Small Molecules Modulating Oligodendrocyte Lineage Progression

小分子调节少突胶质细胞谱系进展

基本信息

批准号：
8031425
负责人：
Guillermo Gerona-Navarro
金额：
$ 8.48万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8031425
关键词：
Acetylation Acetyltransferase Address Affinity Axon Binding Biological Biological Assay Biology Biotin Brain Brain Diseases Bromodomain CREB-binding protein Cell Line Cells Chemicals Chromatin Clinical Demyelinating Diseases Development Epigenetic Process Evaluation Family Fluorescence Fluorescence Polarization Gene Expression Gene Silencing Genetic Transcription Histone Acetylation Histone Deacetylation Histones In Vitro Knock-out Label Laboratories Lead Lysine Measurement Mediating Membrane Methods Myelin Neuraxis Neurodegenerative Disorders Neuroglia Neurons Oligodendroglia Play Preparation Proteins Regulation Reporting Research Research Project Grants Role Staging Structure Technology Transcription Coactivator Zebrafish analog base design experience gene repression histone acetyltransferase human CREBBP protein improved inhibitor/antagonist insight interest nervous system disorder novel oligodendrocyte lineage progenitor promoter protein protein interaction research study small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Oligodendrocytes are specialized glial cells of the central nervous system, whose membrane forms the insulating coating (i.e. myelin) that wraps the axons and allows fast axonal conduction. These cells derive from progenitors that differentiate into myelin-forming oligodendrocytes and are known to play an essential role in modulating neuronal function. Thus, improper progenitor differentiation or myelin formation is detected in distinct neurological disorders and has important clinical consequences. Recent studies have shown that the early progenitor stage is marked by global acetylation of lysine residues on nucleosomal histones and is followed by global histone deacetylation; the latter being required for the initial decrease in gene repression that is essential for the proper onset of myelination1,2. Moreover, studies using pharmacological inhibitors of HDACs3,4, gene silencing in primary cultures of progenitors5 and analysis of zebrafish mutants6 and knockout mice7,8 have clearly shown functional relevance of histone acetylation and deacetylation for oligodendrocyte biology. However, the specific role of this and other mechanisms of epigenetic regulation in the functioning of the brain are still poorly understood. Therefore, novel research tools useful to decipher the mechanistic insights of epigenetic gene expression in the development of brain diseases are of great interest. This proposal attempts to address this need by developing chemical probes with application to study the effect of histone deacetylation states on the development of neurodegenerative disorders associated with demyelinating disorders. Thus, based on the cumulative evidences above presented, we hypothesized that chemical inhibitors of acetyltransferase activity, which favor deacetylated states of lysine residues on nucleosomal histones, could be efficient promoters of the progression of oligodendrocyte progenitors towards a more differentiated state. More specifically, we reasoned that inhibiting the function of the bromodomain of CBP could be a novel and efficient way of favoring nucleosomal histones deacetylation. To this end, this research project focus on the design, synthesis and biological evaluation of inhibitors of the bromodomain of the transcriptional coactivator CBP. PUBLIC HEALTH RELEVANCE: Improper progenitor differentiation or myelin formation is detected in distinct neurological disorders and has important clinical consequences. The present proposal attempts to develop inhibitors of the bromodomain of the transcriptional coactivator CBP as chemical probes to study neurodegenerative diseases associated with demyelinating disorders.

描述（由申请人提供）：少突胶质细胞是中枢神经系统的专门神经胶质细胞，其膜形成包裹轴突并允许快速轴突传导的绝缘涂层（即髓磷脂）。这些细胞来自分化为髓磷脂形成的少突胶质细胞的祖细胞，并在调节神经元功能中起着至关重要的作用。因此，在不同的神经系统疾病中检测到祖细胞分化或髓磷脂形成不当，并具有重要的临床后果。最近的研究表明，早期祖细胞阶段的标志是赖氨酸残基在核小组组蛋白上的全球乙酰化，然后是全球组蛋白脱乙酰基化。后者是基因抑制的初始降低所必需的，这对于髓鞘化的适当发作至关重要1,2。此外，使用HDACS3,4的药理抑制剂，祖细胞原代培养物中的基因沉默以及斑马鱼突变体6和敲除小鼠的分析的研究清楚地表明了组蛋白乙酰化和脱乙酰化的功能相关性。但是，这种表观遗传调节在大脑功能中的具体作用和其他机制仍然很少了解。因此，新颖的研究工具有助于解读脑疾病发展中表观遗传基因表达的机械见解。该提案试图通过开发具有应用化学探针的应用来研究组蛋白脱乙酰化态对与脱髓鞘疾病相关的神经退行性疾病的发展的影响。因此，基于上述累积证据，我们假设乙酰基转移酶活性的化学抑制剂有利于赖氨酸残基在核小组组蛋白上的脱乙酰化态，可以有效地促进少突胶质祖细胞向更分化状态的少突胶质祖细胞的进展。更具体地说，我们认为抑制CBP溴结构域的功能可能是一种新颖而有效的方法，可以偏爱核小体组蛋白脱乙酰化。为此，该研究项目的重点是对转录共激活剂CBP的抑制剂的设计，合成和生物学评估。公共卫生相关性：在不同的神经系统疾病中检测到祖细胞分化或髓磷脂形成不当，并具有重要的临床后果。本提案试图开发转录共激活剂CBP的溴结构域的抑制剂作为化学探针研究与脱髓鞘疾病相关的神经退行性疾病。