Function of LRP-1 in Multiple Sclerosis.

描述（由申请人提供）：多发性硬化症（MS）是一种以中枢神经系统髓磷脂降解为特征的慢性自身免疫性疾病。该病的病因尚不清楚；遗传和环境因素都有牵连。少突胶质细胞凋亡可能是MS的一个起始事件，凋亡细胞体的不适当清除和髓磷脂的释放促进了免疫反应。低密度脂蛋白受体相关蛋白-1 （LRP-1）是一种细胞受体，在细胞内吞作用和细胞信号传导中起重要作用。我们已经证明LRP-1是体外髓磷脂的关键内吞受体。LRP-1也通过控制NF -1抑制炎症反应。B通路。因此，我们假设LRP-1可能直接参与ms的发生和/或进展的调节。我们将通过体内和体外实验的结合来验证这一假设。由于LRP-1完全缺乏是致命的，LRP-1在小鼠EAE模型中的作用将通过使用骨髓谱系中条件性LRP-1缺乏的小鼠来确定。我们的初步结果表明，该模型中LRP-1缺失导致EAE症状显著增加。LRP-1缺陷巨噬细胞的效应功能将被表征。最后，我们建议使用蛋白质组学发现方法鉴定髓磷脂制剂中的LRP-1配体。这项研究申请将为理解LRP-1在多发性硬化症中的功能和开发多发性硬化症的新疗法提供基础。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the degradation of CNS myelin. The etiology of the disease is still unknown; both genetic and environmental factors have been implicated. Oligodendrocyte apoptosis may represent an initiating event in MS, with improper removal of apoptotic cell bodies and released myelin fueling the immune response. Low density lipoprotein receptor-related protein-1 (LRP-1) is a cellular receptor, which functions in endocytosis and cell signaling. We have demonstrated that LRP-1 is a key endocytic receptor for myelin in vitro. LRP-1 also inhibits the inflammatory response by controlling the NF?B pathway. We, therefore, hypothesize that LRP-1 could be directly involved in regulation of the development and/or progression of MS. We will test this hypothesis by a combination of in vivo and in vitro experiments. As complete LRP-1 deficiency is lethal, the role of LRP-1 in a mouse EAE model will be determined using mice with conditional LRP-1 deficiency in the myeloid lineage. Our preliminary results suggest that LRP-1 deficiency in this model leads to a significant increase in EAE symptoms. Effector functions of LRP-1- deficient macrophages will be characterized. Finally, we propose to identify LRP-1 ligands in myelin preparations, using a proteomics discovery approach. This research grant proposal should provide the basis for understanding the function of LRP-1 in MS and for potential development of novel therapeutics for MS. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS) is a chronic disease characterized by the immune system attack on myelin sheath, which is necessary for proper brain function. This proposal is focused on a cell protein, LRP- 1, which we show is important in the clearance of degraded myelin, and controls of the immune response. We hypothesize that LRP-1 regulates the sequence of events leading to MS development. We aim to identify the mechanisms by which LRP-1 functions in MS, with potential of discovering ways leading towards development of novel treatments for MS patients.