Capturing, quantifying, and understanding combinatorial effects in small molecule signaling

项目总结/摘要 生物学中的化学景观由数千到数百万不同的小分子组成， 生物总是在其他分子的环境中体验任何一个小分子。的确， 从决定细胞命运到调节中枢代谢的生物学过程是由联合作用驱动的 多个小分子的混合物然而，对这种组合效应的洞察主要是基于轶事 证据;到目前为止，还没有一致的框架来捕捉和量化小规模的组合效应。 分子信号这一差距限制了科学家研究复杂化学物质中信号的能力。 生物学中发现的景观，以预测小分子的生物活动，并操纵小 分子信号在疾病中的作用。 这项工作将开发一个概念性的，实验性的和分析性的框架， 不同分子的组合效应，或“化学上位性”。作为一个起点，这项工作将侧重于 在人类微生物组和人类宿主之间的通信背景下的信号传导， 一个理想的测试平台在这方面，第一个目标是制定实验和分析方法， 捕捉化学上位性，并使用这些方法来衡量经验如何普遍的化学 上位性是来自人类微生物组的小分子的成对组合。从那里，这项工作将 继续在三个大方向：1）更广泛地探讨化学品的范围和表现形式， 上位性，包括三种或更多种小分子的组合; 2）解剖潜在的机制， 化学上位性，使用系统性CRISPR筛选和聚焦方法的组合;以及3） 探索上位性的生理后果，利用确定的微生物群落， 独立控制体内多种小分子的浓度。这项工作将是变革性的 在宿主-微生物组相互作用中建立因果关系，并预测和操纵 宿主-微生物组通信，例如以减轻微生物组相关疾病。更广泛地说， 复杂的化学景观是生物学的一个中心特征，这项工作将奠定基础， 理解这些景观中的信号。

Project Summary/Abstract Chemical landscapes in biology consist of thousands to millions of different small molecules, such that cells and organisms always experience any single small molecule in the context of other molecules. Indeed, biological processes from cell fate decisions to regulation of central metabolism are driven by combined action of multiple small molecules. Insight into such combinatorial effects, however, is largely based on anecdotal evidence; as yet, there exists no coherent framework to capture and quantify combinatorial effects in small molecule signaling. This gap limits the ability of scientists to study signaling in the complex chemical landscapes found in biology, to predict biological activities of small molecules, and to manipulate small molecule signaling in the context of disease. This work will develop a conceptual, experimental, and analytical framework to capture and quantify combinatorial effects of different molecules, or “chemical epistasis”. As a starting point, this work will focus on signaling in the context of communication between the human microbiome and the human host, which provides an ideal testbed. Working in this context, the first goal is to develop experimental and analytical approaches to capture chemical epistasis and to use these approaches to measure empirically how pervasive chemical epistasis is in pairwise combinations of small molecules from the human microbiome. From there, this work will continue in three broad directions: 1) a broader exploration of the scope and manifestations of chemical epistasis including in combinations of three or more small molecules; 2) a dissection of mechanisms underlying chemical epistasis, using a combination of systematic CRISPR screens and focused approaches; and 3) exploration of the physiological consequences of epistasis, harnessing defined microbiome communities to independently control the concentrations of multiple small molecules in vivo. This work will be transformative for efforts to establish causal links in host-microbiome interactions and to predict and manipulate outcomes of host-microbiome communication, for example to alleviate microbiome-associated diseases. More broadly, complex chemical landscapes are a central feature of biology, and this work will lay the groundwork to understand signaling in these landscapes.