Ketosis as a therapy for polycystic kidney disease

酮症作为多囊肾病的治疗方法

基本信息

批准号：
10377376
负责人：
Thomas Weimbs
金额：
$ 46.65万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10377376
关键词：
Adherence Affect Animal Model Autosomal Dominant Polycystic Kidney Cells Clinical Trials Cyclic AMP Cyst Cystic kidney Data Defect Dietary Intervention Disease Progression Disease model Dose Eating Epithelial Cells FDA approved FRAP1 gene Family Felidae Fatty Acids Fatty acid glycerol esters Fibrosis Formulation Future G-Protein-Coupled Receptors Genetic Diseases Glucose Goals Growth Intervention Investigation Ketone Bodies Ketones Ketosis Kidney Diseases Kidney Failure Knock-out Lead Metabolic Metabolic Diseases Modeling Molecular Mus Myofibroblast Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiological Polycystic Kidney Diseases Quality of life Rattus Regimen Reporting Rodent Rodent Model Signal Transduction Sodium Chloride Starvation Supplementation Testing Time Time-restricted feeding Toxic effect Work base beta-Hydroxybutyrate clinical practice clinical translation cost design dietary supplements drinking water effective therapy experimental study high reward high risk human disease ketogenic diet ketogentic mouse model prevent receptor response side effect

项目摘要

Project Summary/Abstract We have previously shown that a mild reduction in food intake strongly inhibits progression of polycystic kidney disease (PKD) in an orthologous mouse model but we did not understand the mechanism. Now, we discovered that the metabolic state of ketosis is important, not caloric restriction per se. Dietary interventions leading to ketosis profoundly inhibit - and even reverse - PKD progression in orthologous and non-ortholgous mouse, rat and feline models of PKD. Remarkably, treatment with the ketone β-hydroxybutyrate (BHB) alone is almost 100% effective in preventing PKD progression. Preliminary results suggest that BHB acts on PKD kidneys via its receptor GPR109a, a GPCR that suppresses cAMP signaling. Our results suggest that cyst cells in PKD are metabolically in?exible, depend on glucose and are unable to shift to utilizing fatty acids and ketone bodies. The main thrust of this proposal is to generate compelling results to justify clinical trials to investigate the ef?cacy of dietary interventions and/or BHB supplementation in ADPKD, and to inform the design of such trials. The main signi?cance of this proposal is the enormous potential for clinical translation. Dietary interventions to induce ketosis are well-established. Because dietary interventions frequently fail in clinical practice due to poor adherence, our ?nding that BHB (an FDA-classi?ed dietary supplement) has a dominant bene?cial effect could rapidly lead to a highly feasible therapy. To achieve our goals, we will treat rodent and feline models of PKD, with dietary interventions to induce ketosis (time-restricted feeding or ketogenic diets) or mimic ketosis by supplementation with BHB. Ef?cacy on parameters of PKD progression and effects on molecular mechanisms will be assessed. To determine whether BHB acts via GPR109a, we have crossed Gpr109a-/- mice with fast- and slowly-progressing Pkd1 mouse models. We will test whether Gpr109a knock-out affects disease progression and prevents the ef?cacy of ketogenic dietary intervention or BHB. Successful completion of the proposed work could lead to a disruptive change in ADPKD therapy by utilizing dietary interventions and/or dietary supplements without the need for pharmacological intervention.

项目摘要/摘要我们以前已经表明，食物摄入量的轻度降低会强烈抑制多囊性肾脏的进展直系同源的小鼠模型中的疾病（PKD），但我们不了解该机制。现在，我们发现了酮症的代谢状态很重要，而不是热量限制本身。饮食干预导致酮症在直系同源和非透明小鼠的大鼠中深刻抑制 - 甚至反向 - PKD进展和PKD的猫科动物模型。值得注意的是，仅使用酮β-羟基丁酸（BHB）治疗几乎是 100％有效预防PKD进展。初步结果表明，BHB通过它的接收器GPR109A，一种抑制营地信号的GPCR。我们的结果表明，PKD中的囊肿细胞是代谢中，取决于葡萄糖，无法转移到使用脂肪酸和酮体。该提案的主要目的是产生令人信服的结果，以证明临床试验的合理性在ADPKD中补充饮食干预措施和/或BHB的情况，并为此类试验的设计提供了信息。该提案的主要意义是临床翻译的巨大潜力。饮食干预措施诱导酮症是良好的。因为饮食干预措施在临床实践中经常因差而失败遵守，我们的bhb（fda-classi？ed饮食补充剂）具有主要的好处？迅速导致高度可行的疗法。为了实现我们的目标，我们将处理PKD的啮齿动物和猫科动物模型，饮食干预措施诱导酮症（时间限制的喂养或生酮饮食）或模仿酮症。补充BHB。 cacy关于PKD进展的参数和对分子机制的影响将被评估。为了确定BHB是否通过GPR109A起作用，我们已将GPR109A - / - 小鼠越过快速 - 和缓慢促进的PKD1鼠标模型。我们将测试GPR109A敲除是否影响疾病进展并防止基生饮食干预或BHB的EF？成功完成拟议的工作可能会通过使用饮食干预和/或不需要药物干预的饮食补充剂。