Unraveling the Impact of Per- and Polyfluoroalkyl Substances on Early Kidney Injury in Adolescents with Obesity and Diabetes

揭示全氟烷基和多氟烷基物质对肥胖和糖尿病青少年早期肾损伤的影响

• 批准号: 10837574
• 负责人: Petter M Bjornstad
• 金额: $ 46.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-27 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10837574
• 关键词: Acceleration; Address; Administrative Supplement; Adolescent; Adoption; Adult; Aromatic Amino Acids; Beta Cell; Cell physiology; Charge; Chemicals; Climate; Colorado; Data; Deterioration; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Droughts; Enrollment; Environmental Risk Factor; Epidemic; Event; Glycosylated hemoglobin A; Goals; Habits; Heat Waves; Incidence; Individual; Industrial Product; Inflammation; Injury to Kidney; Insulin Resistance; Intervention; Kidney Diseases; Knowledge; Life; Link; Longitudinal Studies; Measures; Metabolism; Multiomic Data; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Parents; Participant; Pathway interactions; Persons; Phenotype; Physiology; Plasma; Play; Poly-fluoroalkyl substances; Precision Health; Prediabetes syndrome; Predisposition; Proteomics; Proxy; Puberty; Public Health; Questionnaires; Recording of previous events; Records; Renal function; Research; Research Design; Risk; Risk Factors; Role; Sampling; Source; Statistical Methods; Subgroup; Testing; Toxic effect; Water; Water consumption; Weather; Weight maintenance regimen; Youth; amino acid metabolism; cell injury; climate change; climate impact; combat; consumer product; contaminated water; data integration; effective therapy; environmental stressor; extreme heat; extreme temperature; girls; ground water; high risk; impaired glucose tolerance; improved; innovation; lipid metabolism; melting; metabolomics; modifiable risk; mortality risk; multidimensional data; multiple omics; precision medicine; premature; prevent; remediation; renal damage; research study; response; standard measure; therapeutic target; water quality; water sampling

PROJECT SUMMARY / ABSTRACT: Youth-onset type 2 diabetes (Y-T2D) is a rapidly growing epidemic in the US, with a severe phenotype and limited modifiable risk factors or effective therapies. Climate change, such as extreme heat, and water contamination by per- and polyfluoroalkyl substances (PFAS) are emerging risk factors for Y-T2D development and early diabetic kidney disease. Adolescents with obesity and pre-diabetes may be more susceptible to PFAS's detrimental effects on β-cell and kidney function due to their developing physiology and increased vulnerability to environmental stressors, including extreme heat. In response to NOT-HD-23-006, we propose an administrative supplement to R01 DK129211 for a first-of-its- kind transdisciplinary study to address knowledge gaps by examining the impact of PFAS exposure and heat waves on β-cell and kidney function during puberty in adolescents with obesity and pre-diabetes. We aim to investigate associations between individual PFAS and PFAS mixtures with β-cell and kidney injury during puberty, and examine whether heat waves modify the relationship between PFAS exposure and β-cell and kidney injury, hypothesizing that extreme heat intensifies this association. We will quantify PFAS in participants' plasma and residential water samples and determine heat wave exposure using data from the Colorado Climate Center and participants' residential history records. Our second aim is to integrate data on PFAS exposure and heat waves to understand pathways of β-cell and kidney injury, hypothesizing that PFAS exposure, heat waves, and multi-omic signatures associated with β-cell toxicity and kidney injury can predict subgroups of youth at risk of T2D onset and progression, and early kidney disease. We will measure proteomics and metabolomics in plasma and perform Latent Unknown Clustering Integrating multi-omics Data (LUCID) to integrate environmental factors with multi-omic features. These findings have the potential to revolutionize our understanding of environmental factors in Y-T2D, including the role of climate change-related weather events, such as extreme heat exposure, and inform precision medicine strategies for reducing modifiable PFAS exposure early in life, ultimately preventing β-cell and kidney damage and alleviating the burden of Y-T2D.

项目摘要 /摘要： 在美国，青年发作2型糖尿病（Y-T2D）是一种迅速增长的流行病，具有严重的表型和 有限的可修改风险因素或有效疗法。气候变化，例如极热和水 per和多氟烷基物质（PFA）污染是Y-T2D发展的新兴风险因素 和早期糖尿病肾脏疾病。肥胖和糖尿病前的青少年可能更容易受到 PFAS对β细胞和肾脏功能的有害影响由于其发展的生理学而增加并增加 对环境压力源的脆弱性，包括极高的热量。 为了响应非HD-23-006，我们建议对R01 DK129211的管理补充 基本的跨学科研究通过检查PFAS暴露和热量的影响来解决知识差距 肥胖和糖尿病前青少年青春期期间β细胞和肾功能的波。我们的目标 调查单个PFA和PFA混合物与β细胞和肾损伤之间的关联 青春 肾脏损伤，假设极高的热量加剧了这种关联。我们将量化PFA 参与者的等离子体和居民的水样，并使用来自 科罗拉多州气候中心和参与者的居民历史记录。 我们的第二个目的是整合有关PFAS暴露和热浪的数据，以了解β细胞的途径和 肾脏损伤，假设PFAS暴露，热浪和与β细胞相关的多摩尼克特征 毒性和肾脏损伤可以预测有T2D发作和进展风险的青年亚组，以及早期肾脏 疾病。我们将测量血浆中的蛋白质组学和代谢组学，并执行潜在的未知聚类 整合多摩学数据（LUCID），以将环境因素与多摩变特征整合在一起。 这些发现有可能彻底改变我们对Y-T2D环境因素的理解， 包括与气候变化相关的天气事件的作用，例如极端热量暴露并告知 精确医学策略，以减少生命早期可修改的PFA暴露，最终阻止β细胞 肾脏损坏并减轻Y-T2D的燃烧。