Small Molecules Modulating Oligodendrocyte Lineage Progression

描述（由申请人提供）：少突胶质细胞是中枢神经系统的特化神经胶质细胞，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）。这些细胞来源于分化成髓鞘形成少突胶质细胞的祖细胞，并且已知在调节神经元功能中起重要作用。因此，在不同的神经系统疾病中检测到不适当的祖细胞分化或髓磷脂形成，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核小体组蛋白上赖氨酸残基的整体乙酰化，然后是整体组蛋白脱乙酰化;后者是最初减少基因抑制所必需的，这对髓鞘形成的适当开始是必不可少的1，2。此外，使用HDACs药理学抑制剂的研究3，4、祖细胞原代培养物中的基因沉默5以及对斑马鱼突变体6和基因敲除小鼠的分析7，8已清楚地表明组蛋白乙酰化和脱乙酰化与少突胶质细胞生物学的功能相关性。然而，这种和其他表观遗传调节机制在大脑功能中的具体作用仍然知之甚少。因此，新的研究工具，可用于破译脑疾病的发展中的表观遗传基因表达的机制的见解是非常感兴趣的。该提案试图通过开发化学探针来解决这一需求，该化学探针应用于研究组蛋白脱乙酰化状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，基于上述累积的证据，我们假设乙酰转移酶活性的化学抑制剂，这有利于核小体组蛋白上赖氨酸残基的脱乙酰化状态，可能是少突胶质细胞祖细胞向更分化状态发展的有效促进剂。更具体地说，我们推断，抑制CBP的溴结构域的功能可能是一种新的和有效的方式，有利于核小体组蛋白脱乙酰化。为此，本研究项目致力于转录辅激活因子CBP的溴结构域抑制剂的设计、合成和生物学评价。 公共卫生相关性：在不同的神经系统疾病中检测到不适当的祖细胞分化或髓鞘形成，并具有重要的临床后果。本提案试图开发转录辅激活因子CBP的溴结构域的抑制剂作为化学探针来研究与脱髓鞘病症相关的神经退行性疾病。

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.