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胶质细胞，其膜形成包裹轴突的绝缘涂层（即髓磷脂），并允许轴突快速传导。这些细胞来源于分化成髓磷脂形成少突胶质细胞的祖细胞，已知在调节神经元功能中起重要作用。因此，不适当的祖细胞分化或髓磷脂形成是在不同的神经系统疾病中检测到的，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，随后是整体组蛋白去乙酰化；后者是基因抑制的初始减少所必需的，这对于髓鞘形成的正常发生至关重要1,2。此外，利用hdac3、4的药理学抑制剂、祖细胞原代培养中的基因沉默、斑马鱼突变体和敲除小鼠的分析等研究已经清楚地表明，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，这种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脑疾病发展中表观遗传基因表达的机制见解是非常有趣的。本提案试图通过开发化学探针来解决这一需求，并应用于研究组蛋白去乙酰化状态对与脱髓鞘疾病相关的神经退行性疾病发展的影响。因此，基于上述累积证据，我们假设乙酰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，可能是少突胶质细胞祖细胞向更分化状态发展的有效促进因子。更具体地说，我们认为抑制CBP的溴结构域的功能可能是促进核小体组蛋白去乙酰化的一种新的有效方法。为此，本课题重点研究转录共激活因子CBP的溴域抑制剂的设计、合成和生物学评价。

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.