Role of Kruppel-like factor 6 in Oligodendrocyte Differentiation

 描述（由申请人提供）：多发性硬化症（MS）是一种CNS白色物质的自身免疫性脱髓鞘疾病，导致传导阻滞和最终轴突横断。损伤后的再髓鞘化自发发生，并导致修复和功能恢复，但效率低下，特别是在疾病的后期。虽然已经开发了靶向MS的免疫组分的治疗，但在产生增强轴突髓鞘再生的疗法方面进展较少。因此，MS研究的一个关键目标是设计和翻译促进髓鞘再生的临床疗法。少突胶质细胞祖细胞（Oligodendrocyte progenitors，OLP）是中枢神经系统中髓鞘形成和髓鞘再生细胞的主要储存库。它们分化成髓鞘少突胶质细胞（OL）是MS损伤修复的限速步骤。因此，了解OL分化和成熟途径对于开发脱髓鞘疾病的新治疗方法至关重要。OLP分化是通过一个逐步的内在转录程序发生的，该程序可以由前髓鞘形成的外在因素调节;然而，该程序的复杂动力学尚未完全表征。了解调节内在分化程序的机制可能会发现新的策略来增强修复。重要的是，我们的实验室最近确定了转录激活因子，Krüppel样因子6（Klf 6），作为CNS髓鞘形成的重要协调。值得注意的是，Klf 6过表达加速成熟，而Klf 6在体外或体内缺失破坏分化中的重要步骤，导致CNS髓鞘形成的严重失败。Klf 6的作用仅限于分化程序-增殖或成熟细胞中的失活不产生病理学。我们的数据进一步提出Klf 6在成人中的重要作用，关键是在髓鞘再生中。Klf 6是强烈诱导髓鞘再生病变和与髓鞘再生相关的MS的外部前髓鞘形成因子。为了了解其在促进OL分化的作用机制，我们进行了全基因组分析的染色质占用Klf 6和它的转录谱。这已经确定了一个新的和预期的Klf 6调控基因的程序。令人兴奋的是，这些基因中有许多是同源异型盒基因，是全身细胞类型分化的重要调节因子。这表明Klf 6激活了一套新的机制来促进分化和髓鞘形成。该提案旨在确定Klf 6如何促进髓鞘形成，以及类似的机制是否对髓鞘再生也很重要。我将测试中心假设，Klf 6调节的 通过同源异型盒因子内在分化程序对于CNS髓鞘形成和髓鞘再生是必不可少的。在目标1中，我将定义Klf 6的关键下游靶点，在目标2中，我将确定Klf 6及其下游效应物在髓鞘再生中的作用。这 这项工作将确定一种新的髓鞘形成机制，这也可能是至关重要的修复。

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an autoimmune demyelinating disease of the CNS white matter resulting in conduction block and eventual axonal transection. Remyelination after injury occurs spontaneously and results in repair and functional recovery but is inefficient, particularly in the later stages of the disease. While treatments targeting the immunological component of MS have been developed, there has been less progress in the generation of therapies to enhance remyelination of axons. Thus, a key goal in MS research is the design and translation to the clinic of therapies that promote remyelination. Oligodendrocyte progenitors (OLP) are the main reservoir of myelinating and remyelinating cells in the CNS. Their differentiation into myelinating oligodendrocytes (OL) is a rate-limiting step in lesion repair in MS. Thus, understanding the OL differentiation and maturation pathway is vital to developing new treatments for demyelinating disorders. OLP differentiation occurs via a step-wise intrinsic transcriptional program, which can be modulated by pro-myelinating extrinsic factors; however the complex dynamics of this program are not fully characterized. Understanding the mechanisms that regulate the intrinsic program of differentiation may identify new strategies to enhance repair. Importantly, our lab recently identified the transcriptional activator, Krüppel-like factor 6 (Klf6), as an essential coordinato of CNS myelination. Notably, Klf6 over-expression accelerates maturation, while Klf6 deletion in vitro or in vivo disrupts important steps in differentiation, leading to profound failure of CNS myelination. Effects of Klf6 are restricted to the differentiation program - inactivation in proliferating or mature cells produces no pathology. Our data further propose an important role for Klf6 in adults, critically, in remyelination. Klf6 is strongly induced in remyelinating lesionsand by extrinsic pro-myelinating factors associated with remyelination in MS. To understand its mechanism of action in promoting OL differentiation, we have conducted genome-wide analysis of chromatin occupancy of Klf6 and its transcriptional profile. This has identified a program of novel and anticipated Klf6- regulated genes. Excitingly, many of these are homeobox genes, important regulators of differentiation in cell types throughout the body. This suggests that Klf6 activates a novel set of machinery to promote differentiation and myelin formation. This proposal aims to determine how Klf6 works to promote myelination and if similar mechanisms are important for remyelination as well. I will test the central hypothesis that Klf6 modulation of the intrinsic differentiation program via homeobox factors is essential for CNS myelination and remyelination in two Specific Aims. In Aim 1, I will define the critical downstream targets of Klf6 and in Aim 2, I will determine the role of Klf6 and its downstream effectors in remyelination. This work will define a novel mechanism for myelin formation, and which may also be vital for its repair.