Bidirectional control of Chd2 haploinsufficiency

Chd2 单倍体不足的双向控制

基本信息

批准号：
10586860
负责人：
Robert F Hunt
金额：
$ 53.72万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586860
关键词：
Address Adult Anatomy Area Automobile Driving Basic Science Behavior Behavioral Benchmarking Brain Brain region Cancer cell line Candidate Disease Gene Chromatin Chromatin Remodeling Factor Chromosome Mapping Clinic Clustered Regularly Interspaced Short Palindromic Repeats Communication Complex DNA Sequence Alteration Data Development Diabetes Mellitus Disease Electrophysiology (science)Embryo Engineering Epilepsy Event Exhibits Gene Expression Gene Mutation Genes Genetic Risk Genetic study Genomics Glutamates Heterozygote Hippocampus Human Immunohistochemistry In Vitro Individual Induced pluripotent stem cell derived neurons Intellectual functioning disability Laboratories Literature Longevity Malignant Neoplasms Mediating Memory Memory impairment Metformin Molecular Mus Mutation National Institute of Neurological Disorders and Stroke Neurodevelopmental Disorder Neurologic Neurons Pathologic Pathology Patients Pharmaceutical Preparations Photosensitivity Disorders Population Proliferating Pyramidal Cells Reporting Research Series Signal Transduction Stem cell transplant Structure Synapses Testing Therapeutic Translating Transplantation Western Blotting Work autism spectrum disorder behavioral study dosage hippocampal pyramidal neuron in vivo induced pluripotent stem cell loss of function mutation migration mouse genetics neurodevelopment neuronal excitability neurotransmission new therapeutic target novel novel therapeutics pharmacologic prevent stem cells synaptic function therapeutic evaluation

项目摘要

ABSTRACT Major advances have been made in mapping the genetic basis of epilepsy and other neurodevelopmental disorders (NDDs). In many cases, a candidate gene mutation has been identified, but there is no robust understanding of the neuronal causes for the particular disorder. Mutations in genes encoding chromatin regulators are commonly identified in human NDDs, with intellectual disability, autism and/or epilepsy often co- occurring in the same individual. Our recent work showed that mice with germline heterozygous mutations in Chd2 exhibit pathological changes across genomic, anatomical, electrophysiological and behavioral domains. Here, we propose studies to bidirectionally control Chd2 dosage in the developing or adult brain. Our approach involves a combination of sophisticated cellular, molecular, pharmacologic and electrophysiological approaches in conditional Chd2+/- mice and human-derived neurons. If successful, our results will provide important new information about the effects of chromatin regulators in driving NDD-associated pathologies in vivo and would provide critical proof-of-concept for the therapeutic potential of pharmacologically increasing Chd2 expression that could be rapidly translated into a new targeted therapy for Chd2 haploinsufficiency.

抽象的在绘制癫痫和其他神经发育疾病的遗传基础方面取得了重大进展疾病（NDD）。在许多情况下，候选基因突变已被识别，但没有可靠的证据了解特定疾病的神经元原因。染色质编码基因突变调节剂通常在人类 NDD 中被识别，智力障碍、自闭症和/或癫痫经常伴随发生在同一个人身上。我们最近的工作表明，具有种系杂合突变的小鼠 Chd2 在基因组、解剖学、电生理学和行为领域表现出病理变化。在这里，我们提出了双向控制发育中或成人大脑中 Chd2 剂量的研究。我们的方法涉及复杂的细胞、分子、药理学和电生理学的结合条件 Chd2+/- 小鼠和人源神经元的方法。如果成功，我们的结果将提供关于染色质调节因子在驱动 NDD 相关病理中的作用的重要新信息体内，将为药理学增加的治疗潜力提供关键的概念验证 Chd2 表达可以快速转化为针对 Chd2 单倍体不足的新靶向疗法。