Defining the cell type-specific role of miR-9-2 in telencephalon development

定义 miR-9-2 在端脑发育中的细胞类型特异性作用

• 批准号: 10747572
• 负责人: Santiago P Fregoso
• 金额: $ 0.25万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-06 至 2025-09-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747572
• 关键词: ATAC-seq; Alzheimer' s Disease; Brain; Cell physiology; Cells; Cellular Morphology; Central Nervous System; Cerebral cortex; Chromatin; Data; Development; Disease; Dose; Elements; Embryo; Enhancers; Epigenetic Process; Etiology; Family; Family member; Fellowship; Forebrain Development; Functional disorder; Gene Dosage; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomics; Goals; Heterozygote; Hippocampus; Histologic; Huntington Disease; Hydrocephalus; In Situ Hybridization; Knock-out; Knockout Mice; Knowledge; Learning; Methodology; Methods; MicroRNAs; Molecular; Mus; Mutant Strains Mice; Neurons; Organ; Parkinson Disease; Pattern; Phenotype; Play; Population; Post-Transcriptional Regulation; Prevalence; Proliferating; Prosencephalon; Regulation; Regulator Genes; Regulatory Element; Research; Resolution; Role; Schizophrenia; Severities; Structure; Telencephalon; Testing; Transcript; Transcriptional Regulation; Untranslated RNA; brain malformation; cell type; critical period; epigenetic regulation; experimental study; gene network; gene regulatory network; in vivo; insight; lateral ventricle; malformation; migration; mouse model; multiple omics; mutant; nerve stem cell; nervous system disorder; neural; neurodevelopment; novel strategies; postnatal; posttranscriptional; single-cell RNA sequencing; spatiotemporal; transcriptomics

PROJECT SUMMARY Dysregulation of gene networks during development can lead to organ malformation, dysfunction and disease, especially neurological diseases such as schizophrenia, Huntington’s and Alzheimer’s disease. Thus, a more comprehensive understanding of the gene regulatory networks that are active during development of the central nervous system are needed to better understand disease etiology and treatment. The long-term goal of this proposal is to define the role of the microRNA miR-9-2 in brain development, function and disease utilizing in vivo knock-out mouse models. My preliminary data show that loss of miR-9-2 during development results in severely malformed forebrains in mice in a gene dose-dependent manner. Based on this and previous studies, I hypothesize that miR-9-2 is a critical regulator of gene networks that instruct neural progenitor proliferation, differentiation and survival. Here, using a combination of transcriptomic, genomic and histological methods, I will uncover the genes, genomic regulatory elements and cellular processes regulated by miR-9-2 during brain development to define the specific role of this important microRNA. Additionally, I will uncover upstream regulators of miR-9-2 expression by investigating the role of a deeply conserved cis-regulatory element, or enhancer in modulating miR-9-2 expression during development. The proposed research is significant because it will provide a comprehensive understanding of the gene networks, cell populations, and brain structures under miR-9-2 regulation, give insight into the regulation of miR-9-2 expression and inform on the consequences of miR-9-2 dysregulation that lead to neurological disease.

项目摘要 发育过程中基因网络的失调可导致器官畸形、功能障碍和疾病， 特别是神经系统疾病如精神分裂症、亨廷顿氏病和阿尔茨海默氏病。因此， 全面了解在发育过程中活跃的基因调控网络， 中枢神经系统需要更好地了解疾病的病因和治疗。长期 该提案的目标是确定microRNA miR-9-2在大脑发育、功能和疾病中的作用 利用体内敲除小鼠模型。我的初步数据显示，在发育过程中miR-9-2的丢失 以基因剂量依赖的方式导致小鼠前脑严重畸形。基于此和 在以前的研究中，我假设miR-9-2是基因网络的关键调节因子， 祖细胞增殖、分化和存活。在这里，使用转录组学、基因组学的组合 和组织学方法，我将揭示基因，基因组调控元件和细胞过程 在大脑发育过程中由miR-9-2调控，以确定这种重要microRNA的具体作用。 此外，我将通过研究miR-9-2表达的上游调控因子， 高度保守的顺式调控元件或发育过程中调节miR-9-2表达的增强子。 拟议的研究是重要的，因为它将提供一个全面的了解， miR-9-2调控下的基因网络、细胞群和大脑结构， 研究miR-9-2表达的调控，并告知miR-9-2失调的后果 导致神经系统疾病