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。从个体细胞到复杂的多细胞生物体，从个体细胞的生长取决于适当的营养水平，从复杂的多细胞生物体到饮食对老年人的寿命和健康有重大影响的所有生物尺度都可以观察到它的影响。因此，了解饮食和营养对生物体的影响对于改善人类健康到老年具有重要意义。细胞培养的工作发现，所有细胞中专门的营养感应途径都根据营养物质的可用性调节细胞生长和增殖。相比之下，在多细胞生物体中，特定器官被认为是感知营养水平的场所，这些器官调节整个动物对营养的生理反应，但人们对单个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仍然知之甚少。许多器官由许多细胞类型组成，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方式不同。果蝇睾丸是研究复杂器官如何协调对营养反应的极好模型。睾丸由两种广泛的细胞类型组成，它们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：最终产生精子的生殖细胞和支持生殖细胞发育的体细胞囊肿细胞。这两种细胞类型都由单独的干细胞群维持。在饥饿过程中，分化的细胞通过细胞死亡被消除，而干细胞被保存下来，但数量较少。这使得睾丸成为研究营养感测如何在复杂组织中协调的理想选择：所有细胞都能感测营养吗？或者这种功能仅限于组织中的专门细胞，甚至是远处的组织？我们的初步数据表明，并非睾丸中的所有细胞都对营养敏感的途径做出反应：胰岛素途径在分化的囊肿细胞中被特异性抑制，导致囊肿细胞和生殖细胞死亡。然而，胰岛素并不影响体干细胞在饥饿状态下的行为。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基因表达与细胞类型和时间精度，它已被证明是一个宝贵的模型，发现动物生物学的许多方面的基本概念，包括第一个干细胞生态位的描述。在本提案中，我们将利用这些优势来研究如何在所有这些细胞类型（索马和生殖细胞、分化细胞和干细胞）中协调对营养的反应。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，我们将询问在饥饿期间营养是否限制了干细胞，或者干细胞是否对不同的信号做出反应。最后，我们将确定远距离器官如何影响睾丸中干细胞的饥饿反应。我们的工作成果将是更好地了解复杂组织如何感知和响应营养水平。从长远来看，这些知识将有助于针对特定的细胞类型或途径进行干预，以维持老年人的健康。

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.