Kruppel-like factor-6 signaling in myelin formation and repair

髓磷脂形成和修复中的 Kruppel 样因子 6 信号传导

• 批准号: 9293399
• 负责人: GARETH R JOHN
• 金额: $ 37.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293399
• 关键词: Adult; Axon; Binding; Blindness; Cell Differentiation process; Cells; Chromatin; Complex; Data; Demyelinations; Disease; Epigenetic Process; Failure; Genes; Genetic Transcription; Goals; In Vitro; Knowledge; Label; Lesion; Link; Morphology; Multiple Sclerosis; Mus; Myelin; Paralysed; Pathology; Pathway interactions; Patients; Pattern; Proliferating; RXR; Recovery of Function; Recruitment Activity; Research; Role; Signal Transduction; Symptoms; Testing; Time; Transactivation; Transcription Coactivator; Work; design; genome-wide analysis; histone acetyltransferase; in vivo; multiple sclerosis patient; myelination; novel; oligodendrocyte progenitor; overexpression; programs; public health relevance; remyelination; repaired; white matter

DESCRIPTION (provided by applicant): In multiple sclerosis (MS), demyelination of axons produces conduction block and symptoms including paralysis and blindness, while myelin repair (remyelination) brings functional recovery. A key goal in MS research is to enhance remyelination, which occurs spontaneously but is inefficient, especially in the later stages of the disease. Oligodendrocyte progenitors (OLP) are the major reservoir of remyelinating cells. Their differentiation occurs via an intrinsic transcriptional program, which is promoted by extrinsic pathways, including Stat3, Smad3, Akt-PI3kinase, Erk1/2 and Tralpha1/RXR signaling. Elucidating how these pathways promote differentiation may identify new strategies to enhance remyelination. Recently, we identified the Kr�ppel-like transcriptional activator Klf6 as an essential coordinator of CNS myelination. Importantly, our data also indicate that Klf6 signaling links extrinsic pathways to the intrinsic differentiation program. Notably, key extrinsic pro-myelinating pathways (Stat3 and Smad3 signaling) strongly induce Klf6 in differentiating cells, and Klf6 over-expression accelerates differentiation. Conversely, Klf6 deletion in vitro or in vivo blocks vital steps in differentiation, and leads to complete failure of myelination. This pathology partly mimics deficits resulting from Stat3 or Smad3 inactivation. The effects of Klf6 are restricted to the differentiation program - inactivation in proliferating or mature cells produces o pathology. Our data further suggest important roles in adults, in normal myelin turnover and, critically, in remyelination. Klf6 is strongly induced in remyelinating lesions, paralleling activaion of extrinsic pro-myelinating pathways. To understand Klf6 mechanism of action, we have now used genome-wide analysis of chromatin occupancy, and transcriptional profiling. This work has identified a program of both novel and anticipated Klf6- regulated genes. Importantly, their roles propose Klf6 contributions to sequential steps in differentiation. Moreover, our data further indicate that Klf6 binding also recruits epigenetic coactivators to target loci, and that these enhance transactivation of its transcriptional targets. Together, our findings suggest that Klf6 may form complexes with transcriptional and epigenetic coactivators, to promote differentiation and myelin formation. In this proposal, we will test the central hypothesis that Klf6 linkage of extrinsic regulators with the intrinsic differentiation program is essential for CNS remyelination. We propose three Specific Aims. In Aim 1, we will test the extent to which extrinsic pro-myelinating factors promote differentiation via Klf6 signaling. In Aim 2, we will define the mechanism of action by which Klf6 controls differentiation. In Aim 3, we will then test the role of Klf6 signaling in adult white matter, in normal myelin turnover and, critically, in remyelination. This work will define a new mechanism required for myelin formation, and which may be vital for repair. Elucidating how extrinsic pathways promote maturation may identify new strategies to enhance remyelination.

描述(申请人提供)：在多发性硬化症(MS)中，轴突脱髓鞘会导致传导障碍和瘫痪和失明等症状，而髓鞘修复(重新髓鞘形成)会带来功能恢复。多发性硬化症研究的一个关键目标是加强再髓鞘形成，这是自发发生的，但效率低下，特别是在多发性硬化症的后期阶段。 疾病。少突胶质细胞前体细胞(OLP)是重新髓鞘细胞的主要储存库。它们的分化是通过一个内在的转录程序进行的，该程序由外部途径促进，包括STAT3、SMAD3、Akt-PI3kinaseERK1/2和Tralpha1/RXR信号。阐明这些途径是如何促进分化的，可能会确定促进髓鞘再生的新策略。最近，我们发现Kr�类转录激活子KLF6是中枢神经系统髓鞘形成的重要协调者。重要的是，我们的数据还表明，KLF6信号通路将外部途径与内在分化程序联系在一起。值得注意的是，关键的外源性髓鞘前通路(STAT3和SMAD3信号)强烈诱导KLF6分化细胞，KLF6过表达加速分化。相反，KLF6在体外或体内缺失 阻碍分化的关键步骤，并导致髓鞘形成完全失败。这种病理学 部分模拟STAT3或SMAD3失活造成的缺陷。KLF6的作用仅限于分化程序--在增殖或成熟的细胞中失活会产生病理变化。我们的数据进一步表明，在成人中，在正常的髓鞘转化中发挥重要作用，更重要的是，在重新髓鞘形成中发挥重要作用。KLF6在再髓鞘损伤中被强烈诱导，平行于外源性前髓鞘通路的激活。为了了解KLF6的作用机制，我们现在使用了全基因组的染色质占有率分析和转录图谱。这项工作已经确定了一个新的和预期的KLF6调节基因的程序。重要的是，它们的作用表明KLF6对分化的连续步骤做出了贡献。此外，我们的数据进一步表明，KLF6结合也招募表观遗传共激活子到靶基因位点，这些都增强了其转录靶标的反式激活。综上所述，我们的发现提示KLF6可能与转录和表观遗传共激活因子形成复合体，促进分化和髓鞘形成。在这个提案中，我们将检验中心假设，即KLF6的外在调节因子与内在分化程序的联系对于中枢神经系统的髓鞘再分化是必不可少的。 我们提出了三个具体目标。在目标1中，我们将测试外源性前髓鞘因子通过KLF6信号促进分化的程度。在目标2中，我们将定义KLF6控制分化的作用机制。在目标3中，我们将测试 KLF6信号在成人白质，在正常的髓鞘更新，以及关键的，在重新髓鞘形成中。 这项工作将定义髓鞘形成所需的新机制，这可能对修复至关重要。阐明外在途径是如何促进成熟的，可能会发现促进髓鞘再生的新策略。