A 6BETA 1 INTEGRIN-MEDIATED SURVIVAL OF OLIGODENDROCYTES

描述(申请人摘要逐字复制)：以下拟议的研究项目旨在通过转基因方法阐明α6，β1整合素在调节少突胶质细胞存活中的作用。广泛的细胞程序性死亡(PCD)是中枢神经系统(CNS)发育过程中必不可少的一部分。了解这一过程的调控机制对于我们理解中枢神经系统的正常发育和涉及不适当的细胞死亡的疾病过程是至关重要的，如多发性硬化症、阿尔茨海默氏症和帕金森病。PCD的一个重要功能是调节中枢神经系统中分化的神经元和神经胶质细胞的最终数量。因此，一个广泛的系统，包括积极和消极的调节，以确保存在适当数量的少突胶质细胞，以便髓鞘和促进相关神经元的生存和功能。近年来，许多生长因子被证明可以促进少突胶质细胞的存活和分化，但越来越清楚的是，这些因子与其他机制协同作用。与轴突接触，而不是轴突释放的可溶性因子，已被证明可以防止少突胶质细胞进入默认的死亡途径。最近在费伦奇恒定实验室的工作表明，通过特异性地阻断少突胶质细胞表面受体-α6，β1整合素的相互作用，这种生存信号的执行被阻止，培养的少突胶质细胞死亡。此外，α6和β1的相互作用被证明显著降低了通常诱导生存所需的PDGF水平，这表明接触介导的生存信号和生长因子介导的生存信号之间存在协同作用。这些数据表明，轴突配体与α6、β1整合素之间的接触对少突胶质细胞的生存很重要。在接下来的研究计划中，我概述了旨在直接在体内测试这一假说的实验，以及使用少突胶质细胞-神经元双重培养系统进一步表征这种相互作用。

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.