Discoidin Domain Receptor 1 (DDR1) tyrosine kinase is upregulated in PKD kidneys but does not play a role in the pathogenesis of polycystic kidney disease
| Autor: | James S. Duncan, All On Main List, Zhai Li, Edward Y. Skolnik, Aram Hong, Irfana Soomro |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Nephrology Kinase Inhibitors Pathogenesis Kidney Pathology and Laboratory Medicine Biochemistry Receptor tyrosine kinase Tyrosine Kinases Mice 0302 clinical medicine Antibiotics Drug Discovery Polycystic kidney disease Medicine and Health Sciences Medicine Cyst Enzyme Inhibitors Polycystic Kidney Diseases Multidisciplinary biology Antimicrobials Drugs Animal Models Up-Regulation Enzymes Experimental Organism Systems 030220 oncology & carcinogenesis Doxycycline Anatomy Tyrosine kinase Research Article medicine.medical_specialty Drug Research and Development Science Autosomal dominant polycystic kidney disease Mice Transgenic Mouse Models Research and Analysis Methods Microbiology Gene Expression Regulation Enzymologic 03 medical and health sciences Antimalarials Model Organisms Discoidin Domain Receptor 1 Internal medicine Microbial Control Animals Pharmacology DDR1 business.industry urogenital system Biology and Life Sciences Proteins Kidneys Renal System medicine.disease Disease Models Animal 030104 developmental biology Cancer research biology.protein Animal Studies Enzymology business Protein Kinases Discoidin domain Kidney disease |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 7, p e0211670 (2019) |
| ISSN: | 1932-6203 |
| Popis: | Tolvaptan is the only drug approved to slow cyst growth and preserve kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD). However, its limited efficacy combined with significant side effects underscores the need to identify new and safe therapeutic drug targets to slow progression to end stage kidney disease. We identified Discoidin Domain Receptor 1 (DDR1) as receptor tyrosine kinase upregulated in vivo in 3 mouse models of ADPKD using a novel mass spectrometry approach to identify kinases upregulated in ADPKD. Previous studies demonstrating critical roles for DDR1 to cancer progression, its potential role in the pathogenesis of a variety of other kidney disease, along with the possibility that DDR1 could provide new insight into how extracellular matrix impacts cyst growth led us to study the role of DDR1 in ADPKD pathogenesis. However, genetic deletion of DDR1 using CRISPR/Cas9 failed to slow cyst growth or preserve kidney function in both a rapid and slow mouse model of ADPKD demonstrating that DDR1 does not play a role in PKD pathogenesis and is thus a not viable drug target. In spite of the negative results, our studies will be of interest to the nephrology community as it will prevent others from potentially conducting similar experiments on DDR1 and reinforces the potential of performing unbiased screens coupled with in vivo gene editing using CRISPR/Cas9 to rapidly identify and confirm new potential drug targets for ADPKD. |
| Databáze: | OpenAIRE |
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