Glutathione S-Transferases in Drug and Stress Response

谷胱甘肽 S-转移酶在药物和应激反应中的作用

• 批准号: 8264950
• 负责人: Kenneth D. Tew
• 金额: $ 31.44万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264950
• 关键词: 4-Aminobenzoic Acid; Address; Adverse effects; Animal Model; Animals; Antineoplastic Agents; Area; Award; Biological Assay; Biological Markers; Biotin; Blood Cells; Blood Circulation; Bone Marrow; Catalysis; Cell Proliferation; Cells; Cellular Stress Response; Clinical Trials; Cysteine; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug resistance; Energy Transfer; Exposure to; Funding; Genetic Variation; Glutathione; Glutathione S-Transferase; Goals; Grant; Homeostasis; Human; Immunoblotting; In Vitro; Kinetics; Link; MAPK8 gene; Mainstreaming; Marrow; Measures; Molecular Models; Myeloproliferation; Nitric Oxide; Nitrogen; Oxidation-Reduction; Oxygen; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Plasma; Plasma Proteins; Post-Translational Protein Processing; Prodrugs; Production; Property; Protease Inhibitor; Protein Family; Protein S; Proteomics; Reaction; Regulation; Research; Research Personnel; Role; Series; Serine Proteinase Inhibitors; Signal Transduction; Stem cells; Structure; Therapeutic; Time; Toxic effect; Variant; Work; analog; biological adaptation to stress; cancer pharmacology; cancer therapy; diazeniumdiolate; drug development; drug discovery; in vivo; knockout animal; mast cell; molecular modeling; novel; oxidant stress; penicillamine-glutathione mixed disulfide; peripheral blood; pre-clinical; protein protein interaction; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): This continuation builds on a research platform continuously funded since 1980 that has focused on the importance of targeting GSH and GST homeostasis in anticancer drug discovery and development. Aim 1 will address how human pharmacogenetics might influence the multiple functional properties of GSTP, particularly with respect to protein:protein interactions and the catalysis of S-glutathionylation. Aim 2 seeks to define mechanism(s) of action for a series of nitric oxide (NO) releasing, GSTP activated diazeniumdiolate prodrugs. Structure activity analyses will determine which metabolites of these drugs may act as proximal donors in the S-glutathionylation reaction. In Aim 3 we will elaborate on preliminary observations that serpina1 and serpina3 are S- glutathionylated in the plasma of drug treated animals and may represent novel biomarkers for drug pharmacodynamics or exposure to reactive oxygen or nitrogen species. Aim 4 extends Aim 3 into the bone marrow compartment where NOV-002 and Telintra (small molecule myeloproliferative drugs) may impart proliferative effects through S-glutathionylation of the protease inhibitor serpins. Mechanistically, these protein families are subject to redox regulation and have roles in regulation of marrow progenitor cell proliferation and mobilization into the bloodstream. Since some of the drugs under study are in clinical trial, there is a strong translational component to this work. Moreover, drug development is facilitated by goals to develop GST activated prodrugs and define their mechanism(s) of action. PUBLIC HEALTH RELEVANCE: We have initiated projects with an anticancer drug development focus since this is critical in advancing the therapeutic treatment of cancer. Because one side effect of cancer drugs is bone marrow toxicity, we are trying to understand how certain drugs can influence the production of blood cells. The principle goal of the project is to study how oxidant stresses effect these areas of research.

描述（由申请人提供）：这种延续是在自1980年以来一直在资助的研究平台上建立的，该平台的重点是针对GSH和GST稳态在抗癌药物发现和开发中的重要性。 AIM 1将解决人类药物遗传学如何影响GSTP的多重功能特性，尤其是在蛋白质相互作用方面：蛋白质相互作用和s-谷胱甘肽的催化。 AIM 2旨在定义一系列一氧化氮（NO）释放的作用机制，GSTP激活了重18zeniumdiolate前药。结构活性分析将确定这些药物的哪些代谢产物可以充当S-谷胱甘肽反应中的近端供体。在AIM 3中，我们将详细说明在药物治疗的动物的血浆中被Serpina1和serpina3被S-谷胱甘肽被化为Serpina1和serpina3的初步观察，并可能代表用于药物药效学或暴露于反应性氧或氮种的新型生物标志物。 AIM 4将AIM 3扩展到骨髓室中，其中Nov-002和Teltra（小分子骨髓增生药物）可能通过蛋白酶抑制剂蛇纹蛋白的S-甲基二硫基化而产生增殖作用。从机械上讲，这些蛋白质家族受到氧化还原调节的影响，并在骨髓祖细胞增殖和动员血液中具有作用。由于研究中的某些药物正在临床试验中，因此这项工作有很强的翻译成分。此外，制定GST激活前药并定义其作用机制的目标促进了药物开发。 公共卫生相关性：我们启动了抗癌药物开发重点的项目，因为这对于促进癌症治疗治疗至关重要。因为癌症药物的一种副作用是骨髓毒性，所以我们试图了解某些药物如何影响血细胞的产生。该项目的主要目标是研究氧化应力如何影响这些研究领域。