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.

抽象的阐明疾病背后的分子机制对于开发新药物至关重要研究人员最近开发了多种识别基因的方法，然而，定义联系的补充方法。这些分子之间??连接是疾病和目标生物学模型的基础药品事实证明，开发起来更加困难，因此仍然存在巨大的需求。揭示体内疾病分子成分之间相互作用的创新新方法。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脯氨酰肽酶家族 DMP 整合了一系列生物和化学方法，包括遗传学、药理学和重要的是，通过使用分析化学来识别真正的生理酶-底物相互作用。 DMP 研究实际上缺乏已知内源底物但调节的酶家族具有巨大生物医学意义的表型，这项研究将开始认识到该表型的令人难以置信的潜力此外，DMP 在肽酶中的应用将证明其在医学上的应用。这种方法对于医学相关酶和信号传导的未来表征的通用性途径。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deletion of PREPl causes growth impairment and hypotonia in mice.

PREP1的缺失导致小鼠生长障碍和肌张力减退。

DOI：
发表时间：
2014
期刊：
影响因子：
3.7
作者：
Lone, Anna Mari;Leidl, Mathias;McFedries, Amanda K;Horner, James W;Creemers, John;Saghatelian, Alan
通讯作者：
Saghatelian, Alan

Monoalkylglycerol ether lipids promote adipogenesis.

单烷基甘油醚脂质促进脂肪生成。

DOI：
10.1021/ja111173c
发表时间：
2011-04-13
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Homan EA;Kim YG;Cardia JP;Saghatelian A
通讯作者：
Saghatelian A

A substrate-free activity-based protein profiling screen for the discovery of selective PREPL inhibitors.

基于无底物活性的蛋白质分析筛选，用于发现选择性 PREPL 抑制剂。

DOI：
发表时间：
2011-08-03
期刊：
影响因子：
15
作者：
Lone, Anna Mari;Bachovchin, Daniel A.;Westwood, David B.;Speers, Anna E.;Spicer, Timothy P.;Fernandez-Vega, Virneliz;Chase, Peter;Hodder, Peter S.;Rosen, Hugh;Cravatt, Benjamin F.;Saghatelian, Alan
通讯作者：
Saghatelian, Alan

Functional analysis of protein targets by metabolomic approaches.

通过代谢组学方法对蛋白质靶标进行功能分析。