Influence of Vitamin D Binding Protein on Clinical Measures of Vitamin D Status and Bone Health

项目总结 这是查尔斯·金斯伯格博士在约阿希姆博士的指导下首次提交的K23申请 加州大学圣地亚哥分校(UCSD)。通过这项提议，金斯伯格博士打算建立 他是研究慢性肾脏病-矿物性骨病(CKD-MBD)的独立研究员。 候选人：金斯伯格博士在这份提案中的培训目标包括：1)精通表演 骨活检，2)骨组织形态计量学的解释和3)学习必要的技能 研究团队并进行临床试验。金斯伯格博士将通过指导来实现这些目标， 课程作业，以及参加研讨会和指导委员会。他已经组建了一个多学科的 科学家团队包括他的主要导师约阿希姆九世博士，CKD-MBD专家，弗洛林·瓦伊达博士，以及 加州大学圣迭戈分校的专家生物统计学家和伊西德罗·萨卢斯基博士是骨活检性能和解释方面的领先者。 研究：维生素D缺乏在美国人中很常见，已知会导致骨软化症、软骨病、软骨病、 和骨折。血清25-羟基维生素D[25(OH)D]，推荐用于评估 维生素D缺乏是有缺陷的，因为有相互矛盾的证据表明25(OH)D与骨骼有关 密度和断裂风险。金斯伯格博士假设，25(OH)D作为骨骼标志的弱点 健康在一定程度上是由于维生素D结合蛋白(DBP)的变异性。在金斯伯格博士的初步工作中，他 证明了24，25-二羟基维生素D与25(OH)D的比例[维生素D代谢物比率(VMR)]是 与单独使用25(OH)D相比，老年人骨折风险的更高标记。VMR被假设为一个 与DBP浓度无关的维生素D状态的标志物。在目标1中，金斯伯格博士将评估 25(OH)D等维生素D代谢物及VMR与血清DBP浓度的关系 在健康、老龄化和身体成分(Health ABC)研究中的1142名老年人中；观察性的 队列由患有和不患有CKD的个体组成。这将确定VMR是否实际上独立于 DBP浓度的差异。在目标2中，金斯伯格博士将评估25(OH)D和 其他维生素D代谢物，以及健康ABC研究中骨密度纵向变化的VMR 并将确定考虑舒张压差异是否会影响这些关系。在《目标3》中，金斯伯格博士 将评估25(OH)D、其他维生素D代谢物和VMR与 慢性肾脏病患者行骨活检时的未矿化骨。这将提供一种直接的病理 与骨骼疾病的相关性，并将决定这些关系受DBP影响的程度 浓度。这不仅可以更好地理解骨骼病理中的可变性 但也将确定CKD-MBD的有价值的生物标记物，并可能最终 为维生素D缺乏的测量和治疗提供更合理的方法。

PROJECT SUMMARY This is an initial submission of a K23 application by Dr. Charles Ginsberg, under the mentorship of Dr. Joachim Ix at the University of California San Diego (UCSD). Through this proposal Dr. Ginsberg intends to establish himself as an independent investigator studying the chronic kidney disease-mineral bone disorder (CKD-MBD). Candidate: Dr. Ginsberg's training objectives in this proposal include; 1)become proficient in the performance of bone biopsies, 2)the interpretation of bone histomorphometry and 3)learn the necessary skills to develop a research team and conduct clinical trials. Dr. Ginsberg will accomplish these objectives through mentorship, coursework, and participation in workshops and steering committees. He has assembled a multidisciplinary team of scientists including his primary mentor Dr. Joachim Ix, an expert in the CKD-MBD, Dr. Florin Vaida, an expert biostatistician at UCSD, and Dr. Isidro Salusky a leader in bone biopsy performance and interpretation. Research: Vitamin D deficiency is common among Americans and is known to lead to osteomalacia, rickets, and fractures. Serum 25-hydroxyvitamin D [25(OH)D], the recommended clinical parameter to assess for vitamin D deficiency, is flawed as there is conflicting evidence of association between 25(OH)D with bone density and fracture risk. Dr. Ginsberg hypothesizes that the weakness of 25(OH)D as a marker for bone health is, in part, due to variability in vitamin D binding protein (DBP). In Dr. Ginsberg's preliminary work he demonstrated that the ratio of 24,25-dihydroxyvitamin D to 25(OH)D [the vitamin D metabolite ratio (VMR)] is a superior marker of fracture risk in older adults, compared to 25(OH)D alone. The VMR is hypothesized to be a marker of vitamin D status that is independent of DBP concentrations. In Aim 1, Dr. Ginsberg will evaluate the relationship between 25(OH)D, other vitamin D metabolites, and the VMR with serum DBP concentrations among 1,142 older adults in the Health, Aging and Body Composition (Health ABC) Study; an observational cohort comprised of individuals with and without CKD. This will establish if the VMR is in fact independent of differences in DBP concentrations. In Aim 2, Dr. Ginsberg will evaluate the associations between 25(OH)D, other vitamin D metabolites, and the VMR with longitudinal change in bone density in the Health ABC Study and will determine if accounting for differences in DBP influences these relationships. In Aim 3, Dr. Ginsberg will evaluate the associations of 25(OH)D, other vitamin D metabolites, and the VMR with the degree of unmineralized bone in patients with CKD undergoing bone biopsies. This will provide a direct pathological correlate of bone disease and will determine the degree to which these relationships are influenced by DBP concentrations. This will not only allow for a better understanding of the variability in bone pathology seen across the spectrum of CKD but will also identify valuable biomarkers of the CKD-MBD and may ultimately provide a more rational approach to measurement and treatment of vitamin D insufficiency.