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

• 批准号: 8087261
• 负责人: Ming-Chang Hu
• 金额: $ 39.63万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/8087261
• 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; receptor; research study; response

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. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a formidable public healthy problem that impacts negatively on quality of life, survival, and health care costs but there is limited definitive therapy at present at our disposal. We constructed a model where abnormalities in two proteins called Klotho and Fibroblast Growth Factor-23 triggers a downhill spiral of a host of ill events in kidney disease. In this application, we aim to test this model and also devise novel ways to arrest this spiraling deterioration.

描述（由申请人提供）：慢性肾脏疾病（CKD）是美国和世界范围内的严重健康问题，具有不可接受的高发病率和死亡率。矿物质代谢紊乱普遍存在，并在CKD的进展、并发症和死亡率方面发挥核心作用。CKD中矿物质代谢功能障碍的模型随着时间的推移而发展，并且确实已经开发了一些有效的干预措施，但在预防或逆转这些病态疾病的能力方面仍然相当有限。基于目前的数据库，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，随后是成纤维细胞生长因子-23（FGF 23）的升高和维生素D的下降，然后由甲状旁腺功能亢进和高磷酸盐血症复合。这些干扰相互加剧，导致自我放大的螺旋式下降，导致矿物质干扰的许多病态后果，进而导致骨骼疾病和心血管并发症。我们建议测试我们的假设，利用不观察测量，但干预的方法来中断恶性循环，而不是使用主要的啮齿动物模型的CKD。首先，我们将通过替代疗法恢复Klotho的正常表达，并寻找肾脏疾病进展和并发症的延迟或阻止。其次，我们将使用我们在正常啮齿动物中发现并验证的拮抗肽（FGF 23的C-末端片段）抑制内源性FGF 23。读数将与用于测试Klotho替代疗法的读数相同。第三，我们将测试几个简单的操作，可以潜在地保存或刺激内源Klotho表达。根据这三组研究的初步结果，我们将考虑设计联合治疗。CKD中的矿物质干扰迫切需要新的模型，这些模型包括更多我们的数据库和最关键的，针对问题根源的明确干预措施。拟议的实验具有双重目的。它将证明或反驳我们关于Klotho，FGF 23，维生素D，甲状旁腺激素和磷酸盐恶性循环的假设。此外，它还将为临床前数据奠定基础，以测试Klotho替代和FGF 23拮抗的治疗潜力。 公共卫生相关性：慢性肾病是一个可怕的公共健康问题，对生活质量、生存和医疗保健成本产生负面影响，但目前我们可使用的确定性治疗方法有限。我们构建了一个模型，其中两种名为Klotho和成纤维细胞生长因子-23的蛋白质的异常触发了肾脏疾病中一系列疾病事件的螺旋式下降。在这个应用程序中，我们的目标是测试这个模型，并设计新的方法来阻止这种螺旋式恶化。