Small Molecules Modulating Oligodendrocyte Lineage Progression

描述(申请人提供)：少突胶质细胞是中枢神经系统的特殊神经胶质细胞，其膜形成包裹轴突并允许快速轴突传导的绝缘层(即髓鞘)。这些细胞来源于分化为髓鞘形成的少突胶质细胞的前体细胞，已知在调节神经元功能方面发挥重要作用。因此，不正确的祖细胞分化或髓鞘形成在不同的神经疾病中被检测到，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全局乙酰化，随后是组蛋白全局性去乙酰化；组蛋白去乙酰化是基因抑制的初始减少所必需的，而基因抑制是髓鞘形成的关键1，2。此外，使用HDACs 3，4的药物抑制剂的研究，祖细胞5原代培养中的基因沉默，以及斑马鱼突变体6和敲除小鼠7，8的分析清楚地表明了组蛋白乙酰化和去乙酰化与少突胶质细胞生物学的功能相关性。然而，这一机制和其他表观遗传调控机制在大脑功能中的具体作用仍然知之甚少。因此，新的研究工具有助于破译表观遗传基因表达在脑部疾病发展中的机制洞察力是非常有意义的。这项建议试图通过开发化学探针来研究组蛋白脱乙酰化状态对与脱髓鞘障碍相关的神经退行性疾病的发展的影响，以满足这一需求。因此，基于以上的累积证据，我们推测，乙酰基转移酶活性的化学抑制剂，有利于核小体组蛋白上赖氨酸残基的去乙酰化状态，可能是寡突胶质前体细胞向更分化状态发展的有效促进剂。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的、有效的有利于核小体组蛋白脱乙酰化的方法。为此，本研究项目致力于转录辅活化子CBP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：在不同的神经疾病中检测到不正确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活化子CBP的溴域的抑制剂作为化学探针来研究与脱髓鞘疾病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.