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）尚无有效的治疗方法，这是一种常见且通常是致命的中风亚型。 ICH后的早期脑损伤已知涉及大脑水肿，血脑屏障（BBB）的破坏和神经系统缺陷。这些事件中的许多事件与氧化应激有关，尤其是与NADPH氧化酶有关的，但是，尚未研究ICH中氧化应激的影响，也没有开发出评估这种产生超氧化物的酶作为治疗靶标的诺言的策略。我们的中心假设是，ICH升高了血肿区域的NADPH氧化酶，这会导致氧化应激，导致早期脑损伤（即BBB的破坏，脑水肿和神经系统缺陷）。 NADPH氧化酶增加的来源是循环中性粒细胞和内源性脑实质。该假设来自我们的初步观察结果，即同侧半球中NADPH氧化酶的GP91Phox亚基在ICH之后的转录水平上被上调，并伴随着脂质过氧化，BBB的脂质过氧化，BBB损害和脑湿瘤的增强。最近的研究还支持了其他研究，这些研究发现脑缺血在中枢神经系统或中性粒细胞中缺乏功能性NADPH氧化酶的小鼠中会降低脑损伤。我们的项目目标是探索角色并确定与ICH诱导的脑损伤有关的NADPH氧化酶升高的来源。具体目标1将确定（a）ICH诱导的脑损伤是否与NADPH氧化酶的上调以及脑中氧化应激的上调以及（b）氧化氧化酶的缺乏或抑制会减少对ICH的响应。具体目标2将确定有助于ICH诱导的脑损伤的NADPH氧化酶的来源是神经元，血源性（中性粒细胞）还是两者兼而有之。我们的长期目标是探索重要性并确定与ICH诱导的脑损伤有关的NADPH氧化酶升高的来源，以作为未来评估作为潜在的治疗靶点。