A 6BETA 1 INTEGRIN-MEDIATED SURVIVAL OF OLIGODENDROCYTES

描述（申请人的摘要逐字复制）： 研究项目旨在阐明α 6，β 1整合素的作用 使用转基因方法介导少突胶质细胞的生存。 广泛的程序性细胞死亡（PCD）是发育的必要组成部分， 中枢神经系统（CNS）。了解调控这一过程的机制 这一过程对于我们理解正常发育和疾病至关重要 涉及CNS中不适当的细胞死亡的过程，如多个 硬化症老年痴呆症和帕金森症PCD的一个重要功能是 调节分化的神经元和神经胶质细胞的最终数量， CNS。因此，一个涉及积极和消极监管的广泛系统 已经发展到确保适当数量的少突胶质细胞 存在，以形成髓鞘，并促进生存和功能， 相关神经元近年来，许多增长因素已被证明， 促进少突胶质细胞的存活和分化，但 越来越清楚的是，这些代理人与其他机制一致行动。 与轴突接触，但不是由轴突释放的可溶性因子，已被证明 以防止少突胶质细胞进入默认的死亡途径。最近的工作 在弗伦奇-康斯坦实验室的研究表明，通过特异性阻断 少突胶质细胞表面受体α 6，β 1 整合素，阻止和培养这种生存信号的执行 少突胶质细胞死亡。此外，alpha 6，beta1的相互作用被证明， 显著降低诱导存活通常所需的PDGF水平， 表明接触介导的和生长因子介导的 生存线索这些数据提出了一个假设， 轴突配体和α 6，β 1整合素对少突胶质细胞 生存在下面的研究计划中，我概述了旨在 直接在体内测试这一假设，以及进一步表征这一点， 使用少突胶质细胞-神经元双培养系统的相互作用。

DESCRIPTION (Applicant's abstract reproduced verbatim): The following proposed research project is designed to elucidate the role of the alpha6,beta1 integrin in mediating survival of oligodendrocytes using a transgenic approach. Extensive programmed cell death (PCD) is a necessary part of development in the central nervous system (CNS). Understanding the mechanisms that regulate this process is critical for our understanding of normal development and of disease processes involving inappropriate cell death in the CNS, such as multiple sclerosis, Alzheimer's, and Parkinson's. An important function of PCD is to regulate the final number of differentiated neuronal and glial cells in the CNS. Thus, an extensive system involving both positive and negative regulation has developed to ensure that the appropriate numbers of oligodendrocytes are present in order to myelinate and to promote the survival and function of associated neurons. In recent years, many growth factors have been shown to promote survival and differentiation of oligodendrocytes, but it is increasingly clear that these agents act in concert with other mechanisms. Contact with axons, but not soluble factors released by axons, has been shown to prevent oligodendrocytes from entering a default death pathway. Recent work in the ffrench-Constant laboratory has shown that by specifically blocking the interactions of an oligodendrocyte cell surface receptor, the alpha6,beta1 integrin, execution of this survival signal is prevented and cultured oligodendrocytes die. In addition, alpha6,beta1 interactions were shown to dramatically decrease the level of PDGF normally required to induce survival, indicating a synergy between contact-mediated and growth factor-mediated survival cues. These data suggested a hypothesis in which contact between axonal ligands and the alpha6,beta1 integrins is important for oligodendrocyte survival. In the following research plan I outline experiments designed to directly test this hypothesis in vivo, as well as further characterize this interaction using an oligodendrocyte-neuron double culture system.