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

人类的整个环境，包括饮食、生活方式和环境化学物质，对健康有重大影响。的 环境化学物质的影响是最引人注目的，当他们改变了监管系统，放大了 毒性我们将研究毒素和疾病对脂质化学介质或氧化脂质的影响。有害影响 当环境中的化学物质改变了许多细胞和器官的基本系统时，也更具全球性。 因此，我们将研究环境化学物质如何增加内质网应激， 对多个器官产生负面且经常是慢性的后果。天然环氧脂肪酸（EpFA）是一种 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）的抑制剂 来稳定这些有益的EpFA。各种环境化学品，如三氯生和非甾体抗- 炎性药物破坏这些途径，增强疾病状态。sEHI恢复稳态系统 导致许多疾病模型的改善，包括糖尿病、心力衰竭、神经性和 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 帕金森症和抑郁症。利用RIVER计划提供的灵活性，我们将评估 在这些疾病状态中，确定生化机制，并监测EpFA和其他 化学介质基于这些知识，我们将开发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 为广大科学界开展这项工作而开发的生物化学和分析工具。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，新的生物测定，抗体和 纳米抗体，调节脂质的合成标准，当然还有分析方法。我们将扩大我们 检验毒性和疾病可以通过药物和营养干预改变的假设 无论是内部还是合作者。特别是，我们将扩大我们最近的研究，通过稳定自然 欧米茄6和欧米茄3脂肪酸环氧化物，sEHI可以预防和逆转抑郁症，帕金森氏症， 并阻断由癌症细胞碎片引起的肿瘤复发和转移 化疗和切除。因此，我们将测试这一假设，即细胞-ROS-ER应力轴是一个 许多毒性和病理结果发生的共同机制，这些影响可能是 通过增加环氧脂肪酸来防止或逆转。在进行上述研究的同时，我们继续和 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 研究将与培训和推广部分相结合，以鼓励合作和免费信息 Oxylipin学科的交流。这项工作在强调长期而不是短期方面具有变革性 毒性，说明了ER应激中毒性的新机制，并在探索预防 毒性通过操纵内源性化学介质。

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.