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The influence of tissue-specific heme oxygenase-1 (HO-1) deficiency on neuronal damage induced by subarachnoid hemorrhage in mice: the role of carbon monoxide (CO)

组织特异性血红素加氧酶-1 (HO-1) 缺乏对小鼠蛛网膜下腔出血引起的神经元损伤的影响：一氧化碳 (CO) 的作用

基本信息

批准号：
235925627
负责人：
Professor Dr. Nils Schallner
金额：
--
依托单位：
Center for Life Sciences (aufgelöst)
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/235925627?language=en
关键词：
influence tissue specific heme oxygenase

项目摘要

Endogenous production of carbon monoxide (CO) by heme oxygenase 1 (HO-1) represents an essential cellular protection mechanism. The importance of endogenous CO production is underlined by the facts that 1. deficiency of HO-1 in humans leads to a severe disease state with premature death, 2. classical genetic knockout of HO-1 in animals results in markedly reduced life span, 3. overexpression or induction of HO-1 and exogenous application of CO exerts protective effects in various disease models. Our lab has recently shown that exogenous application of CO, either inhalative or via systemic routes by a CO releasing molecule (CO-RM) exerts neuroprotective effects. Two important aspects remain unclear: 1. What is the distinct role of cell-specific HO-1 expression? 2. Does exogenous CO application equal endogenously generated CO by HO-1 induction regarding its protective effects? To answer these questions, we will use a well established model of cerebral injury (subarachnoid hemorrhage, SAH), in which HO-1 is upregulated and has been shown to be protective. With HO-1 knockout mice either with global HO-1 deficiency or conditional tissue-specific HO-1 deficiency in either endothelial, neuronal or microglial cells, we want to characterize the distinct protective role exerted by HO-1 expression in these cells. We therefore will study the following hypotheses: 1. HO-1 expression ameliorates neuronal injury after SAH. Specific aim 1: To evaluate the effect of global HO-1 deficiency on neuronal cell injury following SAH. 2. Endothelial-specific HO-1 is protective in SAH-induced cerebral vasospasm and endothelial dysfunction in mice. Specific aim 2: To evaluate the contribution of endothelial HO-1 deficiency to neuronal cell death following SAH. 3. Neuron-specific HO-1 prevents cell death following SAH in mice. Specific aim 3: To evaluate the effect of tissue-specific neuronal HO-1 knockout on neuronal cell death following SAH. 4. Microglia-specific HO-1 modulates heme removal and the SAH-induced neuroinflammatory response. Specific aim 4: To evaluate the contribution of microglia-specific HO-1 knockout to neuronal cell death following SAH. 5. CO can compensate for the deficiency of endogenous CO production in the above-described global and tissue-specific HO-1 knockout mice. Specific aim 5: To investigate the potentially protective effect of exogenous application of CO, either inhaled as gas or through the CO releasing molecule (CO-RM) ALF186 on neuronal damage after SAH in HO-1 deficient mice.

血红素加氧酶1（HO-1）内源性产生一氧化碳（CO）是一种重要的细胞保护机制。内源性CO生产的重要性是强调的事实，1。人中HO-1的缺乏导致具有过早死亡的严重疾病状态，2.在动物中经典的HO-1基因敲除导致寿命显著缩短，3. HO-1的过表达或诱导以及外源性应用CO在各种疾病模型中发挥保护作用。我们的实验室最近表明，外源性应用的CO，无论是吸入或通过全身途径的CO释放分子（CO-RM）发挥神经保护作用。有两个重要的方面仍然不清楚：1。细胞特异性HO-1表达的独特作用是什么？2.外源性一氧化碳的应用是否等同于内源性一氧化碳的HO-1诱导其保护作用？为了回答这些问题，我们将使用一个完善的脑损伤模型（蛛网膜下腔出血，SAH），其中HO-1上调，并已被证明是保护性的。对于HO-1基因敲除小鼠，无论是在内皮细胞、神经元细胞还是小胶质细胞中，HO-1基因敲除小鼠都具有整体HO-1缺陷或条件性组织特异性HO-1缺陷，我们希望表征HO-1表达在这些细胞中所发挥的独特保护作用。因此，我们将研究以下假设：1。HO-1表达改善SAH后神经元损伤。具体目标1：评估全身HO-1缺乏对SAH后神经细胞损伤的影响。2.内皮特异性HO-1对小鼠SAH诱导的脑血管痉挛和内皮功能障碍具有保护作用具体目标2：评估内皮HO-1缺陷对SAH后神经元细胞死亡的影响。3.神经元特异性HO-1可防止小鼠SAH后细胞死亡具体目标3：评估组织特异性神经元HO-1敲除对SAH后神经元细胞死亡的影响。4.小胶质细胞特异性HO-1调节血红素清除和SAH诱导的神经炎症反应具体目标4：评估小胶质细胞特异性HO-1敲除对SAH后神经元细胞死亡的贡献。5. CO可以补偿上述整体和组织特异性HO-1敲除小鼠中内源性CO产生的不足。具体目标5：研究外源性CO（以气体形式吸入或通过CO释放分子（CO-RM）ALF 186吸入）对HO-1缺陷小鼠SAH后神经元损伤的潜在保护作用。