Role of monoacylglycerol lipase in coordinating diverse lipid signaling pathways

项目摘要/摘要。候选人。我唯一的职业目标是在某专业谋得一份教职 研究型大学或研究机构。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)约翰·卡西达教授在加州大学伯克利分校的研究经验侧重于 阐明用作杀虫剂和化学品的有机磷(OP)神经毒剂的脱靶作用 战地特工。这在12篇出版物中产生了：1)确定了未加注释的丝氨酸水解酶的作用 KIAA1363作为大脑中主要的OP解毒酶和2)证明了双重阻断 单酰甘油脂肪酶(MAGL)和脂肪酸酰胺水解酶(FAAH)导致血浆中 脑内大麻素水平和强健的大麻素行为，包括抗伤害感觉。我的博士后 研究的重点是诠释癌症中失调的代谢途径。在我的职业生涯中 博士后任期，我计划磨练我的研究和指导技能，以便我为独立的 职业生涯。研究职业发展计划。本·克拉瓦特教授的研究小组非常适合 继续我的培训，因为他的团队已经开创了多样化的开发和应用 在化学和生物的界面，我将能够学习和应用于我的研究的技术。 这个实验室还具有高度的协作性，使我能够扩展我的科学广度。克拉瓦特教授和我会专注于 关于我继续独立开发实验计划，以及我提出和辩护这些计划的能力 计划和更广泛的假设，同时我还参加了几个培训课程，以进一步培养技能 成为一名成功的调查员并参加几次会议以获得经验是必不可少的 展示我的工作，并与其他科学家建立关系。研究。脂质信号分子 控制广泛的细胞和生理过程。主要脂质信号通路的失衡 在慢性炎症、癌症、代谢和退行性疾病的发病机制中起重要作用。 许多脂质传递体、它们的修饰酶和它们的下游靶标相互关联，从而产生 到高度集成的新陈代谢和信号网络。这种网络连接允许潜在的坐标 通过靶向关键节点控制点对脂质信号通路的干扰和控制。我目前的研究 已经发现单甘油脂肪酶(MAGL)是这样一种节点酶，它控制着一系列不同的 (病理)生理上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-花生四烯基甘油，但也调节一个不同的脂肪酸网络，产生一个阵列 促肿瘤脂质信号分子。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。这项建议将集中在解剖的功能和治疗 MAGL在癌症和神经炎性疾病中控制脂质信号网络的潜力。这些 目标属于国家普通医学科学研究所(NIGMS)的任务。

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).