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: 10738265
• 负责人: Santiago P Fregoso
• 金额: $ 7.63万
• 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/10738265
• 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。的长期目标 该提案旨在确定microRNA miR-9-2在脑发育、功能和疾病利用中的作用， 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的缺失导致了 严重畸形的前脑在小鼠中以基因剂量依赖的方式。基于这一点和以前的研究， 我假设miR-9-2是指导神经祖细胞增殖的基因网络的关键调节因子， 分化和生存。在这里，使用转录组学，基因组学和组织学方法的组合，我 将揭示大脑中miR-9-2调控的基因、基因组调控元件和细胞过程， 我们正在研究如何确定这种重要的microRNA的具体作用。另外，我会发现上游 通过研究高度保守的顺式调控元件的作用来研究miR-9-2表达的调控因子，或 在发育过程中调节miR-9-2表达的增强子。这项研究意义重大，因为 它将提供对基因网络、细胞群和大脑结构的全面了解， 在miR-9-2调控下，深入了解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。