Role of monoacylglycerol lipase in coordinating diverse lipid signaling pathways

单酰甘油脂肪酶在协调不同脂质信号通路中的作用

基本信息

批准号：
8294540
负责人：
Daniel Nomura
金额：
$ 24.41万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294540
关键词：
2-arachidonylglycerol Agonist Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Atherosclerosis Behavior Biology Brain Cancer cell line Cannabinoids Cell physiology Cells Cellular biology Chemical Warfare Agents Chemistry Chronic Colon Carcinoma Complex Cyclooxygenase Inhibitors Data Degenerative Disorder Development Development Plans Disease Disease model Doctor of Philosophy Drug Metabolic Detoxication Eicosanoids Endocannabinoids Enzymes Faculty Fatty Acids Goals Human Impairment Individual Inflammation Insecticides Lead Learning Light Link Lipids Lysophospholipids Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mediating Mentors Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mission Modeling Molecular Molecular Biology Molecular Toxicology Monoacylglycerol Lipases Monoglycerides Mus National Institute of General Medical Sciences Nerve Degeneration Nervous system structure Nodal Pathogenesis Pathogenicity Pathway interactions Phenotype Physiological Processes Play Positioning Attribute Prostaglandins Publications Receptor Signaling Research Research Institute Research Personnel Role Scientist Secure Serine Hydrolase Signal Pathway Signal Transduction Signaling Molecule Techniques Testing Therapeutic Training Tumorigenicity Universities Work abstracting cancer cell cancer type cannabinoid receptor career career development cell motility experience falls fatty acid amide hydrolase in vivo inhibitor/antagonist malignant breast neoplasm melanoma nerve agent nervous system disorder neuroinflammation skills symposium therapeutic target tumor tumor growth tumorigenic

项目摘要

Project Summary/Abstract. Candidate. My sole career objective is to secure a faculty position at a major research university or research institute. My undergraduate (B.A. in molecular and cell biology) and graduate (Ph.D. in molecular toxicology) research experience at the UC Berkeley under Prof John Casida focused on elucidating off-targets of organophosphorus (OP) nerve agents that are used as insecticides and chemical warfare agents. This yielded in 12 publications that 1) established a role for the unannotated serine hydrolase KIAA1363 as the primary OP detoxification enzyme in the brain and 2) demonstrated that dual blockade of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) resulted in dramatic elevations in brain endocannabinoid levels and robust cannabinoid behaviors, including antinociception. My postdoctoral studies have focused on annotating dysregulated metabolic pathways in cancer. For the duration of my postdoctoral tenure, I plan to hone my research and mentoring skills so that I am prepared for my independent career. Research Career Development Plan. The research group of Prof. Ben Cravatt is perfectly suited for the continuation of my training, as his group has pioneered the development and application of diverse techniques at the interface of chemistry and biology that I will be able to learn and apply towards my research. This lab is also highly collaborative, allowing me to expand my scientific breadth. Prof. Cravatt and I will focus on my continued independent development of experimental plans, and my ability to present and defend these plans and broader hypotheses, while I also participate in several training courses to further cultivate the skills essential to becoming a successful investigator and attend several conferences to gain experience in presenting my work and establish relationships with other scientists. Research. Lipid signaling molecules control a wide range of cellular and physiological processes. Imbalances in major lipid signaling pathways contribute to the pathogenesis of chronic inflammation, cancer, and metabolic and degenerative diseases. Many lipid transmitters, their modifying enzymes, and their downstream targets are interconnected giving rise to highly integrated metabolic and signaling networks. This network connectivity allows for potential coordinate perturbation and control of lipid signaling pathways by targeting key nodal control points. My current research has uncovered that monoacylglycerol lipase (MAGL) is one such nodal enzyme that controls a diverse array of (patho)physiologically relevant lipid signaling pathways. In cancer cells, MAGL not only mediates the endocannabinoid 2-arachidonoylglycerol but also regulates a diverse fatty acid network that generates an array of protumorigenic lipid signaling molecules. In brain, MAGL controls endocannabinoids and prostaglandins- both important in neuroinflammation. This proposal will focus on dissecting the function and therapeutic potential of MAGL in controlling lipid signaling networks in cancer and neuroinflammatory disorders. These goals fall under the missions of the National Institute of General Medical Sciences (NIGMS).

项目摘要/摘要。候选人。我的职业生涯唯一目标是确保在一个专业的教师职位研究大学或研究所。我的本科（分子和细胞生物学学士学位）和研究生（分子毒理学博士学位）在约翰·卡西达教授下的加州大学伯克利大学研究经验。阐明用作杀虫剂和化学的有机磷（OP）神经剂的靶向靶点战士。这在12个出版物中产生了1）确定了未注释的丝氨酸水解酶的作用 KIAA1363作为大脑中的主要OP解毒酶，2）证明了双重阻滞单酰基甘油脂肪酶（MAGL）和脂肪酸酰胺水解酶（FAAH）导致显着升高大脑内源性大麻素水平和鲁棒的大麻素行为，包括抗伤害感受。我的博士后研究的重点是注释癌症的代谢途径失调。在我的时间里博士后任期，我计划磨练我的研究和指导技能，以便为我的独立职业。研究职业发展计划。 Ben Cravatt教授的研究小组非常适合我的培训的延续，因为他的小组率先开发和应用多样化在化学和生物学界面上的技术，我将能够学习并应用于我的研究。这个实验室也是高度协作的，使我能够扩大科学广度。克拉瓦特教授和我将集中精力关于我的实验计划的持续独立制定，以及我出现和捍卫这些计划的能力计划和更广泛的假设，同时我还参加了几门培训课程，以进一步培养技能成为成功的调查员至关重要的，参加几次会议以获得经验介绍我的工作并与其他科学家建立关系。研究。脂质信号分子控制各种细胞和生理过程。主要脂质信号通路的不平衡有助于慢性炎症，癌症以及代谢和退化性疾病的发病机理。许多脂质发射机，其修饰酶及其下游目标是相互联系的到高度集成的代谢和信号网络。该网络连接允许潜在的坐标通过靶向关键的节点控制点来扰动和控制脂质信号通路。我目前的研究发现单酰基甘油脂肪酶（MAGL）是一种控制各种阵列的淋巴结酶（PATHO）生理相关的脂质信号通路。在癌细胞中，MAGL不仅介导内源性大麻素2-芳基烯丙基甘油，但也调节产生阵列的多种脂肪酸网络原源性脂质信号分子。在大脑中，MAGL控制内源性大麻素和前列腺素 - 两者在神经炎症中都很重要。该建议将重点剖析功能和治疗性 MAGL在控制癌症和神经炎症性疾病中脂质信号网络中的潜力。这些目标属于美国国家一般医学科学研究所（NIGMS）的任务。