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

项目总结/摘要 1型糖尿病（T1 D）与骨折风险增加相关，该风险始于儿童期并延伸至 在整个生命周期中。T1 D患者骨骼脆性增加的病理生理学机制尚不清楚， 现时并没有任何筛选或治疗指引，以协助医生照顾这些病人的骨骼健康。 候选人收集的初步数据表明，患有T1 D的青少年钙含量降低， 骨沉积的可用性是由于在骨的关键年份尿钙流失过多所致 矿物质积累K23指导的以患者为导向的研究职业发展中概述的研究 奖项的目的是测试中心的假设，即过量的尿钙排泄是一个潜在的 T1 D青少年中骨矿物质累积受损的靶向因素。拟议的研究和 职业发展计划将直接支持候选人成为独立医生的目标- 科学家致力于推进对T1 D和其他慢性疾病对健康影响的科学认识。 骨骼健康和应用这些见解，以改善临床护理。这些目标将在课程中推进 通过完成以下职业发展目标获得K23奖：（1）获得技术和 在骨健康领域进行高水平的以患者为导向的研究所需的教学知识。下 在导师奥布莱恩博士的指导下，候选人将学习如何使用稳定的 同位素这将包括研究设计和实施、样品制备和分析以及数据的说明 建模和解释。此外，他将完成临床试验设计课程，以增加他的 接受过临床流行病学培训，并将这些知识应用于试点研究，以调查氯噻酮作为 T1 D相关高钙尿症的潜在治疗。(2)获得评估和管理方面的专业知识 儿科骨病患者。这将通过提供儿科骨的临床护理来实现 健康诊所，获得使用DXA评估骨增量的专业知识，并获得 高钙尿症的评估和治疗。(3)作为临床研究者过渡到独立。的 候选人已经组建了一个导师和顾问团队，他们是本课程相关内容领域的专家。 并建立了确保NIH资金和指导年轻研究人员的记录。他们将 监督他完成拟议的研究，在国家会议上介绍工作，并申请 随后的辅助和R 01赠款。总而言之，拟议项目利用了广泛的资源， 和独特的机会，学习如何从该领域的专家进行稳定同位素研究 研究T1 D的重要临床并发症。这些研究的结果，结合 职业发展活动，为候选人提供明确的途径，以确保独立的资金， 研究改善T1 D患者骨骼健康的临床干预措施。

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.