Cytokine Profiling in Pediatric Obesity

儿童肥胖的细胞因子分析

• 批准号: 10459145
• 负责人: Shannon Rose
• 金额: $ 29.23万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459145
• 关键词: Adult; Bioenergetics; Blood specimen; Body mass index; Child; Data; Exhibits; Future; Glycolysis; Inflammation; Inflammatory; Insulin; Insulin Resistance; Least-Squares Analysis; Measures; Metabolic; Metabolic Pathway; Mitochondria; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pathologic; Peripheral Blood Mononuclear Cell; Physiology; Respiration; Rest; Sampling; Testing; adult obesity; base; cohort; combinatorial; comorbidity; cytokine; fatty acid oxidation; insulin sensitivity; new therapeutic target; novel; obesity in children; obesity prevention; prevent; transcriptome sequencing; treatment strategy

Targeting PBMC bioenergetics is a strongly supported strategy for modulating inflammation and preventing progression from obesity to type 2 diabetes. Our preliminary data show metabolic differences between resting PBMCs in unhealthy obese adults compared to children, which is not surprising given evidence of fundamental differences in the physiology of obesity comorbidities in adults compared to children. Comparing PBMC bioenergetics and cytokine profiles of obese insulin sensitive (IS) and insulin resistant (IR) children, and profiles from obese children to obese adults is vital to define endpoints for future mechanistic studies on pathological inflammation in obese kids, and to suggest new therapeutic targets to halt inflammatory comorbidities in childhood obesity. We hypothesize that compared to insulin sensitive children, stimulated PBMCs from overweight/obese IR children will exhibit altered bioenergetics (e.g. elevated glycolysis and/or reduced OXPHOS and FAO), and they will produce inflammatory profiles that differ from both IS children and obese IR/T2D adults. In aim 1, we will test the hypothesis that stimulationinduced alterations in PBMCs bioenergetics change in children based on obesity and insulin sensitivity. We will leverage blood samples collected from an ongoing study and measure the difference mitochondrial respiration, glycolysis, and fatty acid oxidation PBMCs between resting and stimulated states from 30 children spanning the spectrum of BMI percentiles and insulin sensitivity. We will also conduct RNA sequencing on paired stimulated and unstimulated PBMC samples from a subset of the cohort. In aim 2, we will test the hypothesis that PBMC inflammatory profiles differentiate children based on obesity and insulin sensitivity. Partial least squares regressions of BMI and insulin sensitivity measures on combinatorial cytokine profiles of PBMCs from the 30 children will identify those cytokines that best distinguish children based on obesity and insulin sensitivity. Defining PBMC bioenergetic alterations and cytokine profiles in children based on obesity and insulin sensitivity will provide critical preliminary data to refine mechanistic studies and identify specific metabolic pathways to target as novel treatment strategies.

靶向PBMC生物能量学是一种强有力的调节炎症和预防的策略 从肥胖症进展到2型糖尿病。我们的初步数据显示， 与儿童相比，不健康的肥胖成年人的静息PBMC，这并不令人惊讶，因为有证据表明 与儿童相比，成人肥胖共病的生理学上的根本差异。 肥胖胰岛素敏感型和胰岛素抵抗患者外周血单核细胞生物能量学和细胞因子谱的比较 (IR)儿童，以及从肥胖儿童到肥胖成人的概况对于确定未来的终点至关重要 肥胖儿童病理性炎症的机制研究，并提出新的治疗靶点 阻止儿童肥胖症的炎症性并存。我们假设与胰岛素敏感的人相比 儿童，超重/肥胖IR儿童刺激的PBMC将表现出改变的生物能量(例如 糖酵解升高和/或OXPHOS和FAO减少)，它们将产生炎症情况， 与两者不同的是儿童和肥胖的IR/T2D成人。在目标1中，我们将检验刺激诱导的假设 儿童外周血单核细胞生物能量学的改变基于肥胖和胰岛素敏感性。我们 将利用从一项正在进行的研究中收集的血液样本来测量线粒体的差异 静息状态和刺激状态之间的呼吸、糖酵解和脂肪酸氧化 不同BMI百分位数和胰岛素敏感性的儿童。我们还将进行核糖核酸 从队列的子集中对成对的刺激和未刺激的PBMC样本进行测序。在目标2中， 我们将检验这一假设，即PBMC炎症特征根据肥胖和肥胖来区分儿童 胰岛素敏感性。体重指数与胰岛素敏感性指标的偏最小二乘回归 来自30名儿童的PBMC的细胞因子组合图谱将确定哪些细胞因子最好 根据肥胖和胰岛素敏感性来区分儿童。定义PBMC生物能量变化和 基于肥胖和胰岛素敏感性的儿童细胞因子谱将提供关键的初步数据 完善机制研究，确定特定的代谢途径，将其作为新的治疗策略。