Chemistry and Biology of Novel Arachidonic Acid Metabolites

新型花生四烯酸代谢物的化学和生物学

基本信息

批准号：
9100884
负责人：
GARY ALLEN SULIKOWSKI
金额：
$ 28.87万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9100884
关键词：
Affinity Alcohols Alkynes Amino Acids Anti-Inflammatory Agents Anti-inflammatory Arachidonic Acids Asthma Biological Biological Markers Biological Process Biology Body Fluids Cardiovascular system Cell Proliferation Cell physiology Cells Chemicals Chemistry Clinical Clinical Research Collaborations Constitutional Cyclization Deuterium Development Diagnosis Diagnostic Disease Eicosanoids Endothelial Cells Enzymes Evaluation Event Family Furans G-Protein-Coupled Receptors GPR55 receptor Genetic Crossing Over Gold Health Human Hydroxyeicosatetraenoic Acids In Vitro Inflammation Inflammation Mediators Investigation Isomerism Isoprostanes Ketones LOX gene Label Lead Leukocytes Leukotrienes Life Lipoxygenase Liquid substance Malignant Neoplasms Masks Mediating Metabolic Pathway Metabolism Mus Natural Products Neurodegenerative Disorders Neurologic Organ Organism Outcome Study Oxygen PTGS2 gene Pain Parkinson Disease Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Physiological Play Production Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Proteomics Reactive Oxygen Species Receptor Signaling Recording of previous events Research Personnel Role Route Sampling Scheme Scientist Side Signal Pathway Stereoisomer System Therapeutic Agents Tissues Universities Vascularization angiogenesis autooxidation biomarker identification cell motility cellular targeting chemical synthesis clinical application hemiketal human disease improved in vivo interest novel oxidation programs pulmonary arterial hypertension receptor research study response stereochemistry therapeutic development unpublished works vinyl ether

项目摘要

DESCRIPTION (provided by applicant): Arachidonic acid metabolites are important constituents of humans involved in a variety of cellular functions including mediators of inflammation and a variety of homeostatic biological functions. Their study is important for the improvement of human health as biomarkers of human disease and identification of targets for the development of therapeutic agents. Recently, investigators at Vanderbilt University have described two new groups of arachidonic acid metabolites, the hemiketals and isofurans. The latter are produced by an unprecedented enzymatic cross-over pathway (5-LOX and COX-2) and have been shown to induce cell proliferation using mouse endothelial cells by an unidentified mechanism. The isofurans are generated by non- enzymatic autoxidation and have been associated with the pathogenesis of Parkinson's disease and pulmonary arterial hypertension (PAH) disease. Limiting their further study, both the hemiketals and isofurans are not readily available requiring their total synthesis to provide material for further biological investigations. Thus two primary aims of this proposal are to develop efficient synthetic routes to the hemiketals and isofurans in quantity. The described synthetic schemes also allow access to isotopically labeled derivatives to serve as internal standards for the quantification of these metabolites in cells and human fluid samples of clinical patients. Other derivatives will serve as probes for chemical proteomic studies aimed at the identification of cellular targets possibly relevant to their biological effects. Synthetic isofurans will also support studies aimed at verifyng a hypothetical GPCR target leading to the pulmonary arterial hypertension phenotype. In summary chemical synthesis of these novel arachidonic acid metabolites will enable their study by biomedical and clinical scientists with the purpose of improving human health.

描述（由申请人提供）：花生四烯酸代谢产物是参与各种细胞功能的人类的重要组成部分，包括炎症介质和各种稳态生物学功能。他们的研究对于改善人类健康作为人类疾病的生物标志物和鉴定治疗剂的靶标很重要。最近，范德比尔特大学的研究人员描述了两个新的花生四烯酸代谢产物，半尿和异呋喃。后者是由前所未有的酶促交叉途径（5-lox和Cox-2）产生的，并已证明使用未鉴定的机制使用小鼠内皮细胞诱导细胞增殖。异呋喃是通过非酶促自氧化产生的，与帕金森氏病和肺动脉高压（PAH）疾病的发病机理有关。限制了他们的进一步研究，不容易获得半尿和异呋喃，需要其全合成以提供进一步的生物学研究材料。因此，该提案的两个主要目的是开发有效的合成路线量的半尿和异呋喃。所描述的合成方案还允许访问同位素标记的衍生物，可以作为临床患者细胞和人体液体样品中这些代谢产物定量的内部标准。其他衍生物将用作旨在鉴定可能与其生物学作用相关的细胞靶标的化学蛋白质组学研究的探针。合成异呋喃还将支持旨在验证导致肺动脉高压表型的假设GPCR靶标的研究。总而言之，这些新型的花生四烯酸代谢产物的化学合成将使生物医学和临床科学家的研究能够改善人类健康。