Roles for DevelopmentallyRegulated microRNAs in Neonatal Immunity

发育调控的 microRNA 在新生儿免疫中的作用

• 批准号: 10221489
• 负责人: ANDREW W GRIMSON
• 金额: $ 40.02万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221489
• 关键词: Adult; Antigens; Apoptosis; Bacille Calmette-Guerin vaccination; Bacteria; Behavior; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Data; Development; Effector Cell; Equilibrium; Experimental Models; Gene Targeting; Generations; Genes; Goals; Grant; Human; Immune response; Immunity; Immunologics; Impairment; In Vitro; Infection; Inflammation; Laboratories; Lead; Life; Link; Malawi; Memory; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Neonatal; Newborn Infant; Pattern; Play; Positioning Attribute; Proliferating; Publishing; Regulator Genes; Role; Schools; T cell regulation; T cell response; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Translating; Tropical Medicine; Universities; Up-Regulation; Vaccination; Vaccines; Virus; Work; age related; aged; base; cell behavior; differential expression; improved; in vivo; innovation; insight; interest; neonatal immunity; neonate; next generation sequencing; novel therapeutic intervention; pathogen; predictive marker; response; skills; transcription factor; vaccine efficacy

Project Summary /Abstract Neonates are highly susceptible to infection and respond poorly to vaccination for reasons that are not well understood. Based on our published data, we believe that neonates are particularly vulnerable to repeat infections because their naïve CD8+ T cells are intrinsically defective at differentiating into memory CD8+ T cells. A major goal of this grant is to identify the key gene regulatory networks that underlie cell-intrinsic differences between neonatal and adult CD8+ T cells. Since microRNAs (miRNAs) are developmentally regulated and required for CD8+ T cell function, we hypothesized that defective CD8+ T cell memory formation in early life may be due to differences in miRNA expression patterns between neonatal and adult CD8+ T cells. To test our hypothesis, we used next generation sequencing to identify mouse miRNAs that are differentially regulated in neonatal and adult CD8+ T cells throughout the response to infection. Surprisingly, our results indicated that differences in miRNA expression profiles were most pronounced prior to immunological challenge, suggesting that developmentally-regulated miRNAs do not operate by altering the fate of effector cells at the peak of the response. Instead, these miRNAs appear to set the activation threshold prior to infection, causing neonatal CD8+ T cells to differentiate more rapidly into effector cells and biasing them away from a memory precursor fate. We are particularly interested in two miRNAs (miR-29 and miR-130), which we believe play a major role in cell-intrinsic differences that exist between neonatal and adult CD8+ T cells in mice and humans. MiR-130 is preferentially expressed in neonatal CD8+ T cells and targets a number of genes involved in negative regulation of T cell proliferation or apoptosis. MiR-29, on the other hand, is more abundant in adult CD8+ T cells and regulates the expression of transcription factors involved in effector and memory cell differentiation. We propose that the miR-29/miR-130 axis acts as a developmental rheostat for adjusting the activation threshold of CD8+ T cells, controlling the balance between rapid effector cells (neonates) and long-lived memory cells (adults). The main objectives of this proposal are to determine how age-related changes in miR-29 and miR-130 expression alter the ability of CD8+ T cells to respond to infection (Aim 1); identify the key target genes regulated by miR- 29 and miR-130 prior to activation (Aim 2); and determine whether miR-29 and miR-130 can predict vaccine- specific CD8+ T cell responses in newborns (Aim 3). Accomplishing these aims will lend support for a new model describing how miRNAs regulate the CD8+ T cell response to infection, which can lead to novel therapeutic strategies for enhancing the development of memory CD8+ T cells in early life.

项目摘要 /摘要 新生儿非常容易受到感染的影响，并且由于不良好的原因而对疫苗接种反应不佳 理解。根据我们已发布的数据，我们认为新生儿特别容易重复 感染是因为其幼稚的CD8+ T细胞在分化为记忆CD8+ T细胞时本质上有缺陷。 这项赠款的主要目标是确定细胞内在差异构成的关键基因调节网络 在新生儿和成人CD8+ T细胞之间。由于microRNA（miRNA）受到开发，并且 CD8+ T细胞功能所需 由于新生儿和成人CD8+ T细胞之间miRNA表达模式的差异。测试我们的 假设，我们使用下一代测序来识别在不同调节的小鼠miRNA 在对感染的反应过程中，新生儿和成年CD8+ T细胞。令人惊讶的是，我们的结果表明 在免疫学挑战之前，miRNA表达谱的差异最为明显，表明 开发的受调节的miRNA不能通过改变效应细胞的命运而在 回复。相反，这些miRNA似乎在感染前设置了激活阈值，导致新生儿 CD8+ T细胞以更快地区分效应细胞并将其偏离记忆前体 命运。我们对两个miRNA（miR-29和miR-130）特别感兴趣，我们认为这在 在小鼠和人类中，新生儿和成人CD8+ T细胞之间存在的细胞中性差异。 mir-130是 在新生儿CD8+ T细胞中优先表达，并靶向许多参与阴性调节的基因 T细胞增殖或凋亡。另一方面，miR-29在成人CD8+ T细胞中更丰富 调节效应子和记忆细胞分化中涉及的转录因子的表达。我们建议 miR-29/miR-130轴充当用于调整CD8+ T的激活阈值的发育风湿病 细胞，控制快速效应细胞（新生儿）和长寿记忆细胞（成人）之间的平衡。 该提案的主要目标是确定miR-29和miR-130表达中与年龄相关的变化 改变CD8+ T细胞对感染反应的能力（AIM 1）；确定由miR-调控的关键靶基因 激活之前的29和mir-130（AIM 2）；并确定miR-29和miR-130是否可以预测疫苗 新生儿中的特定CD8+ T细胞反应（AIM 3）。实现这些目标将为新的支持提供支持 描述miRNA如何调节CD8+ T细胞对感染的反应的模型，这可能导致新颖 在早期生命中增强记忆CD8+ T细胞发展的治疗策略。