BAF complex inhibitors in neuronal development and functions

BAF 复合物抑制剂对神经元发育和功能的影响

基本信息

批准号：
10630241
负责人：
Emily Carla Dykhuizen
金额：
$ 22.88万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630241
关键词：
ACTL6B gene ARID1A gene Attenuated Automobile Driving Brain California Cells ChIP-seq Chemicals Child Chromatin Chromatin Remodeling Factor Coffin-Siris Syndrome Combinatorics Complex DNA biosynthesis Data Development Disease Dissociation Early Gene Transcriptions Electrophysiology (science)Epigenetic Process Etiology Eye Fibrinogen Funding Opportunities Future Gene Order Genes Genetic Genetic Transcription Human Immediate-Early Genes In Vitro Intellectual functioning disability Intervention Knowledge Laboratories Mediating Microelectrodes Modification Molecular Mutate Mutation Neurodevelopmental Disorder Neurons Nuclear Pore Complex Nucleosomes Outcome Photoaffinity Labels Polymerase Property Proteomics RNA Polymerase II Rattus Regulation Regulator Genes Risk Factors Role SMARCA2 gene SMARCC2 gene Structure Sucrose Synapses Syndrome Testing Transcriptional Regulation United States National Institutes of Health Universities Up-Regulation analog attenuation autism spectrum disorder cytotoxicity disorder risk efficacy testing follow-up genome-wide genome-wide analysis high throughput screening induced pluripotent stem cell inhibitor insight knock-down loss of function mutation member neurodevelopment neuron development novel pharmacologic prevent promoter repaired response scaffold small molecule small molecule inhibitor synaptic function tool transcriptome sequencing

项目摘要

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.

项目摘要神经发育障碍（NDDS）在我们的孩子中以惊人的速度变得越来越普遍。全基因组的最新研究表明，NDD与功能丧失突变之间存在很强的相关性编码BAF亚基的基因（Alias，MSWI/SNF）染色质重塑复合物。尽管如此强大相关证据，BAF复合物在神经发育基因转录中的精确作用仍然存在部分原因是缺乏有效的化学/药理工具来破坏BAF功能。对NIH资金机会的反应，标题为“发现基于细胞的化学探针的新型大脑的化学探针目标’，该项目将进一步开发和测试一组有前途的BAF抑制剂神经元并使用这些抑制剂探测这些染色质重塑复合物在神经元中的功能活性诱导的基因转录，这是神经元成熟的关键分子驱动力。该项目的具体目标是：1）化学修饰“命中”分子BAFI以增加神经元细胞的效力，2）确定作用 BAF复合物在神经发育中重要的活性引起的基因转录。该项目将是简单地在两个实验室中进行的，具有长期的专业知识 - 尊贵的发展染色质重塑剂的小分子抑制剂（普渡大学的Dykhuizen实验室； AIM 1）和活动引起的神经元基因转录（加利福尼亚大学默塞德分校的SAHA实验室； AIM 2）。综上对驱动正常神经发育的表观遗传机制的见解，这将填补知识差距在BAF突变及其结果之间，例如NDD。