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Myosin Activation as a Novel Therapeutic Strategy for Polycystic Kidney Disease

肌球蛋白激活作为多囊肾病的新型治疗策略

基本信息

批准号：
10313782
负责人：
Louisa M Helms
金额：
$ 2.96万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-03-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10313782
关键词：
3-Dimensional Actomyosin Adhesions Affect Agonist Architecture Autosomal Dominant Polycystic Kidney Biochemical Biological Assay Biological Models Biological Products Biology Blood Urea Nitrogen Blood specimen Body Weight Calmodulin Cell model Cells Clinical Contracts Creatinine Cyst Data Disease Dose Drug Screening Effectiveness Ensure Epithelial Experimental Models Fibrosis Filament Fluorescence Functional disorder G-Protein-Coupled Receptors Genetic Goals Growth Harvest Heart Heart Abnormalities Hemodialysis Hepatic Cyst Human Image Image Analysis In Vitro Individual Kidney Kidney Failure Kidney Transplantation Ligands Light Link Liquid substance Literature Liver Measures Modeling Modification Molecular Motor Movement Mus Mutation Myosin ATPase Myosin Phosphatase Pathway Nonmuscle Myosin Type IIA Organ Organ failure Organism Organoids PKD2 protein Pathway interactions Peptides Pharmaceutical Preparations Phenocopy Phosphorylation Polycystic Kidney Diseases Pre-Clinical Model Preclinical Drug Development Prevention Procedures Production Protein Family Proteins Renal function Renal tubule structure Reporter Signal Transduction Slide Stimulus Structure System Testing Therapeutic Tissues Translating Tubular formation Work base blebbistatin curative treatments disease-in-a-dish drug candidate drug development drug discovery druggable target efficacy evaluation efficacy testing experimental study in vivo inhibitor/antagonist innovation insight kidney cell loss of function member mouse model mutant non-muscle myosin novel novel therapeutic intervention polycystic kidney disease 1 protein pre-clinical prevent protein aminoacid sequence receptor response small molecule stem cells therapeutically effective treatment strategy

项目摘要

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in every 400-1000 people worldwide, causing progressive fluid-filled cyst production in the kidneys, liver, and other organs, resulting in organ failure. PKD is caused by mutations in the polycystin proteins polycystin-1 (PC1) or polycystin-2 (PC2). A clear understanding of how polycystin dysfunction leads to cysts mechanistically is still elusive, due, in part, to the lack of cyst producing model systems that accurately phenocopy the disease. Stem cell derived human kidney organoids model PKD cystogenesis in a specific way and have potential to accelerate drug discovery and development for PKD. Using these PKD organoids, a drug screen was performed identifying blebbistatin, a myosin inhibitor, as a potent cyst agonist. Subsequently, I discovered that EMD, a myosin activator, showed pre-clinical promise in treating PKD cystogenesis in PKD organoids at both early and late stages of disease. Based upon preliminary data and clues from the literature, I hypothesize that PC1 and PC2 positively regulate non-muscle myosin contractility within the tubular epithelium to prevent cystogenesis. Utilizing the unique kidney organoid in vitro system, I propose to analyze myosin modulator compounds and non-muscle myosin dynamics in organoids to pinpoint the myosin domain that governs cyst expansion to inform pre-clinical drug development. Second, I aim to optimize in vivo delivery and treatment strategies of EMD in a mouse model of PKD. Finally, I will utilize the insight that PC1 structurally resembles an atypical adhesion G-protein coupled receptor to analyze whether biochemically activating PC1 can stimulate organoid contraction to link polycystin function to myosin control. Together, these experiments will establish myosin activation as a therapeutic strategy to treat PKD and determine mechanisms of PC1 as a regulator of myosin contractility. The goal of this work is to expedite drug discovery for PKD by utilizing model systems that best represent the disease, and mechanistic studies that inform polycystin function in cystogenesis.

摘要