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）：在肾脏病学研究员培训的早期阶段，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。自从进入实验室以来，矿物质代谢一直是我的主要兴趣领域，并且我对该领域的长期研究和职业目标制定了清晰的愿景。我的职业计划是成为一名成功的独立研究者，利用基础科学方法进行转化研究，旨在确定异常矿物质代谢在与进行性肾病相关的并发症中所起的作用。我相信，我致力于进行实验室研究的时间，加上我之前研究 FGF23 在矿物质代谢中的作用所获得的知识，已经为实现这一长期目标奠定了基础。 越来越多的证据表明 FGF23 在慢性肾病-矿物质和骨病 (CKD-MBD) 的发病机制中发挥着重要作用。我在本申请中概述的初步工作重点是在 FGF23 调节和功能的背景下确定 CKD-MBD 的发病机制。我们假设骨骼中 FGF23 的早期增加是一种刺激事件，有助于在这种情况下发生矿物质代谢异常。我们认为，CKD 并不代表肾损伤导致的真正“维生素 D 缺乏”状态，相反，FGF23 升高抑制 1,25(OH)2D 产生是在进行性肾单位丧失的情况下维持中性磷酸盐平衡的适应性反应。为了阐明 FGF23 在 CKD 中的调节和功能，我们获得了 CKD 基因改造小鼠模型（Col4a3 缺失小鼠），并广泛表征了该模型的骨和矿物质代谢表型。迄今为止，我们的研究结果支持使用该小鼠品系作为人类 CKD-MBD 模型。在该模型中，可以在受控环境中改变矿物质代谢途径，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。 在本提案中，我们计划调查几种旨在阻止 CKD 矿物质代谢变化自然进展的干预措施的影响。我们的具体操作包括：1) 通过限制磷酸盐预防高磷血症，2) 早期骨化三醇治疗，以抵消 1,25(OH)2D 缺乏症的逐渐发展，3) 早期拟钙剂治疗，以预防继发性甲状旁腺功能亢进症的发展，4 ) 施用 FGF23 失活抗体以降低活跃的循环 FGF23 水平，以及 5) klotho 的过度表达以防止肾功能减退克洛托表达式。这些研究将带来关于复杂系统生物学的新知识，该系统生物学已经发展到允许骨骼和肾脏之间的串扰来协调磷酸盐平衡、维生素 D 代谢和骨矿化。这些知识将帮助我们了解和更好地管理 CKD 患者矿物质代谢紊乱。 公众健康相关性：成纤维细胞生长因子 23 (FGF23) 是一种新型激素，被发现可以调节体内磷和维生素 D 的水平，并且在肾病患者中其含量极高。这种激素的发现改变了我们对慢性肾病患者矿物质代谢异常起源的看法。我们计划使用进行性肾病的小鼠模型来研究矿物质代谢途径的复杂相互关系，并确定这些途径对这种情况下常见的血管和骨骼并发症的具体贡献。