An integrated functional genomics screening program reveals a role for BMP-9 in glucose homeostasis
| Autor: | Charles E. Birse, Steve Ruben, Melisa C. Barber, Yanick Lazard, Ya-Qin Zhang, Carrie L. Fischer, Susan Cheng, Qinghai Zhao, Alokesh Duttaroy, Laurie Pukac, Linyi Zhang, Peter Reavey, Qi Wang, Lilin Zhong, Mallika Singh, Timothy A. Coleman, Steve Barash, Cecil Chen, Olivier Blondel, Krzysztof J. Grzegorzewski, Jon Hirsch, Indra Sanyal, Helmut Schneider, Roxanne Duan, Zhi-Dong Ma, Baiqin Teng, Adam Bell |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
animal structures Biomedical Engineering Bioengineering Genomics Computational biology Carbohydrate metabolism Biology Kidney Bone morphogenetic protein Applied Microbiology and Biotechnology Mice Diabetes mellitus genetics Reference Values Sequence Analysis Protein Diabetes Mellitus Growth Differentiation Factor 2 Animals Humans Glucose homeostasis Cells Cultured Genetics Gene Expression Profiling Proteins Kidney metabolism Recombinant Proteins Growth Differentiation Factors Mice Inbred C57BL Systems Integration Glucose Drug Design Bone Morphogenetic Proteins embryonic structures Molecular Medicine Sequence Alignment Functional genomics Homeostasis Biotechnology |
| Zdroj: | Nature Biotechnology. 21:294-301 |
| ISSN: | 1546-1696 1087-0156 |
| DOI: | 10.1038/nbt795 |
| Popis: | A coordinated functional genomics program was implemented to identify secreted polypeptides with therapeutic applications in the treatment of diabetes. Secreted factors were predicted from a diverse expressed-sequence tags (EST) database, representing1,000 cDNA libraries, using a combination of bioinformatic algorithms. Subsequently, approximately 8,000 human proteins were screened in high-throughput cell-based assays designed to monitor key physiological transitions known to be centrally involved in the physiology of type 2 diabetes. Bone morphogenetic protein-9 (BMP-9) gave a positive response in two independent assays: reducing phosphoenolpyruvate carboxykinase (PEPCK) expression in hepatocytes and activating Akt kinase in differentiated myotubes. Purified recombinant BMP-9 potently inhibited hepatic glucose production and activated expression of key enzymes of lipid metabolism. In freely fed diabetic mice, a single subcutaneous injection of BMP-9 reduced glycemia to near-normal levels, with maximal reduction observed 30 hours after treatment. BMP-9 represents the first hepatic factor shown to regulate blood glucose concentration. Using a combination of bioinformatic and high-throughput functional analyses, we have identified a factor that may be exploited for the treatment of diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|