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Identification of new therapeutic targets for ADPKD

ADPKD 新治疗靶点的确定

基本信息

批准号：
10298937
负责人：
EDWARD Y SKOLNIK
金额：
$ 50.82万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298937
关键词：
Affect Affinity Animal Model Autosomal Dominant Polycystic Kidney Binding Biological Assay Clinical Trials Collaborations Combined Modality Therapy Couples Cyclic GMP Cyst Data Doxycycline Drug Targeting End stage renal failure Epithelial cyst Extracellular Matrix Fibrosis Focal Adhesion Kinase 1 Funding Genes Genetic Genetic Transcription Goals Grant Growth Human Kidney Kidney Diseases Lipids Mass Spectrum Analysis Mediating Medicine Messenger RNA Mus Mutation PTK2 gene Pathogenesis Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Play Proprotein Convertase 1 Proprotein Convertase 2 Proteins Renal function Role Signal Pathway Signal Transduction Techniques Technology Testing Therapeutic Time Toxic effect Translating Universities base discoidin domain receptor 1 drug candidate genetic approach human disease in vivo inhibitor/antagonist insight interest interstitial kinase inhibitor mouse model new therapeutic target novel novel strategies polycystic kidney disease 1 protein preservation tandem mass spectrometry therapeutic target tolvaptan

项目摘要

Autosomal-dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide and is a common cause of end-stage kidney disease (ESKD). ADPKD is caused by mutations in one of two genes, PKD1 or PKD2, which encodes polycystin 1 (PC) and PC2 respectively. Loss of PC1 or PC2 results in activation of numerous kinases and downstream signaling pathways, which is central to the pathogenesis of cyst growth in ADPKD. In addition, pharmacologically inhibiting a number of different kinases up-regulated in PKD kidneys has been shown to slow cyst growth in animal models of PKD making kinase inhibitors among the most promising class of drug candidates to treat patients with ADPKD. However, while the human kinome consists of more than 500 kinases, only a fraction of these kinases have been tested to determine if they play a role in ADPKD pathogenesis. As a result, there are likely many kinases that are active in ADPKD kidneys that play prominent roles in cyst growth that are yet-to-be discovered and may be good therapeutic targets. In collaboration with James Duncan at Temple University, we have now adapted a novel approach to broadly screen PKD kidneys in an unbiased manner for kinases that are more active in lysates from PKD kidneys compared with lysates from wild type kidneys. In this assay, active kinases are affinity captured by passing lysates over multiplex inhibitor beads (MIB) containing a cocktail of kinase inhibitors. Bound kinases are then identified by LC separation followed by quantitative tandem mass spectrometry (LC- MS/MS). Using this approach, we have now identified a number of both known and unknown kinases specifically up-regulated and down-regulated in PKD kidneys. The major goal of this proposal is to assess the role of several of the kinases identified thus far whose activity is increased in PKD kidneys and determine whether inhibiting or activating any of the kinases identified slows cyst growth, inhibits interstitial fibrosis, and preserves renal function in animal models of ADPKD. We will then take both biased and unbiased approaches to identify the signaling pathways regulated by these kinases that are critical to pathogenesis with the goal of developing a more complete picture of the relevant signaling hubs and networks that are aberrantly activated in PKD kidneys. In addition, we will use this technology to broadly screen PKD kidneys from a variety of different “early” and “late” mouse models of ADPKD at different stages in cyst formation and in kidneys from human patients with ADPKD to identify in an unbiased manner additional kinases that are activated and inhibited in PKD kidneys to determine the similarities and differences between mouse models, which kinases may be most relevant to human disease, and whether distinct sets of kinases are activated early post cyst induction and function as early “drivers” of cyst growth. Ultimately, we hope this new information will identify new safe drug targets and rational approaches to combination therapies to slow cyst growth that can then be translated into clinical trials.

常染色体显性多囊肾病（ADPKD）影响全球超过1200万人