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： 青年起病的2型糖尿病(Y-T2D)在美国是一种迅速增长的流行病，具有严重的表型和 有限的可改变的危险因素或有效的治疗。气候变化，如酷热和水 全氟烷基物质和多氟烷基物质(PFAS)的污染是Y-T2D发展的新危险因素 和早期糖尿病肾病。患有肥胖和糖尿病前期的青少年可能更容易患上 全氟辛烷磺酸对β细胞和肾功能的不利影响 易受环境应激源的影响，包括酷热。 为了响应NOT-HD-23-006，我们建议对R01 DK129211进行行政补充，以实现ITS- 通过检查全氟辛烷磺酸暴露和高温的影响来解决知识差距的跨学科研究 肥胖和糖尿病前期青少年青春期β细胞和肾功能的波动。我们的目标是 研究单项全氟辛烷磺酸和全氟辛烷磺酸混合物与β细胞和肾脏损伤的关系 青春期，并检查热浪是否改变了PFAS暴露与β细胞和 肾脏损伤，假设极端高温加剧了这种联系。我们将对全氟辛烷磺酸进行量化 参与者的血浆和居民水样，并使用来自 科罗拉多州气候中心和参与者的居住历史记录。 我们的第二个目标是整合关于PFAS暴露和热波的数据，以了解β-CELL和 肾损伤，假设与β细胞相关的PFAS暴露、热浪和多组特征 毒性和肾脏损伤可以预测T2D发病和进展的风险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，并进行潜在的未知聚类 集成多组学数据(LUID)，将环境因素与多组学特征相结合。 这些发现有可能彻底改变我们对Y-T2D中环境因素的理解， 包括与气候变化有关的天气事件的作用，如极端高温暴露，并告知 减少生命早期可改变的PFAS暴露的精准医学策略，最终预防β-细胞 和肾脏损害，减轻Y-T2D的负担。