Aldose Reductase: A Regulator of Inflammatory Signals

醛糖还原酶：炎症信号的调节剂

• 批准号: 7348324
• 负责人: KOTA VENKATA RAMANA
• 金额: $ 28.64万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7348324
• 关键词: 4 hydroxynonenal; Ablation; Affect; Aldehyde Reductase; Aldehydes; Apoptosis; Arteries; Atherosclerosis; Attenuated; Binding; Blood Vessels; Cell Line; Cells; Cyclic AMP; Cytokine Signaling; Development; Dinoprostone; Disease; Doctor of Philosophy; Drug Metabolic Detoxication; Endotoxins; Enzymes; Event; Generations; Glutathione; Goals; Growth; Growth Factor; Healed; Heart; Hyperglycemia; I Kappa B-Alpha; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-6; Intervention; Intraperitoneal Injections; Isoenzymes; Kidney; Lead; Lipid Peroxidation; Lipids; Lipopolysaccharides; Liver; MAP Kinase Gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolism; Modeling; Molecular; Mus; NADPH Oxidase; NF-kappa B; Oxidation-Reduction; Participant; Pathway interactions; Peritoneal Macrophages; Phospholipase; Phosphorylation; Physiological; Play; Protein Biosynthesis; Protein Dephosphorylation; Protein Isoforms; Protein Kinase C; RNA Interference; Reactive Oxygen Species; Regulation; Resolution; Role; Sepsis; Serum; Signal Pathway; Signal Transduction; Small Interfering RNA; Small Intestines; Smooth Muscle Myocytes; Spleen; Testing; Therapeutic Intervention; Tissues; Toxic effect; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Vascular Endothelial Cell; adduct; arterial lesion; attenuation; base; cell growth; chemokine; cyclooxygenase 2; cytokine; cytotoxic; cytotoxicity; experience; healing; human NOS2A protein; human TNF protein; in vivo; inhibitor/antagonist; injured; macrophage; microbial alkaline proteinase inhibitor; novel; novel therapeutics; prevent; receptor; repaired; transcription factor

DESCRIPTION (provided by applicant): Our recent studies have demonstrated that aldose reductase (AR), plays a pivotal rote in the detoxification of lipid peroxidation-generated lipid derived aldehydes (LDAs) and their conjugates with GSH. 4-hydroxy trans-2-nonenal (HNE), one of the most toxic and abundant LDA generated during lipid peroxidation and GS-HNE are efficiently reduced by AR. We have further demonstrated that AR mediates the mitogenic and cytotoxic signals of reactive oxygen species (ROS) generated by TNF-alpha, growth factors and hyperglycemia leading to proliferation and apoptosis of vascular smooth muscle cells and vascular endothelial cells, respectively. We have also observed that inhibition of AR by specific inhibitors or ablation of AR by antisense or RNAi attenuates the activation of PKC and MAPK, phosphorylation and degradation of IkappaB-alpha and activation of NF-kappaB and API. Also, AR inhibition attenuates lipopolysaccharide (LPS)-induced secretion of cytokines such as TNF-alpha, IL-6, and IL-10, secondary messenger cAMP and prostaglandin E2 in mouse peritoneal macrophages. Our hypothesis is that AR plays a pivotal role in the transduction of LPS-induced inflammatory responses mediated via ROS. We will now systematically examine our hypothesis by investigating the release of LPS-induced cytokines and chemokines by mouse peritoneal macrophages and RAW246.7 cells and identify the mechanism(s) of inhibition of these cytotoxic signals by AR ablation. Attenuation of LPS-induced inflammatory cytokines and chemokines by AR inhibition will be investigated in the liver, spleen, small intestine, kidney, heart and serum, and correlated with attenuation of inflammation in tissues of mice. Thus our aims are to 1) Delineate the involvement of AR in bacterial endotoxin (LPS)-induced cytotoxic signals in macrophages, 2) Investigate the role of AR in LPS-induced expression of proinflammatory cytokines and chemokines in mouse macrophages, 3) Identify the molecular mechanisms and possible targets of AR and 4) Investigate the in vivo role of AR in the regulation of cytokine and chemokine generation and inflammation in mice. Completion of these studies will demonstrate how AR inhibitors attenuate the ROS-mediated LPS and cytokine signals, provide a novel therapeutic approach for preventing inflammation-induced toxicity and elucidate the molecular mechanism(s) of AR's involvement in these complications.

描述（由申请人提供）：我们最近的研究表明，醛糖还原酶（AR）在脂质过氧化产生的脂质衍生醛（LDA）及其与GSH的结合物的解毒中起关键作用。 4-羟基反式-2-壬烯醛（HNE）是脂质过氧化过程中产生的最具毒性和最丰富的LDA之一，GS-HNE被AR有效地还原。 我们已经进一步证明，AR介导由TNF-α、生长因子和高血糖产生的活性氧（ROS）的促有丝分裂和细胞毒性信号，分别导致血管平滑肌细胞和血管内皮细胞的增殖和凋亡。 我们还观察到，通过特异性抑制剂抑制AR或通过反义或RNAi消除AR可减弱PKC和MAPK的活化、IkappaB-α的磷酸化和降解以及NF-κ B和API的活化。 此外，AR抑制减弱脂多糖（LPS）诱导的细胞因子分泌，如TNF-α，IL-6和IL-10，第二信使cAMP和前列腺素E2在小鼠腹腔巨噬细胞。 我们的假设是，AR在LPS诱导的炎症反应通过ROS介导的转导中起着关键作用。 我们现在将通过研究小鼠腹腔巨噬细胞和RAW246.7细胞释放LPS诱导的细胞因子和趋化因子来系统地检验我们的假设，并确定AR消融抑制这些细胞毒性信号的机制。 将在肝脏、脾脏、小肠、肾脏、心脏和血清中研究通过AR抑制对LPS诱导的炎性细胞因子和趋化因子的减弱，并将其与小鼠组织中炎症的减弱相关联。 因此，我们的目的是1）描述AR在细菌内毒素（LPS）诱导的巨噬细胞毒性信号中的参与，2）研究AR在LPS诱导的小鼠巨噬细胞促炎细胞因子和趋化因子表达中的作用，3）确定AR的分子机制和可能的靶点; 4）研究AR在调节小鼠细胞因子和趋化因子产生和炎症中的体内作用。 这些研究的完成将证明AR抑制剂如何减弱ROS介导的LPS和细胞因子信号，为预防炎症诱导的毒性提供新的治疗方法，并阐明AR参与这些并发症的分子机制。