SMART-2D: Study of Montelukast's Effects on Renal and Cardiovascular Health in Adolescents and Young Adults with Type 2 Diabetes

About This Grant

PROJECT SUMMARY/ABSTRACT: CANDIDATE: Angelina Dixon, MD, is currently Chief Medicine/Pediatric Nephrology Fellow, and will join the faculty as an Instructor in July 2025 in the Division of Renal Diseases and Hypertension at the University of Colorado Anschutz Medical Campus (UC-AMC). Dr. Dixon has thrived in the field of research with a strong publication record and postdoctoral grant funding and awards. Dr. Dixon’s overarching career goal is to independently conduct research to improve outcomes for adolescents and young adults (AYA) with type 2 diabetes (T2D). CAREER DEVELOPMENT PLAN: Dr. Dixon’s proposed training plan is designed for her to develop proficiency in clinical and translational research methods, expand her professional development, and develop skills to progress towards research independence through presentations at seminars and national scientific meetings, coursework, grant writing and mentoring experience, leadership training, and regular interactions with her mentoring team. Her proposed project and training plan are a direct extension of the knowledge and skills she has acquired thus far in her mentor’s laboratory. ENVIRONMENT: The training environment at UC-AMC is outstanding. Dr. Dixon’s primary mentor, Dr. Kendrick has been continuously funded by NIH and has a strong record of successful mentoring junior investigators. Dr. Dixon’s mentorship team includes co-mentors, Dr. Bjornstad (pediatric endocrinology and expert in advanced methods of intrarenal hemodynamic function), Dr. Furgeson (expert in cysteinyl leukotrienes) and Dr. You (expert in biostatistics). Dr. Dixon will be provided with protected time, equipment, and other resources needed for the K23 by the Division. RESEARCH: Diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading cause of morbidity and mortality in AYA with T2D. T2D leads to release of proinflammatory lipid mediators, termed leukotrienes, which are implicated in endothelial dysfunction and microcalcification, resulting in increased renal vascular resistance (RVR) and arterial stiffness. Montelukast, a cysteinyl leukotriene inhibitor, widely used in asthma with an excellent safety profile in both pediatric and adult populations, may represent a promising intervention for AYA with T2D. Our group’s preliminary data show that using montelukast in mice with acute kidney injury prevents chronic kidney disease, and our observational data in adults suggest a significantly reduced risk of incident kidney failure with montelukast use. We also find attenuated arterial stiffness in mice treated with montelukast and lower systolic blood pressure in human participants exposed to montelukast. Dr. Dixon will conduct a randomized, double-blind trial in 50 AYA aged 12-24 years with T2D examining the effect of 6 months of montelukast vs. placebo on: intrarenal hemodynamics (RVR, glomerular pressure) measured by p-amminohippurate and iohexol clearance (Aim 1); vascular endothelial function (measured by brachial artery flow-mediated dilation), and large elastic artery stiffness (measured by aortic pulse wave velocity) (Aim 2); and kidney and vascular inflammation (measured by urinary, blood, and endovascular cell markers) (Aim 3).