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Development of quantitative metabolomics analyses to understand cystic kidney diseases

开发定量代谢组学分析以了解囊性肾病

基本信息

批准号：
387259123
负责人：
Professor Dr. Markus Rinschen
金额：
--
依托单位：
The Scripps Research Institute
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/387259123?language=en
关键词：
Development quantitative metabolomics analyses understand

项目摘要

Chronic kidney disease (CKD) is one of the most important risk factor for cardiovascular events and requires dialysis or renal transplantation. One frequent cause of CKD is autosomal dominant polycystic kidney disease. Autosomal dominant polycystic kidney disease is characterized by an altered metabolism which drives the proliferation of hundreds and thousands of small fluid-filled cysts, which ultimately destroy the kidney. The metabolic pathways which lead to this phenotype, however, are not completely understood. To answer this question, I will use untargeted, mass-spectrometry based analyses of the entitity of metabolites, the metabolome. Although metabolomic analysis are largely utilized in biomarker studies, the potential of the method to understand (renal) diseases mechanisms is largely unexplored, and the effect of phyisological perturbation is not well characterized. In the project proposed here, I will apply targeted and untargeted metabolomics to understand physiology and pathology of the distal nephron. First, I intend to use nanostructure imaging mass spectrometry to discover which metabolites specifically occur in which region of the kidney and how they change by physiological stimuli (urine concentration). Second, I aim to use a global metabolomics strategy to learn how metabolism changes in the kidneys which are developing cysts. Third, I want to utilize targeted metabolomics analysis to characterize a substrates of an enzyme I found to be upregulated in aged and cystic kidneys. Alltogether, the data generated in this project will generate new insights into renal metabolism and complement previously generated proteomic data in a "multi-omics" approach. The study suggested here will be among the first applications of metabolomics to distal nephron pathophysiology.

慢性肾脏病（CKD）是心血管事件最重要的危险因素之一，需要透析或肾移植。CKD的一个常见原因是常染色体显性遗传性多囊肾病。常染色体显性遗传性多囊肾病的特点是代谢改变，导致成百上千个充满液体的小囊肿增殖，最终破坏肾脏。然而，导致这种表型的代谢途径尚未完全了解。为了回答这个问题，我将使用非靶向的，基于质谱的代谢物的实体分析，代谢物组。虽然代谢组学分析主要用于生物标志物研究，但该方法理解（肾）疾病机制的潜力在很大程度上未被探索，生理学扰动的影响也没有得到很好的表征。在本计画中，我将应用靶向与非靶向代谢组学来了解远端肾单位的生理与病理。首先，我打算使用纳米结构成像质谱法来发现哪些代谢物具体发生在肾脏的哪个区域，以及它们如何通过生理刺激（尿液浓度）发生变化。其次，我的目标是使用一个全球代谢组学策略，以了解如何代谢变化的肾脏正在发展囊肿。第三，我想利用靶向代谢组学分析来表征我发现在老年和囊性肾脏中上调的酶的底物。总之，该项目产生的数据将产生对肾脏代谢的新见解，并以“多组学”方法补充先前产生的蛋白质组学数据。这项研究表明，这将是代谢组学在远端肾单位病理生理学中的首次应用。