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

协调复杂器官中不同细胞类型的营养反应

• 批准号: BB/W008149/1
• 负责人: Marc Amoyel
• 金额: $ 72.13万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW008149%2F1
• 关键词: Coordination; nutrient; response; across; cell

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.

饮食是影响动物生理的最重要因素之一。它的影响在所有生物尺度上都可以观察到，从单个细胞的生长取决于适当水平的营养物质，到复杂的多细胞生物体，其中饮食对老年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老年健康具有重要意义。细胞培养工作发现，所有细胞中专门的营养感应途径根据营养的可用性调节细胞生长和增殖。相比之下，在多细胞生物中，特定器官被认为是感知营养水平的部位，这些器官根据营养物质调节整个动物的生理机能。然而，人们对单个组织如何响应营养水平或来自这些器官的系统信号的变化仍知之甚少。许多器官由多种细胞类型组成，其中包括履行组织功能的分化细胞，以及负责提供新细胞以响应组织损伤或自然更新的干细胞。鉴于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。果蝇睾丸是研究复杂器官如何协调对营养的反应的绝佳模型。睾丸由两种广泛的细胞类型组成，通过其形态、在组织内的位置和基因表达很容易识别：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。这两种细胞类型均由单独的干细胞群维持。在饥饿期间，分化的细胞通过细胞死亡而被消除，而干细胞被保留，但数量较少。这使得睾丸成为研究如何在复杂组织中协调营养感知的理想选择：是否所有细胞都感知营养，或者这种功能仅限于组织中的特殊细胞，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途径做出反应：胰岛素途径在分化的囊肿细胞中受到特异性抑制，导致囊肿细胞和生殖细胞死亡。然而，胰岛素不会影响饥饿期间成体干细胞的行为。果蝇提供了许多无与伦比的遗传工具，这意味着我们可以通过细胞类型和时间精度操纵基因表达，并且它已被证明是发现动物生物学许多方面的基本概念的宝贵模型，包括有史以来描述的第一个干细胞生态位。在本提案中，我们将利用这些优势来探究所有这些细胞类型（体细胞和种系细胞、分化细胞和干细胞）如何协调对营养的反应。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。接下来我们将询问饥饿期间干细胞的营养是否受到限制，或者干细胞是否对不同的信号做出反应。最后，我们将确定远处的器官如何影响睾丸干细胞的饥饿反应。我们工作的结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，这些知识将有益于帮助针对特定细胞类型或途径进行针对性干预，以维持人类老年健康。