Patients with chronic kidney disease (CKD) suffer from excessive rates of cardiovascular disease and death. There is a need for multi-disciplinary research that can bring together scientific discoveries and methodologies from different disciplines to find solutions to this problem. This K23 proposal details a comprehensive 5-year training program for my career development. My principal goal is to develop an independent career in mechanistically-based clinical research studies focused on accelerated atherosclerosis in patients with CKD. Ultimately, I would like to link my findings at the bench with bedside therapeutics that will reduce atherosclerosis and improve the lives of patients with CKD. My primary Mentor Dr. Alan Tall, Tilden-Weger- Bieler Professor of Medicine (with tenure) at Columbia, has pioneered research in mechanisms of atherogenesis and will lead a multi-disciplinary team of mentors. Two ATP-binding cassette transporters, ABCA1 and ABCG1, play key roles in promoting HDL-mediated cholesterol efflux. Murine studies in Dr. Tall's laboratory have shown that their knockout leads to proliferation of hematopoietic stem and multipotential progenitor cells, myeloid progenitor cells, and increased blood monocytes in association with accelerated atherosclerosis. Given the strong clinical association between monocytosis and atherosclerosis, this important basic science finding motivates further study in humans. In preliminary studies for this proposal, we present the first human data suggesting a link between defective cholesterol efflux pathways and monocytosis. The overarching goal of this proposal is to investigate mechanisms of monocytosis in CKD. My short-term goals are to: 1. Receive focused training in two key scientific learning modules: Monocyte/Macrophage Biology &Atherosclerosis and Clinical Phenotyping of Patients via Metabolomics 2. Enhance my understanding of the translational implications of my bench-related findings. I will learn how to link my basic findings at the bench to clinical applications that can improve the health of patient with CKD. 3. Refine my ability to articulate research ideas and findings through publications and oral presentations. 4. Develop independent research projects, and formulate an R01 application in years 3-4 of the K23 award period.
I aim to become an independent investigator with R01 funding by the end of the K23 period. My long-term goals are to: 1. Build a productive, independent career in mechanistically-based clinical research studies focused on alleviating the burden of accelerated atherosclerosis in patients with CKD. My career will have both a laboratory and an active clinical trials component. 2. Expand my network of colleagues and collaborators, both at my own institution and elsewhere. 3. Train and mentor future researchers as they develop into independent investigators.
Cardiovascular disease is the leading cause of death in patients with chronic kidney disease and is not fully explained by traditional risk factors. We have found that patients with chronic kidney disease have high blood monocyte counts, a type of blood cell that has been linked to atherosclerosis. This project aims to identify the mechanisms responsible for high blood monocyte counts in chronic kidney disease patients, which may eventually help guide new therapies that can reduce cardiovascular disease and death in this population.