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Discovery metabolite profiling of the prolyl peptidases

脯氨酰肽酶的代谢物分析的发现

基本信息

批准号：
7431232
负责人：
Alan Saghatelian
金额：
$ 251.45万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431232
关键词：
A 101 Accounting Acute Address Alleles Amino Acids Analytical Chemistry Angiotensin I Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Antibodies Antidiabetic Drugs Antihypertensive Agents Anus Appetite Regulation Area Award Basic Science Behavior Behavioral Belief Binding Binding Sites Biochemical Biochemical Pathway Biochemistry Biological Biological Assay Biological Availability Biological Factors Biological Models Biological Process Biology Birth Blood Blood Glucose Brain Brain region Calcium Cardiovascular Diseases Cations Cell Membrane Permeability Cells Ceramides Chemical Structure Chemicals Chemistry Chromatography Chronic Class Classification Cloning Cognition Disorders Collaborations Complement Complex Condition Coupled Cystinuria Data Defect Detection Development Diabetes Mellitus Dipeptides Dipeptidyl Peptidases Disadvantaged Discipline Disease Disruption Doctor of Philosophy Drug Delivery Systems Drug or chemical Tissue Distribution E 10 Education Educational process of instructing Employee Strikes Endocannabinoids Endocrinology Endopeptidases Engineering Enkephalins Environment Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Ethanolamines Exopeptidase Face Family Family member Fatty Acids Financial compensation Fluorescence Foundations Funding Funding Mechanisms Fura-2 Future Gene Expression Gene Proteins Generations Genes Genetic Genetic Models Genets Genomics Gifts Glucose Glycerol Glycogen Goals Hereditary Disease Homologous Gene Human Hydrolysis Hypertension Hypothalamic structure Image Immunoassay In Vitro Individual Insulin Ion Channel Ions Isotopes Kidney Knock-out Knockout Mice Knowledge Label Laboratories Lead Left Libraries Life Ligands Link Lipase Lipids Liquid Chromatography Liver Malignant Neoplasms Mammals Maps Martens Measurement Measures Mediating Medicine Membrane Metabolic Metabolism Metalloproteases Methodology Methods Modeling Modification Molecular Molecular Biology Molecular Weight Mus Muscle hypotonia N-terminal Nature Neuraxis Neurons Neuropeptides Noise Nonesterified Fatty Acids Nuclear Receptors Numbers Oral Organic Chemistry Output Pain Pan Genus Pathology Pathway interactions Peptide Hydrolases Peptide Signal Sequences Peptides Peptidyl-Dipeptidase A Peripheral Pharmaceutical Preparations Pharmacology Phenotype Phospholipids Physiological Physiology Plasma Play Positioning Attribute Problem Solving Process Production Proline Property Proprotein Convertase 2 Protease Inhibitor Proteins Proteome Proteomics Protocols documentation Publishing Purpose Range Reagent Regulation Relative (related person)Reliance Reporting Research Research Personnel Rewards Rhodamine Rhodamines Risk Rodent Role Role playing therapy Sampling Schizophrenia Science Scientist Screening procedure Sequence Homology Signal Pathway Signal Transduction Sleep Solid Sorting - Cell Movement Spleen Staging Standards of Weights and Measures Structure Substrate Interaction Surface Syndrome Synthesis Chemistry System Systems Biology TRPV1 gene Taurine Techniques Testing Therapeutic Therapeutic Agents Time Tissues Training Translating Translational Research Troglodytinae Trust Trypsin Up-Regulation Vasoconstrictor Agents Western Blotting Wild Type Mouse Work abstracting anandamide anhydrotrypsin base biosynthetic product blood glucose regulation brain tissue carboxypeptidase H cognitive function comparative concept coping cost design enzyme activity enzyme pathway enzyme substrate ethanolamine experience fatty acid amide hydrolase fibroblast-activating factor follow-up genetic inhibitor genetic regulatory protein ghrelin glucagon-like peptide 1 glucose tolerance glucose transport human subject hypertension treatment hypocretin improved in vitro Assay in vivo inhibitor/antagonist innovation insight insulin secretion insulin signaling interest liquid chromatography mass spectrometry mass spectrometer member metabolomics milliliter mouse model mutant neurophysiology novel novel strategies novel therapeutics parkin gene/protein peptide A peptide B peptide hormone preference prevent programs prolyl oligopeptidase protein metabolite prototype receptor receptor binding research study reversed phase chromatography signal recognition particle receptor small molecule small molecule libraries success tool trait vector willingness

项目摘要

Elucidation of the molecular mechanisms that underlie disease is crucial for the development of new therapeutic agents. Researchers have recently developed a number of methods to identify the genes, proteins, and metabolites associated with disease. However, complementary methods that define connections between these molecules—connections that are the foundation of biological models of disease and targeted medicine—have proven much more difficult to develop. As a result, there remains a tremendous need for innovative new approaches that reveal interactions between the molecular components of disease in vivo. The following proposal outlines the continued development and application of one such method, termed discovery metabolite profiling (DMP), for the assignment of endogenous substrates to the prolyl peptidase family of enzymes. DMP integrates an array of biological and chemical methods, including genetics, pharmacology, and analytical chemistry to identify bona fide physiological enzyme-substrate interactions. Importantly, by using DMP to study a family of enzymes that are virtually lacking in known endogenous substrates, but regulate phenotypes of tremendous biomedical interest, this research will begin to realize the incredible potential of the prolyl peptidases in medicine. Furthermore, the application of DMP to peptidases will demonstrate the generality of this approach for the future characterization of medically relevant enzymes and signaling pathways.

阐明疾病背后的分子机制对于开发新的治疗剂。研究人员最近开发了许多方法来识别这些基因，蛋白质和与疾病相关的代谢物。然而，定义连接的补充方法这些分子之间的联系是疾病和靶向生物模型的基础医学-已被证明开发起来要困难得多。因此，仍然有巨大的需求揭示体内疾病分子成分之间相互作用的创新方法。这个以下提案概述了一种称为发现的方法的持续开发和应用代谢物分析(DMP)，用于将内源底物分配给酪氨酸氨基转移酶酵素。DMP集成了一系列生物和化学方法，包括遗传学、药理学和分析化学，以确定真正的生理性酶-底物相互作用。重要的是，通过使用 DMP用于研究一种酶家族，这些酶实际上缺乏已知的内源底物，但可以调节表型的巨大生物医学兴趣，这项研究将开始认识到令人难以置信的潜力医学中的脯氨酸肽酶。此外，DMP在多肽酶中的应用将证明这一方法对于未来医学相关酶和信号转导特性的一般性小路。