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

描述(申请人提供)：出生窒息是导致终生残疾的缺氧缺血性脑损伤的主要原因。为了了解缺氧缺血性脑损伤的机制，本研究将重点放在补体介导的炎症通路上，该通路与缺血后神经元损伤有关。补体C1q是经典补体(C)途径的起始成分，可能通过直接的神经元损伤和间接的炎症放大参与脑缺血损伤。初步数据表明，C1q基因缺失(-/-)的新生小鼠对hl-INSULT具有显著的保护作用，这意味着作为缺血后脑损伤的介体，这一C激活的初始触发因素和经典C级联反应本身都发挥了关键作用。与这些数据一致的是，与C1q-/-小鼠相比，WT-小鼠缺血脑中C1q、C3和C3分裂产物以及C9的沉积显著增加，与脑损伤程度更大相关。在对这一途径的成分的剖析中，我们进一步表明，C1q-/-小鼠的神经保护比C3-/-小鼠更强大，这使我们假设C1q不仅通过C的末端激活，而且通过一种与C3-切割要求无关的更近端的机制来介导神经元损伤。该方案的两个具体目的是：(1)确定C1q的神经元沉积是否导致损伤后依赖于膜攻击复合体(MAC)的神经元损伤；(2)确定C1q是否独立于C末端的激活，加重损伤后线粒体功能障碍和神经元死亡。对于这些实验，将采用分子、遗传和药理学方法来阐明Clq介导的hl神经损伤的机制，并确定围产期神经保护的新治疗靶点。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机制，从而能够开发新的治疗靶点来保护大脑，从而将终身残疾降至最低。

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.