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

• 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
• 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

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.

项目总结