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）：本赠款请求提出了一种集成的多级方法，用于定义细胞色素P450 4F（CYP 4F）亚家族和CYP 2D18在使用受控的皮质影响模型模型系统调制创伤性脑损伤（TBI）后炎症级联反应中的作用。在人类中，由各种创伤来源造成的闭合头部受伤（例如，交通事故，暴力）构成了一个严重的，通常是棘手的临床问题，经常导致死亡或终止人工生命支持的情况成为问题。 TBI触发了通过白细胞B的炎症级联反应，前列腺素引起了液体，离子和细胞流入脑组织的流入 - 随后的脑肿胀通常会导致昏迷。首先证明了CYP 4F亚家族酶可以将炎症产物的白细胞和前列腺素介质代谢为无活性产物，并可能导致炎症性级联反应的可能效果。其次，这是由初步数据引起的，这些数据表明，所研究的大鼠CYP 4F形式中有三分之三显示出创伤后24小时的海马表达降低，并且在皮层影响后三天（即炎症阶段的恢复或逆转）表达增加了）。我们将通过将CYP 4F形式和CYP 2D18在各个大脑区域和远端组织（即肝脏，肾脏等）中的表达变化定义为撞击后时间的函数来追求这些初步数据。我们将表达，纯化和表征CYP 4F1和CYP 4F6的白三烯和前列腺素的催化活性。我们尚未表征的剩余两种形式。我们将将TBI之后CYP4F和2D18表达的变化与炎症的细胞标记以及体液信号分子水平的变化（例如IL-6，IL-LBETA，TNFALPHA）的变化，以测试CYP4FS诸如提议调节炎症反应的假设。我们还将定义CYP4F和2D18表达的变化，以及由P. Dash博士开发的TBI小鼠模型中的炎症和信号分子标记的变化。我们认为这些方法将可以更好地定义TBI后炎症级联的调节。