Mapping protein communication between organs in homeostasis and disease

项目总结 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发现了一些荷尔蒙多肽， 许多重要的生理因素涉及能量平衡、水盐平衡、酸碱度和血液 压力仍有待确定。作为现有的利用质量从血液中识别分泌因子的方法 光谱(MS)有严重的局限性，我们将使用一种工程杂乱的生物素蛋白连接酶来 生物素在特定器官中分泌蛋白质，然后在遥远的靶器官中识别生物素化的蛋白质 通过亲和富集和定量MS，这些实验将分两个阶段进行 有机体、果蝇和老鼠。果蝇有助于快速开发和优化 基础研究策略，对器官通讯中的保守因素产生进化洞察力。这个 MICE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。除了确定在正常和疾病中参与器官交流的因素 条件，我们的发现将提供对新蛋白质的基本见解，这些蛋白质可能在未来用于 治疗学。鉴于我们的目标是广泛互连器官系统，该项目与大多数NIH相关 研究所。

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.