C1q-complement and hypoxic-ischemic injury in the developing brain.

描述（由申请人提供）：出生窒息是导致终身残疾的缺氧缺血性（HI）脑损伤的主要原因。为了理解HI脑损伤的机制，所提出的研究集中于补体介导的炎症途径，其与缺血后神经元损伤有关。C1 q是经典补体（C）通路的起始组分，似乎通过直接神经元损伤和间接通过炎症放大参与HI脑损伤。初步数据表明，C1 q-基因删除（-/-）新生小鼠是惊人的保护免受H1-侮辱，这意味着一个关键的作用，这两个初始触发的C激活和经典的C级联本身作为介质的缺血后脑损伤。与这些数据一致，与C1 q-/-小鼠相比，WT小鼠缺血性脑中C1 q、C3和C3-分裂产物以及C9的显著更大沉积与更大程度的脑损伤相关。在解剖这一途径的组成部分，我们进一步表明，神经保护是更强大的C1 q-/-比C3-/-小鼠，使我们假设，C1 q介导的神经元损伤不仅通过终端激活C，但也通过一个更近端的机制，独立于C3裂解的要求。该建议的两个具体目的是（1）确定在H1损伤后C1 q的神经元沉积是否导致膜攻击复合物（MAC）依赖性神经元损伤，和（2）确定在H1损伤后C1 q是否独立于末端C激活而加剧线粒体功能障碍和神经元死亡。对于这些实验，分子，遗传和药理学的方法将进行阐明Clq介导的H1-神经损伤的机制，并确定一种新的治疗围产期神经保护的目标。这些实验将建立原始免疫防御系统在HI引起的脑损伤中的损伤作用的机制，从而能够开发新的治疗靶点来保护大脑，从而最大限度地减少终身残疾。

DESCRIPTION (provided by applicant): Birth asphyxia is a major cause of hypoxic-ischemic (HI) cerebral injury leading to lifelong disability. In order to understand mechanisms of HI brain injury, the proposed research focuses on a complement- mediated inflammatory pathway which has been implicated in post-ischemic neuronal damage. C1q, the initial component of the classical complement (C) pathway, appears to participate in HI cerebral damage through direct neuronal injury and indirectly through inflammatory amplification. Preliminary data indicate that C1q-gene deleted (-/-) neonatal mice are strikingly protected against Hl-insult, which implies a critical role for both this initial trigger of C activation and for the classical C cascade itself as mediators of post-ischemic cerebral damage. In concordance with these data, significantly greater deposition of C1q, C3 and C3-split products, and C9 in ischemic brain was associated with greater extent of cerebral damage in WT-mice compared to C1q-/- counterparts. In dissecting constituents of this pathway, we have further shown that neuroprotection is more robust in C1q-/- than C3-/- mice, leading us to hypothesize that C1q mediates neuronal injury not only via terminal activation of C, but also by a more proximal mechanism independent of the requirement for C3-cleavage. The two Specific Aims of this proposal are (1) To determine whether neuronal deposition of C1q results in membrane attack complex (MAC)-dependent neuronal injury following Hl-insult, and (2) To determine whether C1q, independent of the terminal C activation, exacerbates mitochondrial dysfunction and neuronal death following Hl-insult. For these experiments, molecular, genetic, and pharmacologic approaches will be undertaken to elucidate Clq-mediated mechanisms of Hl-neurodamage and determine a novel therapeutic target for perinatal neuroprotection. These experiments will establish mechanisms for the injurious role of a primitive immune defense system in brain injury caused by HI, thereby enabling development of new therapeutic targets to protect the brain which could minimize lifelong disability.