MiR-150 regulated adiose tissue B cells in obesity

MiR-150 调节肥胖中的脂肪组织 B 细胞

基本信息

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
项目类别：
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

项目摘要

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细胞是脂肪组织中第二大丰富的免疫细胞，它们占肥胖期间脂肪组织中基质种群的20％以上。临床前和临床研究直到最近才提出，脂肪组织B细胞可以调节脂肪组织功能，并有助于肥胖期间的代谢综合征。但是，我们对脂肪组织B细胞功能的分子机制的理解受到限制，这显着阻碍了靶向靶向掺入脂肪组织中的B细胞以减轻肥胖引起的代谢疾病的潜在转化益处。我们项目的核心目标是在肥胖期间定义这些B细胞的关键调节剂。然而，我们的新数据通过包括miR-150的microRNA的作用，开辟了一种新的干预点，以控制这些引起炎症的B细胞的功能。我们的数据支持中心假设表明：在肥胖症的压力下，miR-150是脂肪组织B细胞激活的关键调节剂，其中miR-150的失调促进了脂肪组织B细胞的促炎反应，并破坏了它们与其他细胞在脂肪组织Niche中与其他细胞相互作用的能力，从而在脂肪症中具有稳定性的稳定性症状，并抑制了脂肪症。我们将通过首先证明miR-150如何调节正常B细胞功能，在三个特定目标中进行批判性检验这一假设。这将通过创建新的和未发表的小鼠菌株来实现，这将使在不同发育阶段在B细胞中精美地控制MiR-150动作。具体而言，我们将利用新型的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作用。在第二个目标中，我们将确定miR-150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通过特定靶基因调节B细胞途径，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靶标。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激活中的作用，然后在肥胖脂肪组织中的体内功能。在AIM 3中，我们将测试以下假设：脂肪组织B细胞中miR-150的破坏会干扰其控制细胞间相互作用的能力。我们将确定与其他细胞种群在串扰过程中miR-150的机理调节，包括脂肪组织和脂肪细胞本身的T细胞和巨噬细胞。我们假设促炎B细胞使用的部分机制是通过MHC II途径，该途径将在各种生理条件下进行测试。总体而言，这三个目标将阐明微肌瘤调节的脂肪组织B细胞的关键调节机制及其在策划脂肪组织代谢/免疫学对肥胖症的贡献中的贡献。