Role of NADPH Oxidase in ICH-Induced Brain Injury

NADPH 氧化酶在 ICH 引起的脑损伤中的作用

• 批准号: 6958794
• 负责人: Jiping Tang
• 金额: $ 22.48万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6958794
• 关键词: NAD(P)H dehydrogenase; blood brain barrier; brain injury; enzyme activity; flow cytometry; genetically modified animals; immunocytochemistry; intracranial hematoma; laboratory mouse; neutrophil; oxidative stress; polymerase chain reaction; technology /technique development; western blottings

DESCRIPTION (provided by applicant): At present, there is no effective treatment for intracerebral hemorrhage (ICH), a common and often fatal stroke subtype. Early brain injury after ICH is known to involve brain edema, disruption of the blood-brain barrier (BBB) and neurological deficits. Many of these events are related to oxidative stress especially to NADPH oxidase, however, the effects of oxidative stress in ICH have not been investigated nor have strategies been developed to evaluate this superoxide-producing enzyme's promise as a therapeutic target. Our central hypothesis is that ICH elevates NADPH oxidase in the peri-hematoma area, which results in oxidative stress, leading to early brain injury (i.e., disruption of BBB, brain edema and neurological deficit). The source of the increased NADPH oxidase is circulating neutrophils and endogenous brain parenchyma. This hypothesis is derived from our preliminary observations that gp91phox subunit of NADPH oxidase in the ipsilateral hemisphere is upregulated at the transcriptional level after ICH, accompanied by enhanced lipid peroxidation, BBB disruption and brain edema. It is also supported by the recent studies of others who find that cerebral ischemia produces less brain injury in mice lacking functional NADPH oxidase in the central nervous system or in neutrophils. Our project goal is to explore the role and identify the source of elevated NADPH oxidase involved in ICH-induced brain injury. Specific Aim 1 will determine whether (a) ICH-induced brain injury is associated with upregulation in NADPH oxidase and increase in oxidative stress in brain and (b) deficiency or inhibition of NADPH oxidase reduces brain injury in response to ICH. Specific Aim 2 will establish whether the source of NADPH oxidase that contributes to ICH-induced brain injury is neuronal, blood-born (neutrophils), or both. Our long-term goal is to explore the importance and identify the source of elevated NADPH oxidase involved in ICH-induced brain injury for future evaluation as a potential therapeutic target.

描述（由申请人提供）：目前，脑出血（ICH）是一种常见且常常致命的中风亚型，尚无有效的治疗方法。众所周知，ICH 后的早期脑损伤涉及脑水肿、血脑屏障 (BBB) 破坏和神经功能缺损。其中许多事件与氧化应激尤其是 NADPH 氧化酶有关，然而，尚未研究氧化应激对 ICH 的影响，也尚未制定策略来评估这种产生超氧化物的酶作为治疗靶点的前景。我们的中心假设是，ICH 会升高血肿周围区域的 NADPH 氧化酶，从而导致氧化应激，从而导致早期脑损伤（即 BBB 破坏、脑水肿和神经功能缺损）。 NADPH氧化酶增加的来源是循环中性粒细胞和内源性脑实质。这一假设来源于我们的初步观察，即ICH后同侧半球NADPH氧化酶的gp91phox亚基在转录水平上调，并伴有脂质过氧化增强、血脑屏障破坏和脑水肿。其他人最近的研究也支持了这一观点，这些研究发现，在中枢神经系统或中性粒细胞中缺乏功能性 NADPH 氧化酶的小鼠中，脑缺血产生的脑损伤较少。我们的项目目标是探索 NADPH 氧化酶升高在 ICH 引起的脑损伤中的作用并确定其来源。具体目标 1 将确定 (a) ICH 诱导的脑损伤是否与 NADPH 氧化酶的上调和脑中氧化应激的增加有关，以及 (b) NADPH 氧化酶的缺乏或抑制会减少 ICH 引起的脑损伤。具体目标 2 将确定导致 ICH 诱发脑损伤的 NADPH 氧化酶来源是神经元、血源性（中性粒细胞）还是两者。我们的长期目标是探索 NADPH 氧化酶升高在 ICH 引起的脑损伤中的重要性并确定其来源，以便未来将其作为潜在的治疗靶点进行评估。