CYPs/2D18 Limit Inflammation Cascade Following Brain Injury

CYP/2D18 限制脑损伤后的炎症级联反应

• 批准号: 6986042
• 负责人: HENRY W STROBEL
• 金额: $ 26.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986042
• 关键词: brain injury; cytochrome P450; cytokine; eicosanoid metabolism; enzyme activity; enzyme mechanism; gene expression; immune response; inflammation; isozymes; laboratory mouse; laboratory rat; leukotrienes; neuroprotectants; prostaglandins; recombinant proteins; trauma

DESCRIPTION (provided by applicant): This grant request proposes an integrated multilevel approach to define the role of the cytochrome P450 4F (CYP 4F) subfamily and CYP 2D18 in modulation of the inflammatory cascade following traumatic brain injury (TBI) using a controlled cortical impact model system. In humans, closed head injury resulting from various sources of trauma to the brain (e.g., traffic accidents, violence) constitutes a serious, often intractable clinical problem frequently leading to death or the situation where discontinuation of artificial life support becomes a question. TBI triggers the inflammatory cascade prompted through leukotriene B, and prostaglandins causing the influx of fluids, ions and cells into brain tissue - the subsequent brain swelling often leading to coma. Our approach to this problem is prompted first by the demonstration that the CYP 4F subfamily enzymes can metabolize the leukotriene and prostaglandin mediators of inflammation to inactive products with the possible effect of moderating the inflammatory cascade. Second, it is prompted by preliminary data which show that three out of four of the rat CYP 4F forms studied show a decrease in expression in the hippocampus at 24 hours after trauma and an increase in expression at three days through three weeks after cortical impact (i.e., the recovery or reversal of inflammation phase). We will pursue these preliminary data by defining the changes in expression of CYP 4F forms and CYP 2D18 in various brain regions and distal tissues (i.e., liver, kidney, etc.) as a function of time after impact. We will express, purify and characterize the catalytic activities toward leukotriene and prostaglandin of CYP 4F1 and CYP 4F6 the two remaining forms we have not characterized. We will correlate changes in CYP4F and 2D18 expression following TBI with cellular markers of inflammation and changes in levels of humoral signaling molecules (e.g. IL-6, IL-lbeta, TNFalpha) to test the hypothesis that CYP4Fs modulate inflammatory response as proposed. We will also define changes in the expression of CYP4F and 2D18 and changes in markers of inflammation and signaling molecules in the mouse model of TBI developed by Dr. P. Dash the co-investigator in order for normal and CTP4F14 null phenotype mice after TBI to define the role of a specific CYP4Fs. We feel these approaches will allow a better definition of the modulation of the inflammatory cascade after TBI.

描述（由申请人提供）：本授权申请提出了一种综合的多层次方法，以使用受控皮质撞击模型系统来定义细胞色素P450 4F（CYP 4F）亚家族和CYP 42 D18在创伤性脑损伤（TBI）后炎症级联反应的调节中的作用。在人类中，由脑的各种创伤源（例如，交通事故、暴力）构成严重的、通常难以解决的临床问题，经常导致死亡或人工生命支持中断成为问题的情况。TBI通过白三烯B和肾上腺素引发炎症级联反应，导致液体，离子和细胞流入脑组织-随后的脑肿胀通常导致昏迷。我们对这个问题的方法首先是由以下事实所提示的，即B14 F亚家族酶可以将炎症的白三烯和前列腺素介质代谢为无活性产物，其可能具有缓和炎症级联反应的作用。其次，这是由初步数据所提示的，这些数据显示，所研究的四种大鼠β 4F形式中的三种在创伤后24小时显示海马中的表达减少，而在皮质撞击后三天至三周显示表达增加（即，炎症阶段的恢复或逆转）。我们将通过定义不同脑区域和远端组织（即，肝脏、肾脏等）作为撞击后时间的函数。我们将表达，纯化和表征的催化活性对白三烯和前列腺素的β 4F 1和β 4F 6的两个剩余的形式，我们还没有表征。我们将TBI后CYP 4F和2D 18表达的变化与炎症的细胞标志物和体液信号传导分子（例如IL-6、IL-1 β、TNF α）水平的变化相关联，以检验CYP 4F调节所提出的炎症反应的假设。我们还将确定CYP 4F和2D 18表达的变化以及共同研究者P. Dash博士开发的TBI小鼠模型中炎症标志物和信号分子的变化，以确定TBI后正常和CTP 4F 14无效表型小鼠中特定CYP 4Fs的作用。我们认为这些方法将允许更好地定义TBI后炎症级联反应的调节。