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Design and Validation of Easy-to-Adopt Mass Spectrometry Assays of Importance to Obesity

对肥胖具有重要意义的易于采用的质谱分析的设计和验证

基本信息

批准号：
9918008
负责人：
Kimia Sobhani
金额：
$ 93.26万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918008
关键词：
Address Adipocytes Adopted Apolipoproteins B Biological Assay Biological Availability Biological Markers Characteristics Chronic Disease Communities Comorbidity Complex Consult Coronary Arteriosclerosis Degenerative polyarthritis Development Diabetes Mellitus Dyslipidemias Epidemiology Food Fractionation Functional disorder Future Gastrins Gastrointestinal tract structure Generations Genetic Glucagon Glycosylated hemoglobin A Goals Grant Guidelines Health Heart failure Hormone use Hormones Human Hypertension Individual Inflammation Insulin Insulin-Like Growth Factor I Knee Osteoarthritis Leptin Life Style Liver Mass Spectrum Analysis Measurement Metabolic Methods Molecular Weight Monitor National Institute of Diabetes and Digestive and Kidney Diseases Obesity Organ Peptide Fragments Peptide Hydrolases Peptides Performance Phenotype Plant Resins Plasma Play Preparation Production Proteins Proteolysis Proteolytic Processing Regulation Regulatory Pathway Renal function Reproducibility Research Research Personnel Risk Factors Role Sampling Secretin Sensitivity and Specificity Serum Smoking Somatostatin Techniques Validation Weight Work adiponectin biomarker performance cancer type candidate marker clinical diagnostics design enzyme activity genetic analysis ghrelin glucagon-like peptide 1 heart disease risk in vivo insight liquid chromatography mass spectrometry motilin novel novel strategies peptide I peptide hormone post gamma-globulins prohormone protein biomarkers proteomic signature resistin response tool

项目摘要

PROJECT SUMMARY Obesity now surpasses smoking as a negative health risk factor. Epidemiologic and genetic analyses have demonstrated excess weight is a causal factor for diabetes, coronary artery disease, hypertension, dyslipidemia, heart failure, multiple types of cancer, knee osteoarthritis, and other co-morbidities and complications. Expanded understanding of the pathophysiology of obesity is critically needed to reduce its impact on human health. We are proposing practical and impactful biomarker tools that allow researchers to decipher circulating obesity proteomic signatures from the complex background of serum or plasma. We will apply liquid chromatography-mass spectrometry (LC-MS) techniques using top-down (Aim 1) and bottom-up (Aim 2) workflows, which can be scaled to include other potential candidate markers (Aim 3). Aim 1 focuses on obesity-related peptide hormone processing using top-down targeted LC-MS multiplexed assays. We hypothesize that dysregulated processing of small molecular weight (MW) bioactive hormones is involved in obesity and alters their circulating concentrations. We have two approaches to quantify the processing of key obesity related bioactive peptides: i) top-down LC-MS analysis of endogenous peptide fragments generated during processing (initially) for insulin, IGF-1, glucagon, GLP-1, GIP, ghrelin, motilin, obestatin, and somastatin, with secondary targets approached later; and ii) a novel method to assess plasma proteolytic enzyme activity and the simultaneous generation/loss of peptide fragments focusing specifically on GLP-11-41, GIP1-42, proghrelin and somatostatin-28 and the production of low MW peptides generated from these. In Aim 2, we hypothesize that regulation of adipocytes, liver, gut, and other organs impact obesity via circulating proteins and vice versa. To address this, we will develop a bottom-up targeted multiplex assay for precise quantification of leptin, adiponectin, gastrin (and modified forms), resistin, and secretin, which are all involved in obesity. Additionally, we will include protein markers representing inflammation (CRP), cardiac disease risk (ApoB/ApoA1), diabetes (hemoglobin A1C), and kidney function (cystatin C) for the assessment of obesity as it relates to comorbid conditions. In Aim 3 we will produce additional multiplex assays associated with obesity assigned in consult with our experts and NIDDK. For each assay developed we will demonstrate analytical validity (following CPTAC guidelines) by appropriately evaluating performance characteristics (e.g., precision, accuracy, linearity, sensitivity, specificity, etc.). We will additionally work to increase transferability and access of the assays to the broader obesity-research community. In summary, the development of robust protein biomarker assays that represent broad obesity pathophysiology will assist researchers in further understanding obesity regulatory pathways, developing new treatments, monitoring the effects of lifestyle and genetics on individual phenotypes, and evaluate the potential for future clinical diagnostic biomarker utility.

项目总结