Bilirubin oxidation and intracerebral hemorrhage

胆红素氧化与脑出血

基本信息

批准号：
7092514
负责人：
JOSEPH Floyd CLARK
金额：
$ 34.66万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-15 至 2010-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a type of stroke caused by bleeding into the brain, which leads to significant death and disability. Secondary and delayed pathophysiologic events can contribute to the death and disability of the ICH patient. These events are characterized by a breakdown of the blood brain barrier, edema development and cell death in white and gray matter. We have recently discovered that following hemorrhage in the brain, a new molecular species, bilirubin oxidation species (BOXes), are produced within the hematoma during the first 24 hours following ICH. Importantly, the concentration of BOXes in the hematoma is the highest (approximately 20 \iM) that we have observed in any of our experimental and clinical evaluations thus far. This finding is especially significant since we have previously demonstrated that BOXes are cytotoxic and our preliminary data indicates that they can contribute to the pathophysiological events leading to brain injury following ICH. Our overall goal in this research project is to test the Hypothesis that BOXes are acutely generated within the hematoma and contribute to edema formation and perihematomal brain injury following ICH. To address this hypothesis we will use our porcine ICH model. In Aim #1 we will measure the concentration of BOXes in the hematoma and perihematomal brain tissue to define the time course of production. In Aim #2 we will add BOXes to the infused blood to produce the hematoma and assess the damage and examine the underlying pathogenesis observed following experimental ICH. In Aim #3 we will investigate the mechanism(s) for BOXes production by examining 2 biochemical pathways required to generate BOXes: bilirubin generation and oxidative stress. It is anticipated the inhibition of bilirubin production and/or antioxidants will decrease BOXes production in the hematoma. These studies are important because we believe that strategies designed to prevent BOXes production in the hematoma should provide a novel and beneficial therapeutic option for patients who have suffered an ICH.

描述（由申请人提供）：脑出血（ICH）是一种由脑部出血引起的中风，可导致严重死亡和残疾。继发性和迟发性病理生理事件可能导致 ICH 患者的死亡和残疾。这些事件的特征是血脑屏障崩溃、白质和灰质中出现水肿和细胞死亡。我们最近发现，脑出血后，在 ICH 后的最初 24 小时内，血肿内会产生一种新的分子物质，即胆红素氧化物质 (BOX)。重要的是，血肿中 BOX 的浓度是迄今为止我们在任何实验和临床评估中观察到的最高浓度（约 20 μM）。这一发现尤其重要，因为我们之前已经证明 BOX 具有细胞毒性，并且我们的初步数据表明它们可能导致 ICH 后导致脑损伤的病理生理事件。我们在这个研究项目中的总体目标是检验以下假设：BOX 在血肿内急剧生成，并导致 ICH 后水肿形成和血肿周围脑损伤。为了解决这个假设，我们将使用我们的猪 ICH 模型。在目标 1 中，我们将测量血肿和血肿周围脑组织中 BOX 的浓度，以确定产生的时间过程。在目标 #2 中，我们将在输注的血液中添加 BOX，以产生血肿并评估损伤并检查实验性 ICH 后观察到的潜在发病机制。在目标 #3 中，我们将通过检查生成 BOX 所需的 2 种生化途径来研究 BOX 生成的机制：胆红素生成和氧化应激。预计胆红素产生和/或抗氧化剂的抑制将减少血肿中BOX的产生。这些研究很重要，因为我们相信旨在防止血肿中 BOX 产生的策略应该为 ICH 患者提供一种新颖且有益的治疗选择。