Chen Cecil, Grzegorzewski Krzysztof J, Barash Steve, Zhao Qinghai, Schneider Helmut, Wang Qi, Singh Mallika, Pukac Laurie, Bell Adam C, Duan Roxanne, Coleman Tim, Duttaroy Alokesh, Cheng Susan, Hirsch Jon, Zhang Linyi, Lazard Yanick, Fischer Carrie, Barber Melisa Carey, Ma Zhi-Dong, Zhang Ya-Qin, Reavey Peter, Zhong Lilin, Teng Baiqin, Sanyal Indra, Ruben Steve M, Blondel Olivier, Birse Charles E
Department of Lead Development and Characterization, Human Genome Sciences, Inc., 9800 Medical Center Dr., Rockville, MD 20850, USA.
Nat Biotechnol. 2003 Mar;21(3):294-301. doi: 10.1038/nbt795. Epub 2003 Feb 24.
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, representing >1,000 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.
实施了一项协调的功能基因组学计划，以鉴定在糖尿病治疗中具有治疗应用的分泌多肽。利用生物信息学算法的组合，从代表>1000个cDNA文库的多样化表达序列标签（EST）数据库中预测分泌因子。随后，在基于细胞的高通量检测中筛选了大约8000种人类蛋白质，这些检测旨在监测已知在2型糖尿病生理学中起核心作用的关键生理转变。骨形态发生蛋白9（BMP-9）在两项独立检测中给出阳性反应：降低肝细胞中磷酸烯醇丙酮酸羧激酶（PEPCK）的表达，并在分化的肌管中激活Akt激酶。纯化的重组BMP-9有效抑制肝脏葡萄糖生成并激活脂质代谢关键酶的表达。在自由进食的糖尿病小鼠中，单次皮下注射BMP-9可将血糖降低至接近正常水平，治疗后30小时观察到最大降幅。BMP-9是首个被证明可调节血糖浓度的肝脏因子。通过生物信息学和高通量功能分析的结合，我们鉴定出了一种可用于糖尿病治疗的因子。
