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：
10580722
负责人：
Thomas Weimbs
金额：
$ 48.18万
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/10580722
关键词：
Acceleration Adherence Affect Animal Model Autosomal Dominant Polycystic Kidney Cells Classification Clinical Trials Cyclic AMP Cyst Cystic kidney Data Defect Dietary Intervention Disease Progression Disease model Dose Eating Epithelial Cells FDA approved 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 Ketoses Ketosis Kidney Diseases Kidney Failure Knock-out Lead Metabolic Metabolic Diseases Modeling Molecular Mus Myofibroblast Pathway interactions Patients Pharmaceutical Preparations Physiological Polycystic Kidney Diseases Proliferating Quality of life Rattus Regimen Reporting Risk Rodent Rodent Model Signal Transduction Sodium Chloride Starvation Supplementation Testing Time Time-restricted feeding Toxic effect Work beta-Hydroxybutyrate clinical practice clinical translation cost design dietary supplements drinking water effective therapy experimental study high reward human disease ketogenic diet ketogentic mTOR inhibition mouse model pharmacologic 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.

项目概要/摘要我们之前已经证明，轻微减少食物摄入量可以强烈抑制多囊肾的进展疾病（PKD）在直系同源小鼠模型中，但我们不了解其机制现在，我们发现了。酮症的代谢状态很重要，而不是导致饮食干预的热量限制。酮症深刻抑制甚至逆转直系同源和非直系同源小鼠、大鼠的 PKD 进展值得注意的是，单独使用酮 β-羟基丁酸酯 (BHB) 治疗几乎可以治愈多囊肾 (PKD) 和猫科动物模型。初步结果表明，BHB 通过 PKD 肾脏发挥作用，100% 有效。它的受体 GPR109a，一种抑制 cAMP 信号传导的 GPCR，我们的结果表明 PKD 中的囊细胞是代谢不灵活，依赖葡萄糖并且无法转变为利用脂肪酸和酮体。该提案的主旨是产生令人信服的结果，以证明临床试验的合理性，以调查饮食干预和/或 BHB 补充剂对 ADPKD 的疗效，并为此类试验的设计提供信息。该提案的主要意义在于将饮食干预转化为临床的巨大潜力。因为饮食干预在临床实践中经常因不良而失败。坚持不懈，我们发现 BHB（FDA 分类的膳食补充剂）具有显着的有益作用，可以为了实现我们的目标，我们将治疗 PKD 的啮齿动物和猫科动物模型，通过饮食干预来诱发酮症（限时喂养或生酮饮食）或通过以下方式模拟酮症补充 BHB 对 PKD 进展参数的功效及其对分子机制的影响。为了确定 BHB 是否通过 GPR109a 起作用，我们将 Gpr109a-/- 小鼠与 fast- 小鼠进行了杂交。我们将测试 Gpr109a 敲除是否会影响疾病。进展并阻止生酮饮食干预或 BHB 的功效。拟议的工作可能会通过利用饮食干预和/或来导致 ADPKD 治疗的颠覆性改变膳食补充剂，无需药物干预。