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

项目摘要/摘要 生物学中的化学景观由数千到数百万个不同的小分子组成，比如细胞 生物体总是在其他分子的背景下体验任何单一的小分子。的确， 从细胞命运的决定到中枢代谢的调节的生物过程是由联合作用驱动的 由多个小分子组成。然而，对这种组合效应的洞察很大程度上是基于轶事。 证据；到目前为止，还没有一致的框架来捕捉和量化小范围的组合效应 分子信号。这一差距限制了科学家研究复杂化学物质中的信号的能力。 在生物学中发现的景观，用来预测小分子的生物活动，并操纵小分子 疾病背景下的分子信号。 这项工作将开发一个概念性的、实验性的和分析的框架来捕获和量化 不同分子的组合效应，或“化学上位论”。作为起点，这项工作将重点放在 在人类微生物群和人类宿主之间的通信环境中发出信号，这提供了 一张理想的试验床。在这种情况下工作，第一个目标是开发实验和分析方法，以 捕捉化学上位性并使用这些方法来经验性地测量化学物质的普遍程度 上位性疾病是由来自人类微生物组的小分子成对组合而成的。从那里开始，这项工作将 继续朝着三个大方向前进：1)更广泛地探索化学物质的范围和表现形式 上位性，包括三个或更多小分子的组合；2)对潜在机制的剖析 化学上位论，使用系统的CRISPR筛选和有重点的方法相结合；以及3) 探索上位性的生理后果，利用定义的微生物群落来 独立控制体内多个小分子的浓度。这项工作将具有变革性 努力在宿主-微生物组相互作用中建立因果联系，并预测和操纵结果 宿主-微生物组通信，例如减轻与微生物组相关的疾病。更广泛地说， 复杂的化学景观是生物学的中心特征，这项工作将为 了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.