Investigation of Hypercalciuria as a Cause of Impaired Bone Mineral Accrual in Type 1 Diabetes

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PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is associated with an increased risk of fracture that begins in childhood and extends across the lifespan. The pathophysiology underlying the increased skeletal fragility in T1D is not known, and there are no screening or treatment guidelines to aid practitioners caring for the bone health of these patients. The candidate has collected preliminary data suggesting that adolescents with T1D have decreased calcium availability for bone deposition as a result of excess urinary calcium loss during the critical years for bone mineral accrual. The studies outlined in this K23 Mentored Patient-Oriented Research Career Development Award are designed to test the central hypothesis that excess urinary calcium excretion is a potentially targetable contributor to impaired bone mineral accrual in adolescents with T1D. The proposed studies and career development plan will directly support the candidate's goals of becoming an independent physician- scientist working to advance the scientific understanding of the effects of T1D and other chronic disease on bone health and applying these insights to improve clinical care. These goals will be advanced over the course of the K23 award by completion of the following career development objectives: (1) Acquire the technical and didactic knowledge necessary to conduct high-level patient-oriented research in the field of bone health. Under the direction of mentor Dr. O'Brien, the candidate will learn how to perform clinical studies using stable isotopes. This will include instruction in study design and conduct, sample preparation and analysis, and data modeling and interpretation. Additionally, he will complete coursework in clinical trial design to augment his prior training in clinical epidemiology and apply this knowledge in a pilot study to investigate chlorthalidone as a potential treatment for T1D related hypercalciuria. (2) Gain expertise in the evaluation and management of patients with pediatric bone disease. This will be accomplished by providing clinical care in Pediatric Bone Health Clinic, gaining expertise in the use of DXA to evaluate bone accrual, and gaining expertise in the evaluation and treatment of hypercalciuria. (3) Transition to independence as a clinical investigator. The candidate has assembled a team of mentors and advisors who are expert in the relevant content areas of this proposal and have established records of securing NIH funding and mentoring young investigators. They will oversee his progress as he completes the proposed studies, presents work at national meetings, and applies for subsequent ancillary and R01 grants. In summary, the proposed project leverages the extensive resources of URMC and the unique opportunity to learn how to perform stable isotope studies from an expert in the field to investigate an important clinical complication of T1D. The results of these studies, in-conjunction with the career development activities, provide a clear path for the candidate to secure independent funding to investigate clinical interventions to improve bone health in T1D.