Autoimmune encephalomyelitis and Bcl-2- interacting mediator

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是人类多发性硬化症（MS）的动物模型。虽然引发疾病的病因学因素各不相同，但MS和EAE的最终病理结果是由炎性细胞破坏产生髓鞘的少突胶质细胞及其相关的神经元轴突。虽然死亡的少突胶质细胞和炎性细胞的形态学特征被充分记录，但MS和EAE中细胞死亡的细胞和分子机制尚不清楚。 包括我们在内的几个实验室最近的研究表明，细胞凋亡或程序性细胞死亡在疾病的发病机制中起着重要作用。因此，介导细胞凋亡的基因缺陷的小鼠对EAE具有抗性，并且细胞凋亡的选择性操作对于治疗该疾病是有效的。细胞凋亡可以通过至少两种不同的途径介导：线粒体！由B细胞白血病（Bcl）-2家族成员控制的死亡受体途径和由肿瘤坏死因子家族成员启动的死亡受体途径。我们最近发现，Bim（Bcl-2相互作用介质），细胞凋亡的线粒体途径的关键启动子，在EAE中起着至关重要的作用，这一建议的灵感。Bim缺陷的小鼠对髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE具有抗性，并且在其抗MOG T细胞应答中具有选择性缺陷。本研究的目的是阐明Bim在自身免疫性脑脊髓炎中作用的细胞和分子机制。我们假设Bim通过涉及Bax的机制介导EAE中淋巴细胞和骨髓细胞以及少突胶质细胞的死亡，并且线粒体凋亡途径（Bim途径）的Bim-Bax轴在EAE中起双重作用（即，它可以促进和抑制疾病，这取决于它的作用靶点）。这些理论将在多发性硬化症的动物模型中在分子、细胞和组织水平上进行测试，具体目标如下。 具体目的1：验证免疫系统和神经系统表达的Bim和Bax在EAE中发挥不同作用的假设。 具体目的2：检验Bim和Bax决定EAE中髓鞘特异性T细胞命运的假设。 具体目标3：检验Bim通过Bax介导少突胶质细胞死亡的假设。 从这些研究中产生的信息不仅有助于我们进一步了解多发性硬化模型中Bim和Bax作用的机制，而且有助于开发基于多发性硬化的疾病治疗策略。

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is an animal model for human multiple sclerosis (MS). Although the etiological factors that trigger the disease vary, the final pathological outcome of MS and EAE is the destruction of myelin-producing oligodendrocytes and their associated neuronal axons by inflammatory cells. While the morphological characteristics of dying oligodendrocytes and inflammatory cells are well documented, the cellular and molecular mechanisms of cell death in MS and EAE are not clear. Recent studies from several laboratories including ours indicate that apoptosis, or programmed cell death, plays an essential role in the pathogenesis of the disease. Thus, mice deficient in genes that mediate apoptosis are resistant to EAE, and selective manipulation of apoptosis is effective for the treatment of the disease. Apoptosis can be mediated by at least two distinct pathways: the mitochondria! pathway, which is controlled by members of the B cell leukemia (Bcl)-2 family and the death receptor pathway, which is initiated by the members of the tumor necrosis factor family. This proposal is inspired by our recent discovery that Bim (Bcl-2-interacting mediator), a key initiator of the mitochondrial pathway of apoptosis, plays essential roles in EAE. Mice deficient in Bim are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG), and have a selective defect in their anti-MOG T cell responses. The goal of this proposal is to elucidate the cellular and molecular mechanisms of Bim action in autoimmune encephalomyelitis. We hypothesize that Bim mediates the death of lymphoid and myeloid cells as well as oligodendrocytes in EAE through a mechanism that involves Bax, and that the Bim-Bax axis of the mitochondrial pathway of apoptosis (the Bim pathway) plays a dual role in EAE (i.e., it can both promote and inhibit the disease depending on its target of actions). These theories will be tested in animal models of multiple sclerosis at molecular, cellular and organismal levels under the following specific aims. Specific Aim 1: To test the hypothesis that Bim and Bax expressed by the immune system and the nervous system play different roles in EAE. Specific Aim 2: To test the hypothesis that Bim and Bax dictate the fates of myelin-specific T cells in EAE. Specific Aim 3: To test the hypothesis that Bim mediates the death of oligodendrocytes through Bax. Information generated from these studies will not only help advance our understanding of the mechanisms of Bim and Bax actions in models of multiple sclerosis but also aid in the development of apoptosis-based strategies for the treatment of the disease.