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Illuminating serine hydrolase activity

照亮丝氨酸水解酶活性

基本信息

批准号：
9265060
负责人：
STEPHEN C. MILLER
金额：
$ 46.79万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265060
关键词：
2-arachidonylglycerol ABHD12 gene ABHD6 gene Affect Agonist Amides Animals Arachidonic Acids Biological Assay Bioluminescence Blood - brain barrier anatomy Blood-Testis Barrier Brain CNR1 gene Cells Cleaved cell Data Dependence Detection Diabetes Mellitus Diglycerides Disease Drug effect disorder Drug or chemical Tissue Distribution Endocannabinoids Enzyme Inhibitor Drugs Enzymes Ethanolamines Evaluation Fatty Acids Fatty acid glycerol esters Glucose Intolerance Goals Grant Hydrolase Hydrolysis Image Imagery In Vitro Inflammation Ligands Light Lipase Lipids Malignant Neoplasms Mammalian Cell Mediating Monoacylglycerol Lipases Monoglycerides Mus Mutation Nerve Degeneration Neurodegenerative Disorders Nonesterified Fatty Acids Obese Mice Pain Pain management Parents Pathologic Perception Performance Pharmaceutical Preparations Physiological Processes Play Prodrugs Property Proteins Pump Reaction Regulation Reporter Research Role Second Messenger Systems Serine Hydrolase Signal Transduction Signaling Molecule Techniques Testis Therapeutic Time Tissues Translating Work addiction analog anandamide anxiety treatment base bioluminescence imaging cancer cell cancer invasiveness cannabinoid treatment design efflux pump experience experimental study fatty acid amide hydrolase fatty acid analog imaging approach improved in vivo inhibitor/antagonist luciferin lysophosphatidic acid neuroinflammation novel protein expression protein purification public health relevance receptor response sensor small molecule inhibitor targeted treatment temporal measurement tool

项目摘要

DESCRIPTION (provided by applicant): Many lipids and their derivatives are potent ligands for cellular receptors. The action of lipid second messengers is regulated by lipases and related enzymes that limit the lifetime and sphere of action of these bioactive molecules. The products of these hydrolytic reactions can themselves be second messengers and precursors to other bioactive molecules. For example, the serine hydrolase monoacylglycerol lipase (MAGL) is responsible for limiting the lifetime and sphere of action of the endocannabinoid 2-arachidonoylglycerol (2-AG) and for generating the fatty acid product, arachidonic acid. Inhibitors of these enzymes are potential therapeutics for the treatment of pain, anxiety, addiction, inflammation, and a myriad of diseases where inflammation or lipid regulation play central roles. However, the tools currently available for the evaluation of serine hydrolase activity and inhibition are primarily limited to use in vitro. In this grant, we will develop luminogenic sensors for serine hydrolases (Aim 1), and apply them to the imaging of serine hydrolase activity in live cells and identification of novel inhibitors for this class of enzymes (im 2). Finally, we will perform real-time imaging of serine hydrolase activity in vivo, to determine where and when these enzymes are active, and how the action of drug pumps affect the tissue distribution of small molecule inhibitors of their function (Aim 3).

描述（由申请人提供）：许多脂质及其衍生物是细胞受体的有效配体。脂质第二信使的作用受限制这些生物活性分子的寿命和作用范围的脂肪酶和相关酶的调节。这些水解反应的产物本身可以是第二信使和其他生物活性分子的前体。例如，丝氨酸水解酶单酰基甘油脂肪酶（MAGL）负责限制内源性大麻素2-花生四烯酸酰甘油（2-AG）的寿命和作用范围，并负责产生脂肪酸产物花生四烯酸。这些酶的抑制剂是用于治疗疼痛、焦虑、成瘾、炎症和其中炎症或脂质调节起中心作用的无数疾病的潜在治疗剂。然而，目前可用于评估丝氨酸水解酶活性和抑制的工具主要限于体外使用。在这项资助中，我们将开发丝氨酸水解酶的发光传感器（目的1），并将其应用于活细胞中丝氨酸水解酶活性的成像和这类酶的新型抑制剂的鉴定（im 2）。最后，我们将在体内对丝氨酸水解酶活性进行实时成像，以确定这些酶在何处以及何时活跃，以及药物泵的作用如何影响其功能的小分子抑制剂的组织分布（目的3）。