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）：这项拟议的研究的长期目标是鉴定慢性肾脏疾病（CKD）的血浆和/或尿液生物标志物，这些疾病（CKD）比肾功能的当前指标提供了更好的诊断，机械和预后信息。该提案催化了分析化学的最新进展，再加上计算能力，将代谢物分析与获得良好特征的临床队列的访问相结合，以满足人们对改善CKD生物标志物的广泛认识的需求。小分子代谢物在这种情况下是有希望的生物标志物，其原因是：1）CKD是由异常过滤，重新吸收和排泄小分子代谢物所定义的疾病； 2）CKD在各种代谢疾病途径的交集中，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，例如控制血压，能量，能量稳态和白细胞募集； 3）高通量代谢物分析是实用的，并且与当前技术相比是可行的。我们假设患有CKD的个体具有不同的血浆和尿液代谢物谱，与正常人相比，与CKD相关的代谢物的子集将预测CKD的进展。我们的假设将通过以下特定目的进行检验：目标1。使用靶向的，基于LC/MS/MS的代谢组学平台在具有糖尿病和非糖尿病患者的受试者中发现CKD的新血浆和尿液生物标志物。 - 糖尿病性肾病。目的2。通过验证基线时与CKD的定量和定性关联（AIM 2A），并证明其预测CKD随着时间的推移的能力（AIM 2B），以验证CKD的新型血浆和尿液生物标志物。与这些目标无关，我们认为这些初步的努力在各种CKD严重性和病因中介绍血浆和尿液将是对持续注释人类代谢组的努力的宝贵贡献，并将为人类疾病的未来代谢组学提供信息。当前的肾脏疾病标记无法可靠地检测到早期肾脏疾病，无法预测哪些人会恶化肾脏功能。现在，新技术允许对肾脏疾病的新标记进行快速和广泛的筛查。肾脏疾病的更好标记可以允许较早的诊断，将允许更早的治疗和计划，并有助于努力发现针对肾脏疾病的新疗法。