Klotho and FGF23 in Chronic Kidney Disease: Pathogenesis and Theraputics

Klotho 和 FGF23 在慢性肾脏病中的作用：发病机制和治疗

基本信息

批准号：
8638958
负责人：
Ming-Chang Hu
金额：
$ 34.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-10 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638958
关键词：
Animals Biological Preservation Blood Bone Diseases C-terminal Calcitriol Cardiovascular system Characteristics Chronic Kidney Failure Clip Combined Modality Therapy Data Databases Deterioration Diet Disease Disease Progression Endocrine Endocrine disruption Epithelial Cells Equilibrium Event Excretory function Extracellular Domain Foundations Functional disorder Gene Expression Goals Health Health Care Costs Homeostasis Hormones Hyperparathyroidism Injection of therapeutic agent Integral Membrane Protein Interruption Intervention Intestines Kidney Kidney Diseases Length Link Measurement Membrane Metabolism Methods Minerals Mixed Function Oxygenases Modeling Morbidity - disease rate Organ Outcome Parathyroid gland Parathyroidectomy Pathogenesis Patients Peptide Hydrolases Plant Roots Plasma Proteins Quality of life Reading Recombinants Regulation Renal Mass Renal function Replacement Therapy Resistance Risk Rodent Rodent Model Role Serum Staging Testing Therapeutic Time Vitamin D absorption base bone calcification design effective intervention fibroblast growth factor 23 improved inhibitor/antagonist inorganic phosphate klotho protein loss of function mutation mortality novel novel therapeutic intervention novel therapeutics polypeptide C pre-clinical prevent public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is grave health problem in the U.S.A. and worldwide with unacceptably high morbidity and mortality. Disorders of mineral metabolism are ubiquitous and assume a central role in CKD in terms of contribution to its progression, complications, and mortality. Models of dysfunctional mineral metabolism in CKD have evolved over time and some effective interventions have indeed been developed but are still rather limited in terms of their ability to prevent or reverse these morbid disorders. Based on the current database including our own preliminary data, we present a model where Klotho deficiency is an early event in CKD followed by rise in fibroblast growth factor-23 (FGF23) and decline in vitamin D, which is then compounded by hyperparathyroidism and hyperphosphatemia. These disturbances aggravate each other resulting in a self-amplifying downward spiral that leads to numerous morbid consequences of mineral disturbance that ramifies into bone disease and cardiovascular complications. We propose to test our hypothesis utilizing not observational measurements, but an interventional approach to interrupt the vicious cycle rather than using primarily rodent models of CKD. First, we will restore normal Klotho expression by replacement therapy and look for retardation or arrest of progression and complications of kidney disease. Second, we will suppress endogenous FGF23 using an antagonistic peptide (C-terminal fragment of FGF23) that we discovered and verified in normal rodents. The read-out will be the same as that used for testing Klotho replacement therapy. Third, we will test several simple maneuvers that can potentially preserve or stimulate endogenous Klotho expression. Depending on the initial findings from these three sets of studies, we will consider designing combination therapy. Mineral disturbances in CKD is in dire need for novel models that encompass more of our database and most critically, definitive interventions that target the root of the problem. The proposed experiments serve dual purposes. It will prove or refute our hypothesis of the vicious cycle of Klotho, FGF23, vitamin D, parathyroid hormone, and phosphate. In addition, it will also lay the foundation of preclinical data to test the therapeutic potential of Klotho replacement and FGF23 antagonism.

描述（由申请人提供）：慢性肾脏疾病（CKD）在美国是严重的健康问题，在全球范围内，发病率和死亡率很高。矿物质代谢的疾病无处不在，并且在对其进展，并发症和死亡率的贡献方面扮演着核心作用。随着时间的推移，CKD中矿物质代谢功能失调的模型已经发展，并且确实已经开发出一些有效的干预措施，但在预防或扭转这些病态疾病的能力方面仍然相当有限。基于当前数据库（包括我们自己的初步数据），我们提出了一个模型，其中klotho缺乏症是CKD的早期事件，随后成纤维细胞生长因子23（FGF23）和维生素D的下降，而维生素D的下降则是由甲状腺甲状腺功能亢进和高磷酸化血症复杂的。这些干扰彼此加剧，导致自我扩增的向下螺旋形，从而导致矿物质干扰的许多病态后果，从而将骨骼疾病陷入骨骼疾病和心血管并发症。我们建议利用不是观察性测量值来检验我们的假设，而是一种干预方法来中断恶性循环，而不是主要使用CKD的啮齿动物模型。首先，我们将通过替换疗法来恢复正常的克洛托表达，并寻求阻碍或阻止肾脏疾病的进展和并发症。其次，我们将使用我们在正常啮齿动物中发现和验证的拮抗肽（FGF23的C末端片段）抑制内源性FGF23。读出将与测试Klotho替代疗法的读取物相同。第三，我们将测试一些可以潜在地保留或刺激内源性klotho表达的简单操作。根据这三组研究的初步发现，我们将考虑设计组合疗法。 CKD中的矿物质干扰迫切需要新的模型，这些模型包括我们的数据库，以及针对问题根源的最关键的确定干预措施。提出的实验具有双重目的。它将证明或反驳我们对克洛托，FGF23，维生素D，甲状旁腺激素和磷酸盐的恶性循环的假设。此外，它还将奠定临床前数据的基础，以测试克洛托替代和FGF23拮抗作用的治疗潜力。