Obeticholic acid as a novel treatment for Alport syndrome

奥贝胆酸作为阿尔波特综合征的新型治疗方法

• 批准号: 10315231
• 负责人: Bryce Alan Jones
• 金额: $ 3.33万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-27 至 2025-08-26
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315231
• 关键词: Acids; Adrenal Glands; Age; Agonist; Arginine; Bile Acids; Binding; Biochemical; Biopsy; Blood Pressure; Chronic Kidney Failure; Clinical; Clinical Trials; Collagen; Collagen Type IV; Data; Defect; Diabetic Nephropathy; Diet; Disease Progression; Etiology; FDA approved; Female; Fibrosis; Fluorescein-5-isothiocyanate; Gene Activation; Generations; Genes; Genetic Transcription; Genotype; Glomerular Filtration Rate; Glycolysis; Goals; Hereditary Disease; Hereditary nephritis; Human; Image; Immune response; Immunohistochemistry; Inflammation; Inherited; Investigational Drugs; Kidney; Kidney Diseases; Kidney Transplantation; Label; Left; Liver; Measures; Mediating; Metabolic; Metabolism; Metadata; Microscope; Modeling; Mus; NADH; Nitric Oxide Synthetase Inhibitor; Nuclear Receptors; Nuclear Translocation; Organ; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Primary biliary cirrhosis; Proteolysis; Ramipril; Rare Diseases; Receptor Activation; Recovery; Renin-Angiotensin-Aldosterone System; Resolution; Risk Factors; Serum; Severities; Slide; Small Intestines; Techniques; Testing; Tissues; Transactivation; Transgenic Mice; Urine; Work; biological adaptation to stress; dimethylargininase; drug repurposing; effective therapy; fluorescence lifetime imaging; kidney biopsy; kidney fibrosis; lipid biosynthesis; male; mouse model; multi-photon; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; prevent; promoter; receptor; receptor expression; second harmonic; transcription factor; treatment duration

PROJECT SUMMARY / ABSTRACT Current treatment options for Alport syndrome are extremely limited: Alport syndrome is a hereditary orphan disease arising from defects in the collagen IV α3α4α5 heterotrimer, and it invariably results in chronic kidney disease (CKD). A kidney transplant is the definitive cure for CKD arising from Alport syndrome, but the need for kidney donors far exceeds the availability. Renin-angiotensin-aldosterone system (RAAS) blockade, such as the drug ramipril, is the pharmacological mainstay used to treat CKD in patients with Alport syndrome. Bardoxolone methyl (BdMe) is a promising investigational drug that is very close to being approved to treat Alport syndrome. Nevertheless, developing additional therapies for Alport syndrome is critically important. Farnesoid X receptor (FXR): FXR is a nuclear receptor that is highly expressed in the kidneys, liver, adrenals, small intestines, and vasculature. It is endogenously activated by bile acids. Obeticholic acid (OCA) is a specific FXR agonist that is already approved by the FDA. Thus, OCA could be repurposed to treat Alport syndrome if it is shown to be effective. Importantly, OCA has been shown to be protective in many other models of chronic kidney disease. The OVERARCHING GOAL OF THIS PROPOSAL is to investigate OCA as a novel treatment for Alport syndrome using a transgenic mouse model. We will test the hypothesis that OCA treatment, with or without coadministration of either ramipril or BdMe, is nephroprotective in a mouse model of Alport syndrome. These combinations were chosen in part because evidence in other models of kidney disease suggests that OCA may work through similar pathways as ramipril and BdMe. Thus, it is plausible that OCA could potentiate the beneficial effects of ramipril and BdMe. This may occur independently of any other beneficial effects of OCA. In addition, we will investigate levels of FXR and its well-defined target genes in renal biopsies from patients with Alport syndrome. Label-free imaging will be performed to quantify fibrosis and metabolism, and their correlation with FXR expression will be investigated with spatial resolution within the same biopsy. Correlations will also be sought between these data and the clinical metadata associated with each biopsy.

项目摘要/摘要