Bioactive lipids as effectors and indicators of the deleterious effects of environmental exposure on chronic diseases

生物活性脂质作为环境暴露对慢性疾病有害影响的效应物和指标

• 批准号: 10615675
• 负责人: BRUCE D HAMMOCK
• 金额: $ 75.68万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615675
• 关键词: Acids; Antibodies; Biochemical; Biological Assay; Biological Markers; Cells; Central Nervous System Diseases; Chemicals; Chemotherapy-Oncologic Procedure; Chronic; Chronic Disease; Collaborations; Communities; Coupled; Diabetes Mellitus; Diet; Dietary Intervention; Discipline; Disease; Disease model; Education and Outreach; Environment; Environmental Exposure; Enzymes; Epoxide hydrolase; Epoxy Compounds; Excision; Fatty Acids; Fibrosis; Health; Heart failure; Homeostasis; Knowledge; Life Style; Lipids; Malignant Neoplasms; Mediator; Mental Depression; Mitochondria; Monitor; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Nutritional; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Organ; Outcome; Pain; Parkinson Disease; Pathologic; Pathway interactions; Pharmaceutical Preparations; Proteins; Reagent; Reporting; Research; Services; Stress; System; Testing; Toxic effect; Toxin; Triclosan; Work; analytical method; analytical tool; biochemical tools; depressive symptoms; endoplasmic reticulum stress; environmental chemical; flexibility; improved; inflammatory pain; inhibitor; man; nanobodies; novel; nutrition; painful neuropathy; pharmacologic; prevent; programs; response; tool; tumor

Man’s total environment including diet, lifestyle and environmental chemicals has a major impact on health. The effects of environmental chemicals are most dramatic when they alter a regulatory system that amplifies the toxicity. We will examine effects of toxins and disease on lipid chemical mediators or oxylipins. Deleterious effects also are more global when the environmental chemicals alter a system fundamental to many cells and organs. Thus, we will investigate how environmental chemicals increase endoplasmic reticulum stress resulting in negative and often chronic outcomes in multiple organs. Natural epoxyfatty acids (EpFA) are a component of a regulatory system that maintains homeostasis. We are using inhibitors of the soluble epoxide hydrolase (sEHI) to stabilize these beneficial EpFA. A variety of environmental chemicals such as triclosan and nonsteroidal anti- inflammatory drugs damage these pathways enhancing disease states. sEHI restore the homeostatic systems leading to improvement in many disease models including for diabetes, heart failure, neuropathic and inflammatory pain, fibrosis and toxicities. Recently, we reported sEHI beneficial for treating cancer as well as Parkinson’s and depression. With the flexibility offered by the RIVER program, we will evaluate the relationships among these disease states, determine biochemical mechanisms, and monitor the levels of EpFA and other chemical mediators. Based on this knowledge we will develop cellular and biochemical biomarkers of health and disease particularly for diseases related to endoplasmic reticulum stress. We will continue providing the biochemical and analytical tools developed for this work for the broad scientific community. These tools include clones and proteins of the sEH enzyme, sEH inhibitors as probes and drugs, novel bioassays, antibodies and nanobodies, synthetic standards of regulatory lipids, and of course analytical methods. We will expand our testing of the hypothesis that toxicity and disease can be altered by pharmacological and nutritional intervention both in house and with collaborators. In particular, we will expand our recent studies that by stabilizing natural omega 6 and omega 3 fatty acid epoxides, sEHI can prevent and reverse symptoms of depression, Parkinson’s disease and other CNS disorders and block tumor resurgence and metastasis caused by cell debris from cancer chemotherapy and resection. Thus, we will test the hypothesis that the mitochondrial–ROS–ER stress axis is a common mechanism in the onset of many toxicities and pathological outcomes and that these effects can be prevented or reversed by increasing epoxyfatty acids. While carrying out the above research we continue and expand our work to reduce barriers to entering the oxylipin research field by providing service and reagents. Our research will be coupled with a training and outreach component to encourage collaboration and free information exchange in the oxylipin discipline. The work is transformative in emphasizing chronic rather than short-term toxicities, illustrating a new mechanism of toxicity in ER stress, and in exploring approaches to prevent the toxicities by manipulating endogenous chemical mediators.

人类的整体环境，包括饮食、生活方式和环境化学物质，对健康有重大影响。这 当环境化学物质改变了放大了环境影响的监管体系时，其影响最为显着。 毒性。我们将研究毒素和疾病对脂质化学介质或氧脂质的影响。有害影响 当环境化学物质改变许多细胞和器官的基本系统时，它也会变得更加全球化。 因此，我们将研究环境化学物质如何增加内质网应激，从而导致 多个器官的负面且通常是慢性的结果。天然环氧脂肪酸 (EpFA) 是 维持体内平衡的调节系统。我们正在使用可溶性环氧化物水解酶 (sEHI) 抑制剂 稳定这些有益的 EpFA。多种环境化学品，如三氯生和非甾体抗氧化剂 炎症药物会破坏这些通路，从而加剧疾病状态。 sEHI 恢复体内平衡系统 导致许多疾病模型的改善，包括糖尿病、心力衰竭、神经病和 炎性疼痛、纤维化和毒性。最近，我们报道了 sEHI 有益于治疗癌症以及 帕金森氏症和抑郁症。凭借 RIVER 计划提供的灵活性，我们将评估这些关系 在这些疾病状态中，确定生化机制，并监测 EpFA 和其他疾病的水平 化学介质。基于这些知识，我们将开发健康和健康的细胞和生化生物标志物。 疾病，特别是与内质网应激相关的疾病。我们将继续提供 为此工作为广大科学界开发的生化和分析工具。这些工具包括 sEH 酶的克隆和蛋白质、作为探针和药物的 sEH 抑制剂、新型生物测定法、抗体和 纳米抗体、监管脂质的合成标准，当然还有分析方法。我们将扩大我们的 检验药物和营养干预可以改变毒性和疾病的假设 无论是在内部还是与合作者。特别是，我们将扩展我们最近的研究，通过稳定自然 欧米伽 6 和欧米伽 3 脂肪酸环氧化物、sEHI 可以预防和逆转抑郁症、帕金森氏症的症状 疾病和其他中枢神经系统疾病，并阻止癌症细胞碎片引起的肿瘤复发和转移 化疗和切除。因此，我们将检验线粒体-ROS-ER 应激轴是一个假设 许多毒性和病理结果发生的共同机制，并且这些影响可以通过 通过增加环氧脂肪酸可以预防或逆转。在进行上述研究的同时，我们继续并 通过提供服务和试剂，扩大我们的工作，减少进入氧脂素研究领域的障碍。我们的 研究将与培训和外展相结合，以鼓励合作和免费信息 氧脂学科的交流。这项工作具有变革性，强调长期而非短期 毒性，阐明了 ER 应激中毒性的新机制，并探索了预防方法 通过操纵内源性化学介质来消除毒性。