PFAS and Diabetic Kidney Disease in Young Onset Type 2 Diabetes: Emerging Risk Factors and Underlying Mechanisms - PROJECT SUMMARY / ABSTRACT Diabetic kidney disease (DKD) develops in more than 50% of youth with type 2 diabetes (T2D) as they transition to young adulthood. Early identification of youth at risk of DKD, either due to environmental or biological factors, has the potential to inform clinical care and alter the course of disease. Despite the substantial burden of DKD in youth with T2D, however, modifiable risk factors and effective therapies remain limited. Emerging evidence links per- and polyfluoroalkyl substances (PFAS), a group of ubiquitous artificial chemicals used for more than 60 years in consumer and industrial products, with impaired kidney function, worse glucose regulation, and higher levels of uremic toxins, key risk factors for DKD in youth with T2D. This study proposes to perform the first prospective study to examine the association of PFAS exposure with DKD risk in youth with T2D and to investigate potential biological mechanisms by integrating key information on metabolites and protein levels. The project will build upon existing health and omics data (metabolomics and proteomics) in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, a longitudinal study of youth with T2D who underwent annual measures of kidney function for an average of 10.2 years. Using archived plasma samples, this project will measure levels of 10 common PFAS and up to 250 novel and emerging PFAS at baseline. Due to the long biological half-lives of most of these chemicals, single PFAS measures are a good proxy for medium to long-term PFAS exposures. Analyses will examine associations between individual PFAS and PFAS mixtures with risk and progression of DKD using survival analysis and mixture methods. To examine the potential biological pathways that link PFAS exposure with DKD, analyses will then examine associations of PFAS (individual and mixtures) with metabolites and proteins potentially associated with DKD risk. Further, a novel latent unknown clustering approach will be applied to comprehensively analyze PFAS exposure, multiomics, and clinical data to identify subgroups of youth with T2D at high risk of DKD. These research findings will contribute to the body of evidence needed to inform PFAS regulation and develop innovative environmental health interventions to detect and prevent DKD in youth with T2D. The culmination of my scientific training has prepared me to successfully carry out the proposed K01 research. Through a multifaceted training plan supported by a strong transdisciplinary mentoring and advisory team, this K01 will provide the necessary support for me to further develop as an independent environmental health researcher. In addition to the proposed research project, a robust yet attainable training plan incorporating didactic instruction, seminars, conferences, and mentorship will prepare me to successfully complete a future NIEHS R01 to examine personalized DKD prevention strategies in young individuals, when potential lesions may still be reversible, to promote healthier lives in this at-risk population.
