Exploring the interrelationships of mineral metabolism pathways in kidney disease

探索肾脏疾病中矿物质代谢途径的相互关系

• 批准号: 8044333
• 负责人: Jason Stubbs
• 金额: $ 15.14万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-21 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044333
• 关键词: Exploring; interrelationships; mineral; metabolism; pathways

DESCRIPTION (provided by applicant): In the early stages of my fellowship training in nephrology, I began working with Dr. Darryl Quarles to investigate the role of fibroblast growth factor 23 (FGF23) in phosphate and vitamin D homeostasis. Since these early days in the lab, mineral metabolism has remained my primary area of interest, and I have developed a clear vision of my long-term research and career goals within this field. My career plan is to become a successful independent investigator using basic science methodology to perform translational research aimed at defining the role of aberrant mineral metabolism as a contributor to the co-morbidities associated with progressive kidney disease. I believe the time I have dedicated to performing bench research, combined with the knowledge I have gained through my previous work investigating the role of FGF23 in mineral metabolism, has laid the groundwork for the realization of this long-term goal. There is emerging evidence that FGF23 is important in the pathogenesis of chronic kidney disease-mineral and bone disorder (CKD-MBD). The preliminary work that I have outlined in this application has focused on defining the pathogenesis of CKD-MBD in the context of FGF23 regulation and function. We postulate that early increments of FGF23 from bone are an inciting event which contributes to the development of mineral metabolism abnormalities in this setting. We believe that CKD does not represent a true "vitamin D deficient" state resulting from renal injury, rather suppression of 1,25(OH)2D production by elevated FGF23 is an adaptive response to maintain neutral phosphate balance in the setting of progressive nephron loss. To elucidate the regulation and function of FGF23 in CKD, we have obtained a genetically altered mouse model of CKD (Col4a3 null mouse) and extensively characterized the bone and mineral metabolism phenotype of this model. Our findings thus far have supported the use of this mouse strain as a model of CKD-MBD found in humans. In this model, mineral metabolism pathways can be altered in a controlled environment to gain insight into the interrelationships and tissue specific effects of individual mineral metabolism pathways. In this proposal, we plan to investigate the impact of several interventions aimed at preventing the natural progression of mineral metabolism changes in CKD. Our specific manipulations will include: 1) the prevention of hyperphosphatemia with phosphate restriction, 2) early calcitriol therapy to counteract the progressive development of 1,25(OH)2D deficiency, 3) early calcimimetic therapy to prevent the development of secondary hyperparathyroidism, 4) the administration of FGF23-deactivating antibodies to lower active circulating FGF23 levels, and 5) the over-expression of klotho to prevent decrements in renal klotho expression. These studies will lead to new knowledge of a complex systems biology that has evolved to permit cross-talk between bone and kidney to coordinate phosphate balance, vitamin D metabolism and bone mineralization. Such knowledge will help us understand and better manage disordered mineral metabolism in patients with CKD. PUBLIC HEALTH RELEVANCE: Fibroblast growth factor 23 (FGF23) is a novel hormone that has been found to regulate phosphorus and vitamin D levels in the body, and it is extremely elevated in patients with kidney disease. The discovery of this hormone has changed our thinking regarding the origins of mineral metabolism abnormalities in patients with chronic kidney disease. We plan to use a mouse model of progressive kidney disease to investigate the complex interrelationships of mineral metabolism pathways and to identify the specific contributions of these pathways to the vascular and bone co-morbidities that are common in this setting.

描述（由申请人提供）：在我在肾脏学研究金培训的早期阶段，我开始与Darryl Quarles博士合作研究成纤维细胞生长因子23（FGF23）在磷酸盐和维生素D稳态中的作用。自从实验室的早期以来，矿物质代谢仍然是我感兴趣的主要领域，并且我对我在该领域的长期研究和职业目标有了清晰的愿景。我的职业计划是使用基础科学方法学成为一名成功的独立研究者，以进行转化研究，旨在定义异常矿物代谢作为与渐进肾脏疾病相关的合并症的贡献的作用。我相信我致力于进行板凳研究的时间，再加上我以前的工作所获得的知识，研究了FGF23在矿物代谢中的作用，为实现这一长期目标的实现奠定了基础。 有新兴的证据表明，FGF23在慢性肾脏疾病矿物质和骨病（CKD-MBD）的发病机理中很重要。我在本应用程序中概述的初步工作重点是在FGF23调节和功能的背景下定义CKD-MBD的发病机理。我们假设FGF23从骨头提早增加是一个煽动性事件，在这种情况下有助于矿物质代谢异常的发展。我们认为，CKD并不代表肾脏损伤导致的真正“维生素D缺乏”状态，而是FGF23升高的1,25（OH）2D产生的抑制是一种适应性反应，以在渐进式肾脏损失的情况下保持中性磷酸盐的平衡。为了阐明FGF23在CKD中的调节和功能，我们获得了CKD的遗传改变的小鼠模型（COL4A3无效小鼠），并广泛地表征了该模型的骨骼和矿物质代谢表型。迄今为止，我们的发现支持将这种小鼠菌株用作人类中发现的CKD-MBD模型。在此模型中，可以在受控环境中改变矿物代谢途径，以深入了解各个矿物质代谢途径的相互关系和组织特异性影响。 在该提案中，我们计划研究旨在防止CKD矿物质变化自然发展的几种干预措施的影响。我们的具体操作将包括：1）预防具有磷酸盐限制的高磷酸血症，2）早期骨化三醇治疗以抵消1,25（OH）2D缺乏症的进行性发育，3）早期钙化疗法，以防止二级高甲状腺功能亢进症的发展，4）FGF23-循环较低的fgf23-循环，并降低了fgf23-Decepivative fgf FGF的抗体，以降低抗体的活性，克洛托的过表达，以防止肾脏klotho表达的降低。这些研究将导致对复杂系统生物学的新知识，该学已经发展为允许骨骼和肾脏之间的串扰以协调磷酸盐平衡，维生素D代谢和骨矿化。这些知识将帮助我们理解并更好地管理CKD患者的矿物质代谢。 公共卫生相关性：成纤维细胞生长因子23（FGF23）是一种新型激素，已发现可以调节体内磷和维生素D水平，并且在肾脏疾病患者中它极高。这种激素的发现改变了我们关于慢性肾脏疾病患者矿物代谢异常起源的思想。我们计划使用进行性肾脏疾病的小鼠模型研究矿物质代谢途径的复杂相互关系，并确定这些途径对在这种情况下常见的血管和骨骼合并症的特定贡献。