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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：
7938243
负责人：
Alan Saghatelian
金额：
$ 7.83万
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/7938243
关键词：
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 Classification Cloning Cognition Disorders Collaborations Complement Complex Coupled Cystinuria Data Defect Detection Development Diabetes Mellitus Dipeptides Dipeptidyl Peptidases Disadvantaged Discipline Disease Doctor of Philosophy Drug Delivery Systems Drug or chemical Tissue Distribution Education Educational process of instructing Employee Strikes Endocannabinoids Endocrinology 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 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 Reagent Regulation Relative (related person)Reliance Reporting Research Research Personnel Rhodamine Rhodamines Risk Rodent Role Sampling Schizophrenia Science Scientist Screening procedure Sequence Homology Signal Pathway Signal Transduction Sleep Solid Sorting - Cell Movement Spleen Staging 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 activity-based protein profiling anandamide anhydrotrypsin base biological systems biosynthetic product blood glucose regulation brain tissue carboxypeptidase H cognitive function comparative coping cost design empowered enzyme activity enzyme pathway enzyme substrate experience fatty acid amide hydrolase fibroblast-activating factor follow-up genetic regulatory protein ghrelin glucagon-like peptide 1 glucose tolerance glucose transport high reward high risk 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

Abstract 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.

摘要阐明疾病背后的分子机制对于开发新的治疗方法至关重要。治疗剂。研究人员最近开发了许多方法来识别这些基因，与疾病相关的蛋白质和代谢物。然而，定义连接的补充方法这些分子之间的联系是疾病生物模型的基础，事实证明，医学的发展要困难得多。因此，仍然存在巨大的需求，创新的新方法，揭示了体内疾病分子成分之间的相互作用。的下面的建议概述了继续发展和应用这样一种方法，称为发现代谢物谱分析（METALITE PROPPING），用于将内源性底物分配给脯氨酰肽酶家族，内切酶生物学整合了一系列生物学和化学方法，包括遗传学，药理学，分析化学，以确定真正的生理酶底物相互作用。重要的是，通过使用为了研究一个几乎缺乏已知内源性底物的酶家族，表型的巨大生物医学利益，这项研究将开始实现令人难以置信的潜力，脯氨酰肽酶在医学上的应用此外，将α-淀粉酶应用于肽酶将证明这种方法的一般性，为未来的表征医学相关的酶和信号途径。