Function of LRP-1 in Multiple Sclerosis.

描述(申请人提供)：多发性硬化症(MS)是一种以中枢神经系统髓鞘降解为特征的慢性自身免疫性疾病。该病的病因尚不清楚，然而，少突胶质细胞的凋亡可能是一种起始事件。在去除凋亡细胞体和降解的髓鞘的调节上的缺陷可以刺激免疫反应，从而促进疾病的发展和/或进展。低密度脂蛋白受体相关蛋白-1(LRP1)是一种细胞受体，具有内吞作用和细胞信号转导功能。我们在体外已经证明LRP1是髓鞘的一个关键的内吞受体。此外，受到MS、EAE模型影响的小鼠的大脑和脊髓中LRP1水平增加。我们推测LRP1可能通过调节髓鞘降解和细胞凋亡而直接参与MS的调节。我们将通过体内和体外实验相结合的方式来检验这一假设。由于LRP1完全缺乏是致命的，LRP1在EAE模型中的作用将通过患有条件性LRP1缺陷的小鼠的髓系细胞来确定。利用这个模型，我们在初步实验中证明了LRP1缺乏会导致EAE症状的显著增加，这表明LRP1在髓系细胞中的功能抑制了疾病。LRP1缺陷的巨噬细胞和小胶质细胞的效应功能将被表征。最后，我们建议使用蛋白质组学的发现方法来鉴定髓鞘制剂中的LRP1配体。这项研究拨款提案应该为了解LRP1在MS中的功能以及为MS患者开发新的治疗方法提供基础。 公共卫生相关性：多发性硬化症(MS)是一种慢性疾病，其特征是免疫系统攻击髓鞘，这是正常大脑功能所必需的。这项建议的重点是一种细胞蛋白LRP1，我们表明它在清除降解的髓鞘方面很重要，并可能抑制疾病。我们的目标是确定LRP1在多发性硬化中发挥作用的机制，并有可能发现导致多发性硬化症患者新疗法开发的方法。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune disease characterized by degradation of the CNS myelin. Etiology of the disease is still unknown; however, oligodendrocyte apoptosis may represent an initiating event. Defects in the regulation of the removal of apoptotic cell bodies and degraded myelin can fuel the immune response and, thus, contribute to disease development and/or progression. Low density lipoprotein receptor-related protein-1 (LRP1) is a cellular receptor which functions in endocytosis and cell signaling. We have demonstrated that LRP1 is a key endocytic receptor for myelin in vitro. In addition, LRP1 levels are increased in the brains and spinal cords of mice subjected to a model of MS, EAE. We hypothesize that LRP1 could be directly involved in the regulation of MS by mediating degraded myelin and apoptotic cell removal. We will test this hypothesis by a combination of in vivo and in vitro experiments. As complete LRP1 deficiency is lethal, the role of LRP1 in the EAE model will be determined using mice with the conditional LRP1 deficiency in myeloid cells. Using this model, we demonstrate in preliminary experiments that LRP1 deficiency leads to a significant increase in EAE symptoms, suggesting that LRP1 function in myeloid cells inhibits disease. Effector functions of LRP1-deficient macrophages and microglia will be characterized. Finally, we propose to identify LRP1 ligands in myelin preparations, using a proteomics discovery approach. This research grant proposal should provide the basis for understanding the function of LRP1 in MS and for the potential development of novel therapeutics for MS patients. 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 cellular protein, LRP1, which we show is important in the clearance of degraded myelin and may inhibit disease. We aim to identify the mechanisms by which LRP1 functions in MS, with potential of discovering ways leading towards development of novel treatments for MS patients.