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

项目总结/摘要： 青年型2型糖尿病（Y-T2 D）在美国是一种快速增长的流行病，具有严重的表型， 有限的可改变的风险因素或有效的治疗。气候变化，如极端高温和水 全氟烷基和多氟烷基物质（PFAS）的污染是Y-T2 D发展的新风险因素 和早期糖尿病肾病。患有肥胖症和糖尿病前期的青少年可能更容易患上 PFAS对β细胞和肾功能的不利影响是由于它们的发育生理和增加 易受环境压力的影响，包括极端高温。 作为对NOT-HD-23-006的回应，我们建议对R 01 DK 129211进行行政补充，以进行以下第一项- 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 波对青春期肥胖和糖尿病前期青少年的β细胞和肾功能的影响。我们的目标是 研究PFAS单独和PFAS混合物与β细胞和肾损伤之间的关系， 青春期，并检查热浪是否改变PFAS暴露与β细胞和 肾损伤，假设极端高温加剧了这种关联。我们将量化PFAS， 参与者的血浆和住宅水样，并确定热浪暴露使用的数据， 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、热浪和与β细胞相关的多组学特征 毒性和肾损伤可以预测处于T2 D发作和进展风险的青年亚组， 疾病我们将测量血浆中的蛋白质组学和代谢组学，并进行潜在未知聚类 整合多组学数据（LUCID）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-T2 D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， 精确的医学策略，以减少生命早期可改变的PFAS暴露，最终预防β细胞 和肾脏损害，减轻Y-T2 D的负担。

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.