Metabolomic Biomarkers of CKD

CKD 的代谢组生物标志物

• 批准号: 7807297
• 负责人: EUGENE P. RHEE
• 金额: $ 3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807297
• 关键词: Address; Analytical Chemistry; Biological Markers; Chronic Kidney Failure; Clinical; Consensus; Coupled; Diabetic Nephropathy; Diagnostic; Disease Pathway; Disease Progression; Dyslipidemias; Early Diagnosis; Early treatment; Enrollment; Epidemiology; Etiology; Excretory function; Filtration; Future; Goals; Homeostasis; Human; Hypertension; Individual; Inflammation; Insulin Resistance; Kidney Diseases; Leukocytes; Link; Measures; Metabolic Diseases; Plasma; Process; Renal function; Research; Sampling; Screening procedure; Severity of illness; Signal Transduction; Staging; Technology; Testing; Time; Translational Research; Urine; Validation; absorption; base; blood pressure regulation; clinically relevant; cohort; diabetic; human disease; improved; indexing; meetings; metabolomics; new technology; non-diabetic; novel; novel marker; prognostic; prospective; small molecule; treatment planning

DESCRIPTION (provided by applicant): The long-term goal of this proposed research is to identify plasma and/or urine biomarkers of chronic kidney disease (CKD) that provide better diagnostic, mechanistic, and prognostic information than current indices of kidney function. Catalyzed by recent advances in analytical chemistry, coupled with computational power, this proposal integrates metabolite profiling with access to well-characterized clinical cohorts to address a widely recognized need for improved biomarkers of CKD. Small molecule metabolites are promising biomarkers in this context for several reasons: 1) CKD is a condition defined by aberrant filtration, re-absorption, and excretion of small molecule metabolites; 2) CKD is at the intersection of various metabolic disease pathways, including hypertension, insulin resistance, dyslipidemia, and inflammation: circulating metabolites may themselves participate as regulatory signals, as in the control of blood pressure, energy homeostasis, and leukocyte recruitment; and 3) High throughput metabolite profiling is practical and feasible with current technology. We hypothesize that individuals with CKD have distinct plasma and urine metabolites profile as compared to normals and that a subset of metabolites associated with CKD will predict CKD progression. Our hypothesis will be tested by the following specific aims: Aim 1. To use a targeted, LC-MS/MS-based metabolomics platform to discover novel plasma and urine biomarkers of CKD in subjects with CKD stages 1-5 with both diabetic and non-diabetic nephropathy. Aim 2. To validate novel plasma and urine biomarkers of CKD in a prospective cohort of CKD subjects by verifying their quantitative and qualitative association with CKD at baseline (Aim 2A), and demonstrating their ability to predict CKD progression over time (Aim 2B). Independent of these aims, we believe these initial efforts to profile plasma and urine across a spectrum of CKD severity and etiology will be a valuable contribution to ongoing efforts to annotate the human metabolome, and will inform future metabolomics studies of human disease. Current markers of kidney disease fail to reliably detect early kidney disease and are unable to predict which individuals will have worsening kidney function. New technologies now allow for rapid and broad screening for new markers of kidney disease. Better markers of kidney disease that permit earlier diagnosis would allow earlier treatment and planning, and would help efforts to discover new treatments for kidney disease.

描述（由申请人提供）：这项拟议研究的长期目标是确定慢性肾脏疾病（CKD）的血浆和/或尿液生物标志物，这些生物标志物比目前的肾功能指标提供更好的诊断、机制和预后信息。在分析化学最新进展的推动下，再加上计算能力，该提案将代谢物分析与具有良好特征的临床队列相结合，以解决对改善CKD生物标志物的广泛认可的需求。在这种情况下，小分子代谢物是有希望的生物标志物，原因如下：1)CKD是一种由小分子代谢物的异常过滤、再吸收和排泄所定义的疾病；2) CKD处于多种代谢疾病途径的交叉点，包括高血压、胰岛素抵抗、血脂异常和炎症：循环代谢物本身可能作为调节信号参与，如控制血压、能量稳态和白细胞募集；3)在现有技术条件下，高通量代谢物谱分析是切实可行的。我们假设CKD患者与正常人相比具有不同的血浆和尿液代谢物特征，并且与CKD相关的代谢物子集可以预测CKD的进展。我们的假设将通过以下具体目标进行检验：目标1。使用靶向的LC-MS/MS-based代谢组学平台，在伴有糖尿病和非糖尿病肾病的1-5期CKD患者中发现新的血浆和尿液生物标志物。目标2。在一项前瞻性CKD受试者队列中，通过验证其在基线时与CKD的定量和定性关联（Aim 2A），并证明其预测CKD随时间进展的能力（Aim 2B），来验证新的血浆和尿液生物标志物。独立于这些目标之外，我们相信这些初步的努力将对血浆和尿液的CKD严重程度和病因谱进行分析，这将对正在进行的人类代谢组学注释工作做出有价值的贡献，并将为未来的人类疾病代谢组学研究提供信息。目前的肾脏疾病标志物不能可靠地检测早期肾脏疾病，也不能预测哪些人会肾功能恶化。现在的新技术允许对肾脏疾病的新标志物进行快速和广泛的筛查。更好的肾脏疾病标记物，允许早期诊断，将允许早期治疗和计划，并将有助于发现肾脏疾病的新治疗方法。