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：
9257449
负责人：
GARY ALLEN SULIKOWSKI
金额：
$ 28.83万
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/9257449
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 Gold Health Human Hydroxyeicosatetraenoic Acids In Vitro Inflammation Inflammation Mediators Investigation Isomerism Isoprostanes Isotope Labeling Ketones LOX gene Label Lead Leukocytes Leukotrienes 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 Tissues Universities Vascularization angiogenesis autooxidation biomarker identification cell motility cellular targeting chemical synthesis clinical application experimental study hemiketal human disease improved in vivo novel oxidation programs public health relevance pulmonary arterial hypertension receptor response stereochemistry therapeutic development unpublished works vinyl ether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）：花生四烯酸代谢物是人体的重要成分，参与多种细胞功能，包括炎症介质和多种稳态生物功能。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确定治疗药物开发的靶点具有重要意义。最近，范德比尔特大学的研究人员描述了两类新的花生四烯酸代谢物：半缩酮和异呋喃。后者是通过前所未有的酶交叉途径（5-LOX 和 COX-2）产生的，并已被证明可以通过一种未知的机制利用小鼠内皮细胞诱导细胞增殖。异呋喃是通过非酶自动氧化产生的，并且与帕金森病和肺动脉高压(PAH)疾病的发病机制有关。限制了他们的进一步研究，半缩酮和异呋喃都不容易获得，需要它们的全合成来为进一步的生物学研究提供材料。因此，该提案的两个主要目标是开发有效的合成路线半缩酮和异呋喃的数量。所描述的合成方案还允许获得同位素标记的衍生物，作为临床患者细胞和人体液体样本中这些代谢物定量的内部标准。其他衍生物将作为化学蛋白质组学研究的探针，旨在鉴定可能与其生物效应相关的细胞靶标。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 靶点的研究。总之，这些新型花生四烯酸代谢物的化学合成将使生物医学和临床科学家能够进行研究，以改善人类健康。