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: 6826252
• 负责人: HENRY W STROBEL
• 金额: $ 27.24万
• 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/6826252
• 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）：本拨款申请提出了一种综合的多层次方法，使用受控皮质影响模型系统来定义细胞色素 P450 4F (CYP 4F) 亚家族和 CYP 2D18 在调节创伤性脑损伤 (TBI) 后炎症级联中的作用。对于人类来说，由各种原因造成的大脑创伤（例如交通事故、暴力）造成的闭合性头部损伤是一种严重的、往往棘手的临床问题，经常导致死亡或停止人工生命支持成为问题。 TBI 通过白三烯 B 和前列腺素引发炎症级联反应，导致液体、离子和细胞流入脑组织 - 随后的脑肿胀通常会导致昏迷。我们解决这个问题的方法首先是因为证明 CYP4F 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，并可能具有缓和炎症级联反应的作用。其次，初步数据表明，所研究的大鼠中四分之三的 CYP 4F 形式在创伤后 24 小时显示海马表达减少，而在皮质冲击（即炎症阶段恢复或逆转）后三天到三周表达增加。我们将通过定义不同大脑区域和远端组织（即肝脏、肾脏等）中 CYP 4F 形式和 CYP 2D18 的表达变化作为撞击后时间的函数来获取这些初步数据。我们将表达、纯化和表征 CYP 4F1 和 CYP 4F6（我们尚未表征的两种剩余形式）对白三烯和前列腺素的催化活性。我们将 TBI 后 CYP4F 和 2D18 表达的变化与炎症细胞标志物和体液信号分子（例如 IL-6、IL-1beta、TNFα）水平的变化联系起来，以检验 CYP4F 调节炎症反应的假设。我们还将定义共同研究者 P. Dash 博士开发的 TBI 小鼠模型中 CYP4F 和 2D18 表达的变化以及炎症和信号分子标记物的变化，以便在 TBI 后正常和 CTP4F14 缺失表型小鼠中定义特定 CYP4F 的作用。我们认为这些方法将有助于更好地定义 TBI 后炎症级联的调节。