Exploring the interrelationships of mineral metabolism pathways in kidney disease

描述(申请人提供)：在我的肾脏病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动态平衡中的作用。从实验室的早期开始，矿物质代谢一直是我主要感兴趣的领域，我对这一领域的长期研究和职业目标有了明确的愿景。我的职业计划是成为一名成功的独立研究员，使用基础科学方法进行翻译研究，旨在确定矿物质代谢异常作为进行性肾脏疾病相关共病的诱因所起的作用。我相信，我致力于板凳研究的时间，再加上我之前研究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在慢性肾脏疾病-矿物质和骨病(CKD-MBD)的发病机制中起重要作用。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定义CKD-MBD的发病机制。我们推测，早期从骨骼中增加的FGF23是一种刺激事件，有助于在这种情况下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的“维生素D缺乏”状态，相反，抑制FGF23升高产生的1，25(OH)2D是在进行性肾单位丢失的背景下维持中性磷酸盐平衡的适应性反应。为了阐明FGF23在CKD中的调控和功能，我们获得了一种CKD的转基因小鼠模型(Col4A3基因缺失小鼠)，并对该模型的骨和矿物质代谢表型进行了广泛的表征。到目前为止，我们的发现支持将这种小鼠品系用作在人类中发现的CKD-MBD模型。在这个模型中，矿物质代谢途径可以在受控环境中改变，以深入了解个别矿物质代谢途径的相互关系和组织特异性影响。在这项提案中，我们计划调查几种干预措施的影响，这些干预措施旨在防止慢性肾脏病矿物质代谢变化的自然进展。我们的具体操作将包括：1)通过限制磷酸盐来预防高磷血症，2)早期骨化三醇治疗以对抗1，25(OH)2D缺乏的进行性发展，3)早期拟钙化治疗以防止继发性甲状旁腺功能亢进的发展，4)给予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Klotho表达的减少。这些研究将带来对复杂系统生物学的新知识，该系统生物学已经进化到允许骨骼和肾脏之间的相互作用，以协调磷酸盐平衡、维生素D代谢和骨骼矿化。这些知识将帮助我们了解和更好地管理CKD患者紊乱的矿物质代谢。

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.