A 6BETA 1 INTEGRIN-MEDIATED SURVIVAL OF OLIGODENDROCYTES

说明(申请人的摘要逐字复制)：建议 一项研究项目旨在阐明α6，β1整合素的作用 使用转基因方法调节少突胶质细胞的存活。 广泛的细胞程序性死亡(PCD)是卵巢癌发育的必要部分。 中枢神经系统(CNS)。了解调节这一过程的机制 过程对于我们对正常发育和疾病的理解至关重要 涉及中枢神经系统中不适当的细胞死亡的过程，如多个 硬化症、阿尔茨海默氏症和帕金森氏症。PCD的一个重要功能是 调节分化的神经细胞和神经胶质细胞的最终数量 中枢神经系统。因此，一个既涉及积极监管又涉及消极监管的广泛系统 已经发展成确保适当数量的少突胶质细胞是 目前是为了促进髓鞘形成和促进生存和功能 相关神经元。近年来，许多增长因素被证明是 促进少突胶质细胞的存活和分化，但它 越来越清楚的是，这些代理人与其他机制协同行动。 已经显示与轴突接触，但不是轴突释放的可溶性因子。 以防止少突胶质细胞进入默认死亡途径。近期工作 在费伦奇恒定实验室中的研究表明，通过专门阻止 少突胶质细胞表面受体α6、β1的相互作用 整合素，这个生存信号的执行被阻止和培养 少突胶质细胞死亡。此外，α6、β1的相互作用被显示为 显著降低正常情况下诱导生存所需的PDGF水平， 表明接触调节和生长因子调节之间的协同作用 生存线索。这些数据表明了一种假设，在这种假设中， 轴突配体和α6、β1整合素对少突胶质细胞很重要 生死存亡。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说，并进一步表征这一点 利用少突胶质细胞-神经元双重培养系统进行相互作用。

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.