Role of monoacylglycerol lipase in coordinating diverse lipid signaling pathways

描述（由申请人提供）：我唯一的职业目标是在一所主要的研究型大学或研究机构获得一个教师职位。我的本科生（B.A.在分子和细胞生物学）和研究生（博士，在加州大学伯克利分校的John Casida教授领导下，他在分子毒理学（分子毒理学）方面的研究经验侧重于阐明用作杀虫剂和化学战剂的有机磷（OP）神经毒剂的脱靶。这在12篇出版物中产生：1）确定了未注释的丝氨酸水解酶KIAA 1363作为大脑中主要OP解毒酶的作用，2）证明了单酰基甘油脂肪酶（MAGL）和脂肪酸酰胺水解酶（FAAH）的双重阻断导致大脑内源性大麻素水平急剧升高和强大的大麻素行为，包括抗伤害感受。我的博士后研究集中在注释癌症中失调的代谢途径。在我的博士后任期内，我计划磨练我的研究和指导技能，使我为我的独立职业生涯做好准备。研究职业发展计划。Ben Cravatt教授的研究小组非常适合我继续接受培训，因为他的小组在化学和生物学的界面上开创了各种技术的开发和应用，我将能够学习并应用于我的研究。这个实验室也是高度合作的，使我能够扩大我的科学广度。Cravatt教授和我将专注于我继续独立开发实验计划，以及我提出和捍卫这些计划和更广泛假设的能力，同时我还参加了几个培训课程，以进一步培养成为成功研究者所必需的技能，并参加了几次会议，以获得展示我的工作并与其他科学家建立关系的经验。Research.脂质信号分子控制着广泛的细胞和生理过程。主要脂质信号传导途径的不平衡导致慢性炎症、癌症以及代谢和退行性疾病的发病机制。许多脂质递质、其修饰酶及其下游靶标相互连接，从而形成高度整合的代谢和信号网络。这种网络连接允许通过靶向关键节点控制点对脂质信号传导途径进行潜在的协调扰动和控制。我目前的研究已经发现，单酰基甘油脂肪酶（MAGL）是一种这样的节点酶，控制着一系列不同的（病理）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-花生四烯酸甘油，而且还调节产生一系列促肿瘤脂质信号分子的多种脂肪酸网络。在大脑中，MAGL控制内源性大麻素和肾上腺素-两者在神经炎症中都很重要。该提案将重点剖析MAGL在控制癌症和神经炎症性疾病中的脂质信号网络中的功能和治疗潜力。这些目标属于国家普通医学研究所的任务范围。 公共卫生相关性：我们的初步研究结果表明，单酰基甘油脂肪酶（MAGL）是一种节点酶在癌症和大脑中，它控制着多种病理相关的信号通路。我们的初步结果表明，阻断MAGL引起脂质信号分子的不同扰动，导致癌症恶性肿瘤以及神经炎症的损害。这项研究的结果不仅应该阐明MAGL在不同疾病背景下控制多种脂质信号通路中的作用，而且还应该阐明这种酶作为癌症和神经炎性疾病的有希望的治疗靶点。

DESCRIPTION (provided by applicant): 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). PUBLIC HEALTH RELEVANCE: Our preliminary results show that monoacylglycerol lipase (MAGL) is a nodal enzyme in cancer and in the brain where it controls multiple pathologically relevant signaling pathways. Our preliminary results show that blockade of MAGL causes diverse perturbation in lipid signaling molecules which lead to impairments in cancer malignancy as well as neuroinflammation. The results yielded from this study should not only clarify the role that MAGL plays in controlling multiple lipid signaling pathways in different disease contexts, but also shine light on this enzyme as a promising therapeutic target for cancer and neuroinflammatory disorders.