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

描述(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不清楚。一个高效的模型系统，可以用于识别肾脏基因，概括致病基因突变，并作为原始药物测试平台，将对肾脏疾病研究领域具有非常高的价值和重要意义。我们已经开发了果蝇肾脏功能的遗传筛查，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高度保守，其中许多与肾脏疾病有关。这些基因编码多种生物过程中的蛋白质和肾脏特有的结构，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)生物合成途径。我们的发现表明，关键肾功能的遗传控制，如滤过和蛋白质重吸收，在进化上是保守的，果蝇可以作为研究肾脏疾病遗传机制的模型系统。这项建议的目标是利用果蝇建立特定的肾脏疾病模型，并建立果蝇作为特定遗传性肾脏疾病的原始药物测试平台。在目标1中，我们将使用辅酶Q途径作为原理的证明，以证明新模型的效率和可行性，以确定肾功能所需的新基因，生成人类疾病突变的准确概括，并测试一种可治愈果蝇特定遗传性肾脏疾病的已知药物。在目标2中，我们将研究两个新的肾脏基因(RhoGDI和KANK2)的发病机制，这两个基因都是从我们的基因筛查和我们的合作者的人类患者外显子序列中鉴定出来的。我们将为这些新基因建立果蝇肾脏疾病模型，并测试一系列化学抑制剂，以确定治疗相关途径基因突变患者的潜在药物。这项建议中概述的一系列实验不仅对了解和治疗这些特定的罕见遗传性肾脏疾病具有广泛的意义，而且可以高度适用于任何一种具有遗传原因的肾脏疾病。

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.