Role of NADPH Oxidase in ICH-Induced Brain Injury

描述(由申请人提供)：目前，脑出血(ICH)还没有有效的治疗方法，ICH是一种常见的、往往是致命的中风亚型。众所周知，脑出血后的早期脑损伤包括脑水肿、血脑屏障(BBB)破坏和神经功能障碍。其中许多事件与氧化应激有关，特别是与NADPH氧化酶有关，然而，氧化应激在脑出血中的作用尚未被研究，也没有制定策略来评估这种产生超氧化物歧化酶作为治疗靶点的前景。我们的中心假设是，脑出血使血肿周围区域的NADPH氧化酶升高，从而导致氧化应激，导致早期脑损伤(即血脑屏障破坏、脑水肿和神经功能障碍)。NADPH氧化酶升高的来源是循环中的中性粒细胞和内源性脑实质。这一假说源于我们的初步观察，即脑出血后同侧大脑半球NADPH氧化酶gp91Phox亚单位在转录水平上上调，伴随着脂质过氧化、血脑屏障破坏和脑水肿。这也得到了最近其他研究的支持，这些研究发现，在中枢神经系统或中性粒细胞缺乏功能性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氧化酶升高在脑出血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)脑出血引起的脑损伤是否与脑内NADPH氧化酶表达上调和脑内氧化应激增加有关，以及(B)脑出血后NADPH氧化酶缺乏或抑制是否会减少脑损伤。具体目标2将确定导致脑出血诱导的脑损伤的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NADPH氧化酶升高在脑出血诱导的脑损伤中的重要性并确定其来源，以便将来作为潜在的治疗靶点进行评估。

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.