A new vessel in the fleet: exploring how enteric tracheal plasticity drives metabolic adaptation in Drosophila

我们的胃肠道具有重要的功能，超越了消化我们吃的食物。它还可以与大脑等器官沟通，以改变我们的食欲或我们的身体如何储存多余的营养。然而，这种交流并不完全清楚;消化道能够感受到什么样的信息，它如何将其传递给其他器官？如果我们能够更好地理解这是如何发生的，就有可能使用药物来“欺骗”消化系统，使我们吃得更少或脂肪更少。然而，在人类或小鼠等模型系统中研究这一点是复杂的;它们有许多不同种类的细胞，这些细胞并不总是容易探测到，以识别重要的细胞，并了解它们如何发出信号或接收信息。相反，我们在果蝇Drosophila melanogaster中解决了这个问题：一个更简单的模型系统，共享我们60%的基因。果蝇有一个功能复杂但遗传上易处理的消化道。我们最近发现，像我们的血管系统一样，将氧气输送到肠道细胞的苍蝇血管在这种通信中发挥了重要且以前未被认识到的作用。事实上，这些血管-所谓的气管-改变其分支，以响应特定的营养。这在某种程度上使苍蝇能够科普营养不良，也影响了它们在体内储存的脂肪量。该提案旨在了解气管的分支对其他肠道细胞的影响，以及这些肠道细胞如何反过来影响新陈代谢和苍蝇对营养不良的反应。我们的实验设计将首先采用无偏的方法来表征气管分支的差异如何影响肠道中基因的表达，然后将重点放在这些变化的子集上，以了解它们如何影响肠道细胞的代谢及其向其他器官的信号传导。我们预计，我们的研究将揭示器官间通讯的基本机制，并确定治疗营养相关疾病和病症的潜在新药靶点。

Our gastrointestinal tract has important functions that go beyond digesting the food we eat. It can also communicate with organs such as the brain to change our appetite or how our body stores excess nutrients. This communication is, however, incompletely understood; what kind of information is the digestive tract able to sense, and how can it relay it to other organs? If we were able to understand better how this happens, it may be possible to use drugs to "trick" the digestive system into making us eat less or get less fat. Investigating this in humans or model systems such as mice is complex, however; they have many cells of many different kinds that are not always easy to probe to identify the ones that matter, and to understand how they signal or receive information. Instead, we tackle this question in the fruit fly Drosophila melanogaster: a simpler model system that shares 60% of our genes. Drosophila has a functionally sophisticated yet genetically tractable digestive tract. We recently found that the fly vessels that, like our vascular system, deliver oxygen to the gut cells play an important and previously unrecognized role in this communication. Indeed, these vessels -the so-called trachea- change their branching in response to specific nutrients. This somehow allows flies to cope with malnutrition and also affects how much fat they store in their bodies. This proposal seeks to understand what the branching of trachea does to other gut cells and how these gut cells, in turn, are able to affect metabolism and the fly's response to malnutrition. Our experimental design will first take an unbiased approach to characterize how differences in tracheal branching affect the expression of genes in the gut, and will then focus on a subset of these changes to understand how they affect the metabolism of the gut cells and their signalling to other organs. We anticipate that our research will both shed light on fundamental mechanisms of inter-organ communication and also identify potential new drug targets for the treament of nutrition-related diseases and conditions.