BAF complex inhibitors in neuronal development and functions

项目摘要 神经发育障碍（NDD）正在以惊人的速度在我们的儿童中变得越来越普遍。 最近的全基因组研究表明，NDD和功能缺失突变之间存在很强的相关性， 编码BAF（别名mSWI/SNF）染色质重塑复合物亚基的基因。尽管如此强大 相关证据表明，BAF复合物在神经发育基因转录中的确切作用仍然存在 部分原因是缺乏有效的化学/药理学工具来破坏BAF功能。在 对NIH资助机会的回应，题为“发现新大脑的细胞基化学探针” 该项目将进一步开发和测试一组有前途的BAF抑制剂， 并使用这些抑制剂来探测神经元中这些染色质重塑复合物的功能。 活动诱导的基因转录，神经元成熟的关键分子驱动力。本项目的具体目标 是：1）化学修饰“命中”分子BAFi以增加神经元细胞中的效力，以及2）确定 BAF复合物在神经发育重要活性诱导的基因转录中的作用。该项目将 在两个实验室同时进行，这两个实验室分别具有开发 染色质重塑的小分子抑制剂（普渡大学Dykhuizen实验室;目标1）和 活动诱导的神经元基因转录（加州大学萨哈实验室，默塞德;目的2）。 总之，这项研究将产生有价值的化学工具，研究BAF复杂的功能和更深层次的 深入了解驱动正常神经发育的表观遗传机制，这将填补知识空白 BAF突变与其结果之间的关系，如NDD。

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.