BAF complex inhibitors in neuronal development and functions

项目总结 神经发育障碍(NDDS)在我们的儿童中正以惊人的速度变得更加普遍。 最近的全基因组研究表明，NDDS与脑功能丧失突变之间存在很强的相关性 编码BAF(别名，mSWI/SNF)染色质重塑复合体亚单位的基因。尽管如此强大 相关证据，BAF复合体在神经发育基因转录中的确切作用(S)仍然存在 很大程度上未被探索，部分原因是缺乏有效的化学/药理工具来扰乱BAF功能。在……里面 对美国国立卫生研究院资助机会的回应，标题为：发现用于新型大脑的基于细胞的化学探针 该项目将进一步开发和测试一组有前景的BAF抑制剂，用于成熟的大鼠大脑皮质 并使用这些抑制物来探索这些染色质重塑复合体在神经元中的功能 活性诱导基因转录，神经元成熟的关键分子驱动因素。本项目的具体目标 它们是：1)化学修饰“Hit”分子Bafi以提高神经细胞的效力；2)确定其作用 BAF复合体在神经发育重要活性诱导基因转录中的作用。该项目将是 在两个实验室同时进行，分别在开发方面拥有长期的专业知识 染色质重构体的小分子抑制物(普渡大学Dykhuizen实验室，目标1)和 活动诱导的神经元基因转录(加州大学默塞德分校的SAHA实验室；目标2)。 综上所述，这项研究将为研究曝气生物滤池的复杂函数和更深层次的功能提供有价值的化学工具 对驱动正常神经发育的表观遗传机制的洞察，这将填补知识空白 BAF突变与其结果之间的关系，例如NDDS。

PROJECT SUMMARY Neurodevelopmental disorders (NDDs) are becoming more prevalent among our children at an alarming rate. Recent genome-wide studies suggest a strong correlation between NDDs and loss-of-function mutations in genes encoding subunits of the BAF (alias, mSWI/SNF) chromatin remodeling complex. Despite such strong correlative evidence, the precise role(s) of the BAF complex in neurodevelopmental gene transcription remains largely unexplored, in part, due to lack of efficient chemical/pharmacological tools to disrupt BAF function. In response to the NIH funding opportunity titled, ‘Discovery of Cell-based Chemical Probes for Novel Brain Targets’, this project will further develop and test a promising group of BAF inhibitors in maturing rat cortical neurons and use these inhibitors to probe the function of these chromatin remodeling complexes in neuronal activity-induced gene transcription, a key molecular driver of neuronal maturation. Specific aims of this project are: 1) Chemically modify ‘hit’ molecule BAFi to increase potency in neuronal cells, and 2) Determine the role of BAF complex in neurodevelopmentally important activity-induced gene transcription. The project will be conducted simultaneously in two laboratories with long standing expertise in –respectively– development of small molecule inhibitors of chromatin remodelers (the Dykhuizen laboratory at Purdue university; aim 1) and activity-induced neuronal gene transcription (the Saha laboratory at University of California, Merced; aim 2). Taken together, this study will generate valuable chemical tools to study BAF complex functions and deeper insights into epigenetic mechanisms driving normal neurodevelopment, which will fill in the knowledge gap between BAF mutations and their outcomes, such as NDDs.