Investigations of Drosophila nephrocytes as central modulators of fly physiology in states of health and disease

果蝇肾细胞属于苍蝇肾，过滤血淋巴。它们在形态和功能上与哺乳动物足细胞有很高的相似性，被视为足细胞同源物。在苍蝇体内，它们位于食道和心管周围。由于这种局部性及其不断暴露于血淋巴成分和循环的变化，肾细胞处于独特的位置来采样和影响血淋巴，以帮助维持健康的生理。作为血淋巴的守护者，肾细胞的这种角色对于维持正常的生理很可能是必不可少的，因为所有的器官都沐浴在血淋巴中，并依赖于它的组成和物理特性，如循环和压力。这一概念也可以很容易地转化为哺乳动物的系统，因为所有的器官都是由血液供应的，并依赖于它的平衡和健康状态，包括成分和物理状态。在慢性肾脏疾病期间，这种平衡和健康的状态会改变，因为足细胞受到损伤，最终丢失到初级尿液中，从而使肾小球中的毛细血管空白，导致血液成分和循环发生变化。足细胞本身的丧失以及血液成分和循环的变化，都会对心脏等其他器官产生有害影响。有趣的是，早期对果蝇的研究揭示了肾细胞对心脏功能的影响，并参与了先天免疫反应。然而，直到今天，肾细胞和足细胞如何影响其他器官功能的详细机制仍然很不清楚。在这项提议中，我们将利用模式生物黑腹果蝇来揭示肾细胞是否作为苍蝇生理的中枢调节器。糖尿病和衰老是众所周知的慢性肾脏疾病的主要易感因素。因此，在这个项目中，我们将确定肾细胞如何在这些疾病状态下保持血淋巴成分的机制，以及它们如何影响其他器官，包括心脏、肠道和免疫系统。通过应用转录分析，我们打算更详细地描绘肾细胞和其他器官之间的细胞-细胞通讯。使用翻译方法，我们将把我们在该项目中获得的蛋白质组学飞行数据与汉堡市健康研究和欧洲肾脏cDNA库的现有人类数据集进行比较，以确定参与调节肾脏、心脏和免疫系统的新风险因素。这一提议将确定肾细胞作为生理调节器的核心作用，并有助于确定人类健康和疾病的新调控途径。

Drosophila nephrocytes belong to the fly kidney and filter the haemolymph. They share a high similarity with mammalian podocytes in their morphology and function, and are seen as podocyte homologues. In the fly, they are positioned around the oesophagus and along the heart tube. Due to this localisation and their constant exposure to changes in haemolymph composition and circulation, nephrocytes are in a unique position to sample and influence the haemolymph to help maintain a healthy physiology. This role of nephrocytes as ‘guardians of the haemolymph’ is likely to be essential for maintaining normal physiology, as all organs are bathed in the haemolymph and are dependent on its composition and physical properties such as circulation and pressure. This concept can easily be translated into the mammalian system as well, as all organs are supplied by blood and are dependent on its’ balanced and healthy state including composition and physical states. During chronic kidney disease, this balanced and healthy state is altered, as podocytes are injured and are finally lost into the primary urine, which leaves the capillaries in the glomeruli blank and results to changes in blood composition and circulation. Both, the loss of podocytes itself and the changes in blood composition and circulation, have a detrimental effect on other organs such as the heart. Interestingly, earlier studies in flies revealed an impact of nephrocytes on heart function and an involvement in the innate immune response. However, detailed mechanisms how nephrocytes and podocytes influence the function of other organs remains largely unknown until today. Within this proposal, we will utilize the model organism Drosophila melanogaster to unravel, whether nephrocytes act as central modulators of fly physiology. Diabetes and aging are well-known and major predisposing factors for chronic kidney disease. Hence, within this project, we will identify mechanisms how nephrocytes maintain haemolymph composition during these disease states and how they impact on other organs, including heart, gut and the immune system. By applying transcriptomic analysis, we intend to delineate the cell-cell-communication between nephrocytes and the other organs in greater detail. Using a translational approach, we will compare our proteomics fly data obtained within this project with available human data-sets of the Hamburg City Health Study and the European Renal cDNA Bank to identify novel risk factors, which are involved in regulating kidney, heart and immune system. This proposal will determine the central role of nephrocytes as modulators of physiology and help identify novel regulatory pathways in human health and disease.