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

果蝇肾细胞属于果蝇肾，过滤血淋巴。它们在形态和功能上与哺乳动物足细胞高度相似，被视为足细胞同源物。在苍蝇中，它们位于食道周围，沿着心管。由于这种定位及其不断暴露于血淋巴组成和循环的变化，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机能。肾细胞作为“血淋巴的监护人”的这种作用可能对于维持正常的生理机能是必不可少的，因为所有器官都沐浴在血淋巴中，并依赖于其组成和物理特性，如循环和压力。这个概念也可以很容易地转化为哺乳动物系统，因为所有器官都由血液供应，并依赖于其平衡和健康的状态，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被改变，因为足细胞受损并最终丢失到初级尿液中，这使得肾小球中的毛细血管空白并导致血液成分和循环的变化。足细胞本身的损失以及血液成分和循环的变化都对心脏等其他器官产生不利影响。有趣的是，早期对苍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，肾细胞和足细胞如何影响其他器官功能的详细机制直到今天仍然很大程度上未知。在这个提议中，我们将利用模式生物果蝇来解开，是否肾细胞作为苍蝇生理学的中央调制器。糖尿病和衰老是众所周知的慢性肾脏疾病的主要诱发因素。因此，在这个项目中，我们将确定肾细胞在这些疾病状态下如何维持血淋巴组成的机制，以及它们如何影响其他器官，包括心脏，肠道和免疫系统。通过应用转录组学分析，我们打算更详细地描述肾细胞和其他器官之间的细胞间通讯。使用翻译的方法，我们将比较我们的蛋白质组学苍蝇在这个项目中获得的数据与汉堡市健康研究和欧洲肾脏cDNA库的可用人类数据集，以确定新的风险因素，这是参与调节肾脏，心脏和免疫系统。该提案将确定肾细胞作为生理调节剂的核心作用，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.