Regulation of neonatal immunity by let-7/Lin28

let-7/Lin28 对新生儿免疫的调节

• 批准号: 8673294
• 负责人: Brian David Rudd
• 金额: $ 38.47万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673294
• 关键词: Adult; Age; Biochemical Pathway; Biological Assay; Bone Marrow; CD8B1 gene; Cell Cycle; Cell Proliferation; Cell Proliferation Regulation; Cell Survival; Cells; Cyclin D1; Development; Family; Gene Expression Profile; Generations; Genes; Genetic Programming; Genomics; Goals; Growth; Hematopoietic stem cells; IGF1R gene; Immunity; Impairment; Individual; Infant; Infection; Infectious Agent; Knowledge; Life; Link; Liver; Maintenance; Mammals; Memory; Metabolic; Metabolic Pathway; MicroRNAs; Morbidity - disease rate; Neonatal; Oncogenes; PIK3CG gene; Pathway interactions; Proliferating; Property; Regulation; Reporter; Repression; Role; Secondary Immunization; Seeds; Staging; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Cell Development; T-Lymphocyte; TSC1 gene; Testing; Therapeutic; Thymus Gland; Vaccination; Vaccines; Work; aged; base; cancer cell; cdc Genes; cell growth; fetal; genome-wide; glucose metabolism; human FRAP1 protein; mortality; mouse model; neonate; novel; pathogen; prevent; progenitor; programs; public health relevance; ras Oncogene; research study; secondary infection; self-renewal; transcription factor

DESCRIPTION (provided by applicant): Neonates are highly susceptible to intracellular pathogens and develop poor immunity to infection. Since immunity against these infectious agents is largely dependent upon memory CD8+ T cells, we have performed detailed analysis of the CD8+ T cell response in early life and found that neonatal CD8+ T cells are intrinsically defective at differentiating into memory CD8+ T cells. Surprisingly, impaired memory formation by neonatal CD8+ T cells was not due to an inability to respond, rather neonatal CD8+ T cells proliferated more rapidly than adult cells and quickly became terminally differentiated. One of the most ancient and conserved regulators of proliferation and differentiation during early stages of development is the let-7 miRNA family. Let- 7 represses cell proliferation and growth by targeting many metabolic genes, cell cycle factors and oncogenes for repression. While let-7 is expressed at high levels in adult CD8+ T cells, its expression is blocked by Lin28b in neonatal CD8+ T cells, creating a genomic landscape that is highly conducive for rapid proliferation. Therefore, we believe that neonatal CD8+ T cells become more terminally differentiated and form poor memory cells, because of an inability to repress major transcriptional and metabolic pathways via let-7. Our proposal will test the hypothesis that different genetic programs, regulated by the let-7/Lin28b axis, alter the generation and maintenance of memory CD8+ T cells following neonatal infection. In the first aim (SA1), we will adjust expression levels of let7 and Lin28b in different aged CD8+ T cells and determine their role in neonatal and adult memory CD8+ T cell formation. In the last 2 aims (SA2 and SA3), we will identify the key transcription factors and metabolic pathways that are regulated by let-7/Lin28b and contributing to impaired development of memory CD8+ T cells in early life. Upon completion of this work, we will have obtained a complete mechanistic understanding of why neonatal CD8+ T cells fail to differentiate into memory and know whether correcting transcriptional and metabolic differences can restore protective immunity in early life. Our focus on let-7/Lin28b, which appears to regulate these differences, will allow us to manipulate the number and type of memory CD8+ T cells that are generated in specific ways. This is a novel and targeted approach to enhance memory T cell development in early life.

描述（由申请人提供）：新生儿非常容易受到细胞内病原体的影响，并且对感染的免疫力不佳。由于针对这些感染剂的免疫力在很大程度上取决于记忆CD8+ T细胞，因此我们对早期生命中CD8+ T细胞反应进行了详细分析，发现新生儿CD8+ T细胞在分化为记忆中的CD8+ T细胞时本质上有固有的缺陷。令人惊讶的是，新生儿CD8+ T细胞的记忆力受损并不是由于无法反应，而是新生儿CD8+ T细胞比成人细胞更快地增殖，并且迅速被终极分化。在发展初期，最古老，最保守的扩散和分化调节因子之一是Let-7 miRNA家族。 Let-7通过靶向许多代谢基因，细胞周期因子和致癌基因来抑制细胞增殖和生长。尽管在成年CD8+ T细胞中以高水平表达Let-7，但在新生儿CD8+ T细胞中，其表达被LIN28B阻塞，从而产生了一种高度利用快速增殖的基因组景观。因此，我们认为，由于无法通过let-7抑制主要的转录和代谢途径，新生儿CD8+ T细胞变得更终端分化并形成较差的记忆细胞。我们的建议将检验以下假设：由Let-7/Lin28b轴调节的不同遗传程序改变了新生儿感染后记忆CD8+ T细胞的产生和维护。在第一个目标（SA1）中，我们将在不同年龄的CD8+ T细胞中调整LET7和LIN28B的表达水平，并确定它们在新生儿和成人记忆CD8+ T细胞形成中的作用。在最后两个目标（SA2和SA3）中，我们将确定由Let-7/Lin28B调节的关键转录因子和代谢途径，并有助于在早期生活中记忆CD8+ T细胞的发展受损。完成这项工作后，我们将对新生儿CD8+ T细胞为何无法区分记忆并知道纠正转录和代谢差异是否可以恢复早期生命中的保护性免疫。我们对似乎调节这些差异的Let-7/Lin28b的关注将使我们能够操纵以特定方式生成的内存CD8+ T细胞的数量和类型。这是一种新颖且有针对性的方法，可增强早期记忆T细胞的发展。