRNAs(MiRNAs)的作用来动态调节，microRNAs是一种非编码的小RNA，主要通过抑制靶mRNAs的翻译来调节蛋白质的表达。我们认为，miRNAs是由DC激活剂差异诱导的，这些miRNAs将有助于DC功能的精确调控。MiRNAs的部分功能是通过抑制核糖体与靶mRNAs的结合来发挥作用，因此能够将mRNAs从多聚体部分移动到低部分，导致翻译减少。我们建议1)识别受DC激活剂差异调控的miRNAs，以及2)从激活的DC的多聚体部分中分离mRNAs，以识别DC中在翻译水平上差异调控的基因。在鉴定了在激活的DC中差异调控的基因和miRNAs之后，我们将使用我的实验室特有的击倒和过表达技术来询问它们的功能。

The immune system possesses the unique capacity to detect and respond to broad range of harmful threats including bacteria, viruses, parasites and cancer. However, all immune responses are not created equal, and to be effective, immune responses must be tailored to the type of threat. The immediate-responding innate immune system sets that stage for pathogen control by creating a pathogen-tailored microenvironment through the generation of secreted mediators and through modification of cell phenotype known as pathogen-specific differentiation. Dendritic cells (DCs), part of the innate arm of the immune system, are key regulators of the microenvironment and integrate environmental stimuli to differentiate accordingly and transmit pathogen-specific information to other components of the immune system. Pathogens, on the other hand, seek to modulate or evade immune responses to promote transmission. Cells that interact directly with microbes, such as DCs, are challenged to respond immediately to pathogens and circumvent evasion mechanisms. We hypothesize that post-transcriptional regulation of gene expression in DCs regulates DC activation and their ability to induce pathogen-specific immune responses. Protein expression can be dynamically regulated through the action of microRNAs (miRNAs), small non-coding RNAs which predominantly regulate protein expression by inhibiting translation of target mRNAs. We propose that miRNAs are differentially induced by DC activators and these miRNAs will contribute to the precise regulation of DC function. miRNAs function in part by inhibiting ribosome association with target mRNAs, and as such are capable of moving mRNAs from the multi-polysome fraction to the low fraction, resulting in decreased translation. We propose to 1) identify miRNAs which are differentially regulated by DC activators, and 2) isolate mRNAs from polysomal fractions of activated DCs to identify genes in DCs which are differentially regulated at the translational level. Following the identification of genes and miRNAs which are differentially regulated in activated DCs, we will interrogate their function using knockdown and overexpression techniques unique to my laboratory.