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

描述（由申请人提供）：基因突变是肾脏疾病的主要原因，但由特定突变引起的许多肾脏疾病的潜在机制在很大程度上仍然未知。一个高效的模型系统，可以用来识别肾脏基因，概括致病基因突变，并作为一个原始的药物测试平台，将是非常有价值的，对肾脏疾病的研究领域具有重要意义。我们已经开发了果蝇肾功能的遗传筛查，并确定了过滤和蛋白质重吸收所需的数百个基因。这些基因中的大多数从果蝇到人类都是高度保守的，其中许多与肾脏疾病有关。这些基因编码各种生物过程和肾脏特异性结构中的蛋白质，包括狭缝隔膜组分、肾小球基底膜组分、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）生物合成途径。我们的研究结果表明，遗传控制的关键肾功能，如过滤和蛋白质重吸收是进化保守的，果蝇可以作为一个模型系统，以研究肾脏疾病的遗传机制。本提案的目标是利用果蝇建立特异性肾脏疾病模型，并将果蝇建立为特异性遗传性肾脏疾病的原始药物检测平台。在目标1中，我们将使用辅酶Q途径作为原理证明，以证明新模型的效率和可行性，以识别肾功能所需的新基因，产生人类疾病突变的精确重现，并测试一种已知的药物，可以治愈果蝇中的特定遗传性肾病。在目标2中，我们将研究两个新的肾脏基因（RhoGDI和KANK2）的疾病机制，这两个基因都是从我们的基因筛选和我们的合作者的人类患者外显子测序中鉴定出来的。我们将为这些新基因建立果蝇肾病模型，并测试一系列化学抑制剂，以确定一种潜在的药物来治疗相关途径中基因突变的患者。该提案中概述的一系列实验不仅对理解和治疗这些特定的罕见遗传性肾脏疾病具有广泛意义，而且还高度适用于任何类型的遗传性肾脏疾病。

DESCRIPTION (provided by applicant): Genetic mutations are major causes of renal disease, but the underlying mechanisms of many renal diseases caused by specific mutations remain largely unknown. A highly efficient model system that could be used to identify renal genes, to recapitulate disease-causing genetic mutations, and to serve as a primitive drug testing platform will be highly valuable and significant for the renal disease research field. We have developed a genetic screen for renal function in Drosophila, and identified hundreds of genes required for filtration and protein reabsorption. Most of these genes are highly conserved from Drosophila to humans, and many of them have been linked to renal disease. These 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. Our findings demonstrated that the genetic control of key renal function such as filtration and protein reabsorption is evolutionarily conserved and Drosophila can be used as a model system to study the genetic mechanism of renal disease. The goal of this proposal is to develop specific renal disease models using Drosophila and to establish Drosophila as a primitive drug testing platform for specific genetic renal disease. In Aim 1, we will use the CoQ pathway as a proof-of-principle to demonstrate the efficiency and feasibility of the new model to identify novel genes required for renal function, to generate the exact recapitulation of human disease mutations, and to test a known drug that could cure specific genetic renal disease in Drosophila. In Aim 2, we will study the disease mechanism of two novel renal genes (RhoGDI and KANK2) that were both identified from our genetic screen and the human patient exon sequencing from our collaborator. We will generate Drosophila renal disease models for these novel genes and test a collection of chemical inhibitors to identify a potential drug to treat patients with genetic mutations in related pathway. The set of experiments outlined in this proposal have broad significance not only for understanding and treatment of these specific rare genetic renal diseases, but also could be highly applicable to any kinds of renal disease with a genetic cause.