Role of NADPH Oxidase in ICH-Induced Brain Injury

描述（由申请人提供）：目前，脑出血（ICH）是一种常见且往往致命的卒中亚型，尚无有效的治疗方法。已知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。这些事件中的许多与氧化应激有关，特别是与NADPH氧化酶有关，然而，氧化应激在ICH中的作用尚未被研究，也没有开发策略来评估这种超氧化物产生酶作为治疗靶点的前景。我们的中心假设是ICH升高血肿周围区域的NADPH氧化酶，这导致氧化应激，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。这一假设来自于我们的初步观察，即脑出血后同侧半球NADPH氧化酶的gp91phox亚基在转录水平上上调，伴随着脂质过氧化作用增强，BBB破坏和脑水肿。这也得到了其他人最近研究的支持，他们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，脑缺血产生较少的脑损伤。我们的项目目标是探索NADPH氧化酶升高在ICH诱导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相关，以及（B）NADPH氧化酶的缺乏或抑制是否减少脑损伤对ICH的响应。具体目标2将确定促成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ICH诱导的脑损伤中NADPH氧化酶升高的重要性，并确定其来源，以作为未来评估的潜在治疗靶点。

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.