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： 青少年发病的 2 型糖尿病 (Y-T2D) 在美国是一种快速增长的流行病，具有严重的表型和 有限的可改变的风险因素或有效的治疗方法，例如极端高温和水。 全氟烷基物质和多氟烷基物质 (PFAS) 污染是 Y-T2D 发展的新风险因素 肥胖和糖尿病前期的青少年可能更容易患糖尿病肾病。 PFAS 对 β 细胞和肾功能的不良影响是由于它们的生理机能发育和增加 容易受到环境压力的影响，包括极端高温。 为了回应 NOT-HD-23-006，我们建议对 R01 DK129211 进行行政补充，以实现其首个- 一种跨学科研究，通过检查 PFAS 暴露和热量的影响来解决知识差距 我们的目标是对肥胖和糖尿病前期青少年的青春期 β 细胞和肾功能产生影响。 研究个体 PFAS 和 PFAS 混合物与 β 细胞和肾损伤之间的关联 青春期，并检查热浪是否改变了 PFAS 暴露与 β 细胞和 肾损伤，假设极端高温会加剧这种关联，我们将量化其中的 PFAS。 参与者的血浆和住宅水样，并使用来自的数据确定热浪暴露 科罗拉多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有关 PFAS 暴露和热浪的数据，以了解 β 细胞和 肾损伤，假设 PFAS 暴露、热浪和多组学特征与 β 细胞相关 毒性和肾损伤可以预测有 T2D 发病和进展风险的青少年亚组，以及早期肾损伤 我们将测量血浆中的蛋白质组学和代谢组学并进行潜在未知聚类。 整合多组学数据 (LUCID)，将环境因素与多组学特征相整合。 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，例如极端高温暴露，并告知 减少生命早期可改变的 PFAS 暴露的精准医疗策略，最终预防 β 细胞 和肾脏损害并减轻 Y-T2D 的负担。