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

维生素 D 结合蛋白对维生素 D 状态和骨骼健康临床指标的影响

• 批准号: 9910387
• 负责人: CHARLES GINSBERG
• 金额: $ 20.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-03 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910387
• 关键词: 25-hydroxyvitamin D; Accounting; Affect; Affinity; Aging; American; Binding Proteins; Bioavailable; Biological Availability; Biological Markers; Biopsy; Body Composition; Bone Density; Bone Diseases; California; Catabolism; Chronic Kidney Failure; Clinical; Conduct Clinical Trials; Conflict (Psychology); Dihydroxycholecalciferols; Educational workshop; Elderly; Fracture; General Population; Goals; Health; Hip Fractures; Hormones; Individual; Lead; Learning; Link; Literature; Measurement; Measures; Mentors; Mentorship; Metabolism; Minerals; Osteoid; Osteomalacia; Pathologic; Pathology; Patients; Performance; Persons; Physiologic calcification; Positioning Attribute; Renal function; Research; Research Personnel; Rickets; Risk; Scientist; Serum; Tissues; Toxic effect; Training; Universities; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin D-Binding Protein; Work; bone; bone health; career; cohort; community living; fracture risk; multidisciplinary; novel; prevent; skills

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.

项目概要 这是 Charles Ginsberg 博士在 Joachim 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) 的 Ix。通过这项提案，金斯伯格博士打算建立 他本人是一名独立研究者，研究慢性肾病-矿物质性骨病（CKD-MBD）。 候选人：金斯伯格博士在本提案中的培训目标包括： 1）熟练掌握表演 骨活检，2）骨组织形态计量学的解释，3）学习必要的技能来开发 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。他集结了多学科 科学家团队包括他的主要导师 Joachim Ix 博士、CKD-MBD 专家、Florin Vaida 博士、 加州大学圣地亚哥分校的生物统计学专家，Isidro Salusky 博士是骨活检表现和解释方面的领导者。 研究：维生素 D 缺乏症在美国人中很常见，已知会导致骨软化症、佝偻病、 和骨折。血清 25-羟基维生素 D [25(OH)D]，评估的推荐临床参数 维生素 D 缺乏症是有缺陷的，因为 25(OH)D 与骨骼之间的关系存在相互矛盾的证据 密度和骨折风险。 Ginsberg 博士推测 25(OH)D 作为骨骼标志物的弱点 健康状况部分取决于维生素 D 结合蛋白 (DBP) 的变化。在金斯伯格博士的前期工作中，他 证明 24,25-二羟基维生素 D 与 25(OH)D 的比率 [维生素 D 代谢物比率 (VMR)] 是 与单独使用 25(OH)D 相比，它是老年人骨折风险的更好标志。 VMR 被假设为 维生素 D 状态的标志，与 DBP 浓度无关。在目标 1 中，金斯伯格博士将评估 25(OH)D、其他维生素 D 代谢物以及 VMR 与血清 DBP 浓度之间的关系 在健康、老龄化和身体成分 (Health ABC) 研究中对 1,142 名老年人进行了调查；观察性的 队列由患有和不患有 CKD 的个体组成。这将确定 VMR 实际上是否独立于 DBP 浓度的差异。在目标 2 中，Ginsberg 博士将评估 25(OH)D 之间的关联， 其他维生素 D 代谢物，以及 Health ABC 研究中骨密度纵向变化的 VMR 并将确定 DBP 差异的解释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 代谢物以及 VMR 与程度的关联 接受骨活检的 CKD 患者的未矿化骨。这将提供直接的病理学 骨疾病的相关性，并将确定这些关系受 DBP 影响的程度 浓度。这不仅可以更好地了解骨病理学的变异性 跨越 CKD 谱系，但还将识别 CKD-MBD 的有价值的生物标志物，并最终可能 为维生素 D 缺乏的测量和治疗提供更合理的方法。