Mapping protein communication between organs in homeostasis and disease

项目摘要 我们的跨学科团队建议开发和应用一种新的方法来系统地识别蛋白质 参与器官间的交流。虽然已经在哺乳动物中鉴定了许多激素肽， 许多生理上重要的因素涉及能量稳态、水盐平衡、pH和血液 压力有待确定。由于现有的使用质谱技术从血液中鉴定分泌因子的方法 质谱法（MS）有严重的局限性，我们将使用一种工程化的混杂生物素蛋白连接酶， 生物素化特定器官中的分泌蛋白，然后鉴定远处靶器官中的生物素化蛋白 通过亲和富集，然后进行定量MS。 果蝇和老鼠。果蝇促进快速发展和优化 基础研究策略，产生对器官通讯中保守因子的进化见解。的 小鼠为生物医学相关的器官间调节通信提供了更直接的发现模型 在人类身上。除了识别参与器官通讯的因素外，无论是在正常还是疾病中， 我们的研究结果将为未来可用于治疗癌症的新型蛋白质提供基本见解。 治疗学鉴于我们的目标是广泛地互连器官系统，该项目与大多数NIH相关。 院所

PROJECT SUMMARY Our interdisciplinary team proposes to develop and apply a novel method to systematically identify proteins involved in inter-organ communication. While a number of hormone peptides have been identified in mammals, many physiologically important factors involved in energy homeostasis, water-salt balance, pH, and blood pressure remain to be identified. As existing methods of identifying secreted factors from the blood using mass spectrometry (MS) have serious limitations, we will use an engineered promiscuous biotin protein ligase to biotinylate secreted proteins in a specific organ, and then identify biotinylated proteins in distant target organs through affinity enrichment followed by quantitative MS. These experiments will be performed in two organisms, Drosophila and the mouse. Drosophila facilitates the rapid development and optimization of the basic research strategy, generating evolutionary insight into conserved factors in organ communication. The mouse provides a more direct discovery model for biomedically-relevant, inter-organ regulatory communication in humans. In addition to identifying factors involved in organ communication, both in normal and disease conditions, our findings will provide fundamental insight into novel proteins that could be used in the future as therapeutics. Given our goal to broadly interconnect organ systems, the project is relevant to most NIH Institutes.