MiR-150 regulated adiose tissue B cells in obesity

MiR-150 调节肥胖中的脂肪组织 B 细胞

• 批准号: 10357914
• 负责人: Anthony T Vella
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-09 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357914
• 关键词: Adipocytes; Adipose tissue; Antigen Presentation; Antigen Presentation Pathway; B-Cell Activation; B-Lymphocytes; Biological Assay; Cell Communication; Cell physiology; Cells; Chronic; Clinical Research; Computational algorithm; Data; Development; Diabetes Mellitus; Ectopic Expression; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Genes; Goals; Health; Hematopoiesis; Homeostasis; Immune; Immune response; Immunoglobulins; Immunologics; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Knock-out; Knowledge; Mature B-Lymphocyte; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; MicroRNAs; Modeling; Molecular; Mouse Strains; Mus; Obesity; Organ; Outcome; Pathway interactions; Patients; Physiological; Population; Process; Production; Publishing; Regulation; Reporter; Reporting; Risk; Role; Small RNA; Stress; System; T-Lymphocyte; Testing; Therapeutic; Thinness; Tissues; Work; adoptive B cell transfer; cell behavior; cell type; diet-induced obesity; in vivo; knock-down; leukemogenesis; macrophage; mouse model; novel; obese patients; overexpression; preclinical study; response; screening; small hairpin RNA; stem cells; transcriptome; transcriptome sequencing; translational potential

Adipose tissue B cells are the second most abundant immune cells found in adipose tissue, and they account for more than 20% of the stromal population within adipose tissue during obesity. Pre-clinical and clinical studies have only recently suggested that adipose tissue B cells can modulate adipose tissue function and contribute to the metabolic syndromes suffered during obesity. However, our understanding of the molecular mechanisms underlying adipose tissue B cell function is limited, and this has significantly hampered the potential translational benefit of targeting B cells that dwell in adipose tissue to mitigate obesity induced metabolic disease. The central goal of our project is to define the key regulators for these B cells during obesity. Nevertheless, our new data has opened a novel point of intervention to control the function of these inflammation-promoting B cells through the action of microRNAs that include miR-150. Our data support the central hypothesis suggesting that: Under the stress of obesity, miR-150 is a key regulator of adipose tissue B cell activation where dysregulation of miR-150 facilitates the pro-inflammatory response of adipose tissue B cells and corrupts their ability to interact with other cells in the adipose tissue niche, which results in exacerbated adipose tissue inflammation and insulin resistance. We will critically test this hypothesis in three specific aims by first demonstrating how miR-150 regulates normal B cell function. This will be achieved with the creation of new and unpublished mouse strains that will allow exquisite control of miR-150 action in B cells during different stages of development. Specifically, we will utilize our novel miR-150 B-cell specific knockout and overexpression mice to define how adipose tissue B cells function under lean and obese conditions. In the second aim we will determine the regulatory role of the gene targets of miR-150 in controlling adipose tissue B cell behavior and function. Specifically, miR-150 regulates B cell pathways through specific target genes and we have screened more than 30 predicted genes and successfully identified several B cell specific miR-150 targets. We will utilize ectopic expression and shRNA knockdown to determine their roles in miR-150-mediated ATB activation and subsequent in vivo function in obese adipose tissue. In aim 3 we will test the hypothesis that disruption of miR-150 in adipose tissue B cells interferes with their ability to control cell-to-cell interactions. We will determine the mechanistic regulation of miR-150 during crosstalk with other cell populations including T cells and macrophages derived from adipose tissue and also adipocytes themselves. We have postulated that part of the mechanism used by the pro-inflammatory B cells is through the MHC II pathway, which will be tested under various physiological conditions. Collectively, these three aims will elucidate the critical regulatory mechanism of microRNA-regulated adipose tissue B cells and their contribution in orchestrating the adipose tissue metabolic/immunologic response to obesity.

脂肪组织B细胞是在脂肪组织中发现的第二丰富的免疫细胞，并且它们占肥胖期间脂肪组织内基质群体的20%以上。临床前和临床研究最近才表明，脂肪组织B细胞可以调节脂肪组织功能，并有助于肥胖期间遭受的代谢综合征。然而，我们对脂肪组织B细胞功能的分子机制的理解是有限的，这显著阻碍了靶向驻留在脂肪组织中的B细胞以减轻肥胖诱导的代谢疾病的潜在转化益处。我们项目的中心目标是确定肥胖期间这些B细胞的关键调节因子。尽管如此，我们的新数据已经打开了一个新的干预点，通过包括miR-150在内的microRNA的作用来控制这些促炎B细胞的功能。我们的数据支持中心假设，表明：在肥胖的压力下，miR-150是脂肪组织B细胞活化的关键调节因子，其中miR-150的失调促进脂肪组织B细胞的促炎反应并破坏它们与脂肪组织生态位中的其他细胞相互作用的能力，这导致脂肪组织炎症和胰岛素抵抗加剧。我们将在三个具体目标中严格检验这一假设，首先证明miR-150如何调节正常B细胞功能。这将通过创造新的和未发表的小鼠品系来实现，这些小鼠品系将允许在发育的不同阶段精确控制miR-150在B细胞中的作用。具体来说，我们将利用我们的新的miR-150 B细胞特异性敲除和过表达小鼠来定义脂肪组织B细胞在瘦和肥胖条件下如何发挥功能。在第二个目标中，我们将确定miR-150的基因靶标在控制脂肪组织B细胞行为和功能中的调节作用。具体而言，miR-150通过特定的靶基因调节B细胞通路，我们已经筛选了30多个预测基因，并成功鉴定了几个B细胞特异性miR-150靶点。我们将利用异位表达和shRNA敲低来确定它们在miR-150介导的ATB激活和随后在肥胖脂肪组织中的体内功能中的作用。在目标3中，我们将检验脂肪组织B细胞中miR-150的破坏干扰其控制细胞间相互作用的能力的假设。我们将确定miR-150在与其他细胞群（包括来自脂肪组织的T细胞和巨噬细胞以及脂肪细胞本身）串扰期间的机制调节。我们假设促炎B细胞使用的部分机制是通过MHC II途径，这将在各种生理条件下进行测试。总的来说，这三个目标将阐明microRNA调节的脂肪组织B细胞的关键调节机制及其在协调脂肪组织代谢/免疫应答肥胖中的作用。