Remyelination by intranasal TIDM peptide

多发性硬化（MS）是人类最常见的中枢神经系统脱髓鞘疾病 （CNS）。虽然MS的病因尚不清楚，但它与自身免疫有关。目前，约40万 美国人患有多发性硬化症，在白种人中更为普遍，尤其是那些北方人 欧洲血统，比其他人。一些证据也表明MS的发病率与 战斗服务。例如，Annals of Neurology（2004，55：65-71）中的一项研究已经确定了5，345个 美国退伍军人中被认为是“与服役有关”的MS病例。“虽然该机制不是 病毒感染、多次接种疫苗和/或接触不同的战区化学品可能会增加 因此，一些曾在海湾战争中服役的老兵以及许多越战老兵都有 虽然有一些针对MS的治疗方法，但没有有效的治疗方法可用于 促进MS的髓鞘再生。 因此，描绘促进髓鞘再生的新技术是一个重要的研究领域。 少突胶质细胞（OL）是CNS中的髓鞘产生细胞，并且Toll样受体2（TLR 2）是CNS中的一种神经递质。 先天免疫的重要成员。已经表明，TLR 2激活抑制细胞的成熟， 少突胶质祖细胞（OPCs）。由于没有特异性的TLR 2抑制剂，从结构上看， 分析TLR 2和MyD 88之间的相互作用，TLR 2的下游伴侣，我们设计了一个 对应于特异性阻断TLR 2的MyD 88（TIDM）的TLR 2相互作用结构域的新肽， 而不是其他TLR。因此，在这里，我们想测试一个翻译，但新的假设，wtTIDM 肽刺激OPCs成熟为OL（具体目的I），并且鼻内施用 wtTIDM肽通过小胶质细胞刺激脱髓鞘动物模型中的髓鞘再生（特异性目的II） 和/或OPC TLR 2（特异性目的III）。这一前沿提案的积极成果将描绘出， 通过wtTIDM肽靶向先天免疫系统的一种组分（TLR 2）的活化状态 增加OPCs的成熟，刺激髓鞘再生，突出了一个前瞻性的发现， 在MS和其它脱髓鞘病症中促进髓鞘再生的鼻内药剂。

Multiple sclerosis (MS) is the most common human demyelinating disorder of the central nervous system (CNS). Although the etiology of MS is unknown, it is connected to autoimmunity. At present, about 400,000 people in the United States have MS. It is more prevalent among Caucasians, particularly those of northern European ancestry, than others. Several evidences also show a potential link between the incidence of MS and combat service. For example, one study in the Annals of Neurology (2004, 55: 65-71) has identified 5,345 cases of MS among U.S. veterans that were considered "service-connected." Although the mechanism is not clear, viral infections, several vaccinations and/or exposure to different war zone chemicals may increase the risk of having MS. Accordingly, several veterans who served Gulf war 1 as well as many Vietnam veterans have been diagnosed with MS. Although there are some therapies against MS, no effective therapy is available to promote remyelination in MS. Therefore, delineation of new technologies for promoting remyelination is an important area of research. Oligodendrocytes (OLs) are the myelin-producing cells in the CNS and toll-like receptor 2 (TLR2) is an important member of innate immunity. It has been shown that TLR2 activation inhibits the maturation of oligodendroglial progenitor cells (OPCs). Since there was no specific inhibitor of TLR2, from structural analysis of the interaction between TLR2 and MyD88, the downstream partner of TLR2, we have designed a novel peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that specifically blocks TLR2, but not other TLRs. Therefore, here, we want to test a translational, but novel, hypothesis that wtTIDM peptide stimulates the maturation of OPCs to OLs (Specific aim I) and that intranasal administration of wtTIDM peptide stimulates remyelination in animal models of demyelination (Specific aim II) via microglial and/or OPC TLR2 (Specific aim III). A positive outcome of this cutting-edge proposal will delineate if selective targeting of activated status of one component (TLR2) of the innate immune system by wtTIDM peptide increases the maturation of OPCs and stimulates remyelination, highlighting the discovery of a prospective intranasal agent to promote remyelination in MS and other demyelinating disorders.