Drosophila, a new genetic model for renal disease and drug discovery

描述(申请人提供)：我们开发了一种新的系统来鉴定和研究果蝇过滤和蛋白质重吸收所需的基因。我们发现，控制这两个关键肾功能的基因和遗传途径从果蝇到人类都是高度保守的，使果蝇成为研究肾脏疾病基因的理想模型。使用我们在果蝇身上开发的一种新的功能读数，我们进行了大规模的遗传筛选，并鉴定了大约150个心包肾细胞功能所需的基因，心包肾细胞是一种发挥昆虫肾脏功能的细胞类型。这150个基因编码多种生物过程和肾脏特定结构中的蛋白质，包括裂隙横隔膜成分、肾小球基底膜成分、膜受体、肌动蛋白细胞骨架、Trp通道、囊泡运输分子、肌球蛋白和动力蛋白马达、转录因子和辅酶Q(CoQ)的生物合成途径。从果蝇到人类，这些基因中的大多数都高度保守，其中许多基因与人类的同源基因已经被认为与肾脏疾病，特别是肾小球疾病有关。四个辅酶Q途径基因的突变与肾脏疾病有关，从我们的肾细胞筛查中发现了它们的苍蝇同源基因。辅酶Q10是辅酶Q途径的最终产物，是一种常见的膳食补充剂。人类COQ2突变患者的肾功能缺陷可以用Q10成功地治疗。我们建议建立苍蝇肾病模型，以概括导致肾脏疾病的人类辅酶Q基因突变，并用Q10治疗这些苍蝇疾病模型，为我们新的苍蝇肾脏疾病模型提供药物治疗方法的原则证明。然后，我们将应用这种方法来研究新的肾脏疾病基因RhoGDIa和KANK2的致病机制，并测试这两个基因突变引起的肾病果蝇模型的潜在药物。总之，这项建议引入了一种新的动物系统来研究肾脏疾病基因，并引入了一种创新的方法来开发用于测试药物的动物疾病模型。鉴于从果蝇到人类的肾脏疾病基因保守性的有希望的发现和确凿的证据，我们相信这个新的Fly系统将提供手段来研究由特定基因突变引起的肾脏疾病的致病机制，并发现临床相关的药物，最终可能导致治愈这些目前无法治愈的肾脏疾病。

DESCRIPTION (provided by applicant): We have developed a new system to identify and study genes required for filtration and protein reabsorption in Drosophila. We found that the genes and genetic pathways controlling these two key renal functions are highly conserved from Drosophila to humans, making Drosophila an ideal model to study renal disease genes. Using a novel functional readout that we developed in Drosophila, we performed a large-scale genetic screen and identified ~150 genes required for the function of pericardial nephrocytes, the cell type that functions as insect kidneys. These 150 genes encode proteins in a variety of biological processes and renal specific structures, including slit diaphragm components, glomerular basement membrane components, membrane receptors, actin cytoskeletons, TRP channels, vesicle trafficking molecules, myosin and dynein motors, transcription factors and the Coenzyme Q (CoQ) biosynthesis pathways. Most of these genes are highly conserved from Drosophila to humans and many have human homologues that have already been linked to renal disease, particularly glomerular diseases. Mutations of four CoQ pathway genes have been linked to renal disease and their fly homologues were identified from our nephrocyte screen. Coenzyme Q10 is the final product of the CoQ pathway and a common dietary supplement. The renal functional defect in human patients with COQ2 mutations can be successfully treated with Q10. We proposed to develop fly renal disease models to recapitulate the human COQ gene mutations that cause renal disease, and to treat these fly disease models with Q10, to provide a proof-of-principle for our new fly renal disease models with a drug treatment approach. We will then apply this approach to study the pathogenic mechanism of novel renal disease genes RhoGDIa and KANK2, and test potential drugs for the fly models of renal disease caused by mutations of these two genes. In summary, this proposal introduced a new animal system to study renal disease genes and an innovated approach to develop animal disease models for testing drugs. Given the promising findings and solid evidence for the conserveness of renal disease genes from Drosophila to humans, we believe that this new fly system will provide the means to study pathogenic mechanisms of renal disease caused by specific gene mutations, and to discover clinically relevant drugs that could eventually lead to cures for these currently untreatable renal diseases.