A model of kidney stone disease using D. melanogaster

使用黑腹果蝇的肾结石疾病模型

• 批准号: 8244229
• 负责人: Pankaj Kapahi
• 金额: $ 25.6万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244229
• 关键词: Affect; Alzheimer' s Disease; American; Animal Feed; Animal Model; Area; Binding; Calcium; Calculi; Cardiovascular system; Characteristics; Databases; Development; Diabetes Mellitus; Diet; Dietary Intervention; Dietary Proteins; Disease; Drosophila melanogaster; Durapatite; Dyes; Electron Microscopy; Employee Strikes; Ethylene Glycols; Event; Functional disorder; Genes; Genetic; Genetic Screening; Goals; Health Care Costs; Hemolymph; Human; Huntington Disease; Hydroxyapatites; Infection; Invertebrates; Ion Transport; Ions; Kidney; Kidney Calculi; Label; Longevity; Maintenance; Malpighian Tubules; Measures; Medical; Microscopy; Modeling; Molecular; Morbidity - disease rate; Nephrolithiasis; Obesity; Operative Surgical Procedures; Orthologous Gene; Pain; Parkinson Disease; Pathogenesis; Patients; Phosphorus; Physiology; Play; Potassium; Prevention; Prevention strategy; Process; Proteins; Recurrence; Role; Screening procedure; Sirolimus; Site; Sodium; Source; Structure; Study models; System; Therapeutic; Tissues; Toxin; United States; Urinary Calculi; Ursidae Family; Vitamin D; Vitamin D3 Receptor; Work; Xanthine Dehydrogenase; Xanthines; base; bisphosphonate; comparative; cost; drug testing; ethylene glycol; experience; fly; gene conservation; human disease; improved; inhibitor/antagonist; innovation; insight; mortality; nanoparticle; novel; novel therapeutics; prevent; protein intake; solute; success; tool

DESCRIPTION (provided by applicant): Symptomatic kidney stones can be a significant source of severe pain, infection, and morbidity, affecting up to 12% of Americans and generating more than $2 billion in healthcare costs annually. The process of kidney stone formation remains poorly understood and there has been limited progress in developing medical or dietary interventions to prevent the occurrence or recurrence of stones due to paucity of good models for kidney stone formation. In Drosophila melanogaster (D. melanogaster), the Malpighian tubule is the functional equivalent of the human convoluted tubule and transports ions and other solutes from the fly circulatory system into the excretory system. Furthermore, a number of genes found in the fly excretory system play a conserved role in the human excretory system. The fly tubule produces crystalline concretions containing calcium, phosphorus, and other ions combined with an organic matrix. These concretions appear to be formed from small spherical structures that bear a striking resemblance to the nanoparticles (spherites) seen in Randall plaques, the nidus of early stone formation in human kidneys. We show that these fly stones contain xanthine and a bisphosphonate-binding substance, presumably hydroxyapatite and calcium, the primary component of early human stones. We have also found that inhibition of xanthine dehydrogenase (XDH) in D. melanogaster leads to increased accumulation of concretions on a high protein diet which can be rescued by inhibition of a Vitamin D receptor ortholog. Notably these genes and a high protein diet have been implicated in human stone disease. Given the similarities in tubule physiology, conservation of genes in the excretory system, and characteristics of stone formation between D. melanogaster and humans, and the availability of powerful genetic tools in the fly, we hypothesize that D. melanogaster can be utilized as a meaningful model to improve understanding of kidney stone disease and to identify novel therapeutics. The aims of the proposed study are: (1) Characterization of early stone formation and tubule physiology in the XDH knockdown fly; and (2) identification of genetic and pharmacologic manipulations that modulate early fly stone formation, The significance of developing D. melanogaster as a translational model for studying nephrolithiasis is that it would provide an opportunity to better understand the mechanism of human kidney stone formation and to discover novel therapeutics for kidney stone disease. This proposal is innovative because of the application of an invertebrate translational model characterized by a short lifespan and relatively low cost of maintenance, to achieve large scale screening of genetic and pharmacological manipulations for developing therapeutics for nephrolithiasis. PUBLIC HEALTH RELEVANCE: While kidney stone disease is a significant source of medical cost and morbidity in the United States, minimal advancement in the areas of medical treatment and prevention has been made in the last several decades. Given the similarity in various aspects of stone formation and renal physiology between flies and humans, this proposal aims to develop a novel animal model for kidney stone disease using D. melanogaster. Such a model holds significant promise for better understanding of the pathophysiologic mechanisms underlying early stone formation as well as for the discovery of novel therapeutics for renal stone disease.

描述（由申请人提供）：有症状的肾结石可能是严重疼痛、感染和发病的重要根源，影响多达 12% 的美国人，每年产生超过 20 亿美元的医疗费用。对肾结石形成的过程仍然知之甚少，并且由于缺乏良好的肾结石形成模型，在开发医疗或饮食干预措施以预防结石发生或复发方面进展有限。 在黑腹果蝇 (D. melanogaster) 中，马氏小管的功能相当于人类曲管，将离子和其他溶质从果蝇循环系统输送到排泄系统。此外，在果蝇排泄系统中发现的许多基因在人类排泄系统中发挥着保守的作用。蝇小管产生含有钙、磷和其他离子与有机基质结合的结晶结核。这些结核似乎是由小型球形结构形成的，这些结构与兰德尔斑块（人类肾脏早期结石形成的巢穴）中看到的纳米颗粒（球体）极为相似。我们发现这些蝇石含有黄嘌呤和一种双膦酸盐结合物质，可能是羟基磷灰石和钙，这是早期人类结石的主要成分。我们还发现，抑制黑腹果蝇中的黄嘌呤脱氢酶 (XDH) 会导致高蛋白饮食中结石积累增加，这可以通过抑制维生素 D 受体直系同源物来缓解。值得注意的是，这些基因和高蛋白饮食与人类结石病有关。鉴于黑腹果蝇和人类在肾小管生理学、排泄系统基因保守性、结石形成特征方面的相似性，以及果蝇中强大遗传工具的可用性，我们假设黑腹果蝇可以作为有意义的模型来提高对肾结石疾病的了解并确定新的治疗方法。 本研究的目的是：(1) XDH 敲低果蝇早期结石形成和肾小管生理学的特征； （2）鉴定调节早期果蝇结石形成的遗传和药理学操作。开发黑腹果蝇作为研究肾结石的转化模型的意义在于，它将提供一个机会，更好地了解人类肾结石形成的机制，并发现肾结石疾病的新疗法。该提案具有创新性，因为应用了寿命短且维护成本相对较低的无脊椎动物转化模型，以实现大规模筛选遗传和药理学操作，以开发肾结石治疗方法。 公共健康相关性：虽然肾结石疾病是美国医疗费用和发病率的重要来源，但过去几十年来，医疗和预防领域取得的进展甚微。 鉴于果蝇和人类在结石形成和肾脏生理学的各个方面的相似性，本提案旨在利用黑腹果蝇开发一种新的肾结石动物模型。这种模型对于更好地理解早期结石形成的病理生理机制以及发现肾结石疾病的新疗法具有重要的前景。