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

果蝇，肾脏疾病和药物发现的新遗传模型

• 批准号: 8629412
• 负责人: ZHE HAN
• 金额: $ 19.01万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2014-07-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629412
• 关键词: Actins; Anabolism; Animal Model; Animals; Biological Models; Biological Process; Chemicals; Collection; Cytoskeleton; Disease; Disease model; Drosophila genus; Dynein ATPase; Exons; Filtration; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Screening; Goals; Human; Kidney; Kidney Diseases; Link; Membrane; Modeling; Motor; Mutation; Myosin ATPase; Pathway interactions; Patients; Pharmaceutical Preparations; Preclinical Drug Evaluation; Proteins; Rare Diseases; Renal function; Research; Structure; System; TRP channel; Testing; Ubiquinone; Vesicle; cost; disease mechanisms study; drug discovery; drug testing; exome sequencing; gene function; glomerular basement membrane; human disease; inhibitor/antagonist; novel; public health relevance; receptor; research study; rhoB p20 GDI; slit diaphragm; trafficking; transcription factor; vif Genes

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.

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仍然很大程度上未知。一个可用于识别肾脏基因、重现致病基因突变并作为原始药物测试平台的高效模型系统对于肾脏疾病研究领域将具有极高的价值和意义。我们开发了果蝇肾功能的遗传筛查，并鉴定了过滤和蛋白质重吸收所需的数百个基因。这些基因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。这些基因编码多种生物过程和肾脏特异性结构中的蛋白质，包括裂隙隔膜成分、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。我们的研究结果表明，过滤和蛋白质重吸收等关键肾功能的遗传控制在进化上是保守的，果蝇可以作为模型系统来研究肾脏疾病的遗传机制。该提案的目标是利用果蝇开发特定的肾脏疾病模型，并将果蝇建立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 CoQ 途径作为原理验证，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，生成人类疾病突变的精确重现，并测试已知可以治疗果蝇特定遗传性肾病的药物。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，这两个基因都是通过我们的基因筛选和我们的合作者的人类患者外显子测序而鉴定的。我们将为这些新基因生成果蝇肾病模型，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。该提案中概述的一组实验不仅对于理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，而且还可以高度适用于任何类型的遗传原因的肾脏疾病。