miRNA-Regulation of Dendritic Cell Function

miRNA-树突状细胞功能的调节

• 批准号: 419537-2012
• 负责人: Krawczyk, Connie
• 金额: $ 1.89万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=531443
• 关键词: miRNA; Regulation; Dendritic; Cell; Function

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.

免疫系统具有独特的能力，可以检测和应对各种有害威胁，包括细菌、病毒、寄生虫和癌症。然而，并非所有免疫反应都是平等的，为了有效，免疫反应必须针对威胁的类型进行调整。即时反应的先天免疫系统通过分泌介质的产生和被称为病原体特异性分化的细胞表型的修饰，创造了一个适合病原体的微环境，为病原体控制奠定了基础。树突状细胞（dc）是免疫系统固有臂的一部分，是微环境的关键调节器，并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作出反应并规避规避机制的挑战。我们假设DC中基因表达的转录后调控调节DC激活及其诱导病原体特异性免疫反应的能力。蛋白质表达可以通过微小rna （miRNAs）的作用进行动态调节，微小的非编码rna主要通过抑制靶mrna的翻译来调节蛋白质表达。我们认为，DC激活剂诱导的mirna存在差异，这些mirna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mrna的结合，因此能够将mrna从多聚体部分移动到低聚体部分，从而减少翻译。我们建议1)鉴定受DC激活因子差异调控的mirna， 2)从活化DC的多染色体部分分离mrna，以鉴定DC中在翻译水平上受差异调控的基因。在确定活化dc中差异调节的基因和mirna之后，我们将使用我实验室独有的敲低和过表达技术来询问它们的功能。