Coordination of the nutrient response across cell types in a complex organ

饮食是影响动物生理的重要因素之一。它的影响在所有生物尺度上都可以观察到，从个体细胞到复杂的多细胞生物体，从个体细胞到复杂的多细胞生物体，在这些细胞中，生长取决于适当的营养水平，而饮食对老年人的寿命和健康有重大影响。因此，了解饮食和营养对生物体的影响对于改善人类进入老年的健康具有至关重要的意义。细胞培养工作发现，所有细胞中专门的营养感应通路根据营养物质的可获得性来调节细胞的生长和增殖。相比之下，在多细胞生物体中，特定的器官被认为是感受营养水平的地方，这些器官调节整个动物对营养的生理反应。然而，人们仍然很少了解个别组织如何对营养水平的变化或来自这些器官的系统信号做出反应。许多器官由许多类型的细胞组成，既有完成组织功能的分化细胞，也有负责提供新细胞以应对组织损伤或自然更新的干细胞。考虑到它们在组织中的不同作用，可以想象不同的细胞对饥饿的反应不同。果蝇的睾丸是研究复杂器官如何协调对营养的反应的一个很好的模型。睾丸由两种广泛的细胞类型组成，这两种细胞类型很容易通过它们的形态、在组织中的位置和基因表达来识别：生殖系细胞，最终产生精子，以及支持生殖系发育的体细胞囊细胞。这两种细胞类型都是由一个单独的干细胞群体维持的。在饥饿期间，分化的细胞通过细胞死亡被消灭，而干细胞被保存下来，但数量较少。这使得睾丸成为研究复杂组织中营养感知是如何协调的理想之选：是所有细胞都感知营养，还是这一功能仅限于组织中的特定细胞，甚至仅限于远处的组织？我们的初步数据显示，并不是所有的睾丸细胞都对营养敏感途径做出反应：胰岛素途径在分化的囊细胞中被特异性地抑制，导致囊细胞和生殖细胞的死亡。然而，胰岛素并不影响躯体干细胞在饥饿期间的行为。果蝇提供了许多无与伦比的遗传工具，这意味着我们可以操纵细胞类型和时间精度的基因表达，它已被证明是一个无价的模型，可以发现动物生物学许多方面的基本概念，包括有史以来描述的第一个干细胞生态位。在这项提案中，我们将利用这些优势来研究对营养的反应是如何在所有这些细胞类型(胞体和生殖系、分化细胞和干细胞)之间协调的。我们将确定分化的体细胞如何感知营养水平的变化，以及它们如何将这些信息传递给生殖细胞。接下来我们要问的是，在饥饿期间，干细胞的营养是否受到限制，或者干细胞是否会对不同的信号做出反应。最后，我们将确定器官对睾丸干细胞饥饿反应的影响程度。我们工作的结果将是更好地理解复杂组织如何感知和响应营养水平。从长远来看，这种知识将有益于帮助针对特定细胞类型或途径的干预，这些细胞或途径可以在老年时维持人类健康。

Diet is one of the most important factors influencing animal physiology. Its effects are observed at all biological scales from individual cells, where growth depends on appropriate levels of nutrients, to complex multi-cellular organisms, where diet has a major effect on lifespan and health in old age. Understanding the effects of diet and nutrition on organisms therefore has critical implications for improving human health into old age.Work in cell culture has found that dedicated nutrient sensing pathways in all cells regulate cell growth and proliferation depending on the availability of nutrients. In multi-cellular organisms, by contrast, specific organs are thought to be the sites where nutrient levels are sensed and these regulate the physiology of the whole animal in response to nutrients.Yet it is still poorly understood how individual tissues respond to changes in nutrient levels or systemic signals from these organs. Many organs are made up of many cell types, both differentiated cells that fulfil tissue function, and stem cells that are responsible for providing new cells in response to tissue damage or natural turnover. Given their different roles in the tissue, it is conceivable that different cells do not respond in the same way to starvation.The Drosophila testis is an excellent model to study how complex organs coordinate the response to nutrition. The testis is composed of two broad cell types which are easily identified by their morphology, position within the tissue, and gene expression: germline cells which eventually give rise to sperm, and somatic cyst cells which support germline development. Both cell types are maintained by a separate stem cell population. During starvation, differentiated cells are eliminated through cell death, while stem cells are preserved but in smaller numbers. This makes the testis ideal for studying how nutrient sensing is orchestrated in a complex tissue: do all cells sense nutrients, or is this function restricted to specialised cells in the tissue, or even to a distant tissue? Our initial data show that not all cells in the testis respond to nutrient-sensitive pathways: the Insulin pathway is specifically inhibited in differentiated cyst cells, leading to the death of both cyst cells and germ cells. However, Insulin does not influence the somatic stem cells' behaviour during starvation.Drosophila provides many unparalleled genetic tools which mean that we can manipulate gene expression with cell type and temporal precision and it has proven to be an invaluable model to discover the basic concepts underlying many aspects of animal biology, including the first stem cell niche ever described. In this proposal, we will capitalise on these advantages to ask how the response to nutrition is orchestrated among all these cell types (soma and germline, differentiated cells and stem cells). We will determine how differentiated somatic cells sense changes in nutrient levels, and how they relay this information to germ cells. Next we will ask if nutrients are limiting for stem cells during starvation, or whether stem cells respond to a different signal. Finally, we will determine how distant organs impact on the starvation response of stem cells in the testis.The outcome of our work will be a better understanding of how complex tissues sense and respond to nutrient levels. This knowledge will be beneficial in the long term to help target interventions at specific cell types or pathways that could maintain human health in old age.