Genomic and functional investigations of the transcriptional regulatory network of tooth enamel development

牙釉质发育转录调控网络的基因组和功能研究

• 批准号: 10720303
• 负责人: Hyuk Jae Edward Kwon
• 金额: $ 62.79万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720303
• 关键词: Address; Ameloblasts; Amelogenesis; Automobile Driving; Binding; Biological; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; ChIP-seq; Chromatin; Clinical; Competence; Congenital Disorders; DNA Sequence Alteration; Data; Data Set; Dental; Dental Enamel; Development; Diagnosis; Disease; Dysplasia; Ectodermal Dysplasia; Embryo; Enamel Formation; Enamel Organ; Environment; Epigenetic Process; Event; Family; Gene Expression Regulation; Gene set enrichment analysis; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Health; Homeostasis; Human; Incisor; Individual; Infant; Investigation; Knock-out; Knockout Mice; Knowledge; Left; Light; Methods; Molecular; Morphogenesis; Mus; Mutation; Oral health; Organogenesis; Pathogenicity; Pathologic; Patients; Penetrance; Personal Satisfaction; Phenotype; Prevention; Protein Isoforms; Publishing; Quality of life; Regulator Genes; Reporting; Research; Role; Salivary Glands; Signal Transduction; Skin; System; TFAP2A gene; TP53 gene; Temporomandibular Joint; Testing; Therapeutic; Tissues; Tooth Diseases; Tooth Germ; Tooth structure; Toothache; Work; causal variant; cell fate specification; comparative; dental infection; differential expression; epigenomics; experimental study; gene regulatory network; genetic signature; human disease; loss of function mutation; malformation; mineralization; mouse model; multiple omics; novel therapeutics; organ growth; prevent; progenitor; programs; response; single-cell RNA sequencing; socioeconomics; transcription factor; transcription regulatory network; transcriptome; transcriptome sequencing

Project Summary/Abstract In the U.S., more than 10% of infants are born with dental anomalies, including tooth agenesis, malformation, and enamel dysplasia (ED). The study of tooth development is critical for understanding these congenital disorders and developing novel therapies and treatments, and thus has implications for oral health. However, the transcriptional and epigenetic mechanisms that control tooth development is not well understood. The long- term goal is to identify and characterize the transcription factors that function as important regulators of tooth development in health and disease. The objective of this proposal is to understand the transcriptional and epigenetic regulatory mechanisms underlying tooth enamel development and to address why loss-of-function mutations of the p63 gene cause tooth anomalies, including ED. p63 is a master transcription factor of ectodermal development and homeostasis, as evidenced by ectodermal dysplasia in individuals with p63 mutations, often involving ED and other dental anomalies. However, the role of ΔNp63, the major isoform of p63, and the mechanisms by which ΔNp63 regulates the chromatin and transcriptional regulatory environment in tooth development is completely unknown due to lack of targeted genetic systems. In response to this need, a well- defined ΔNp63 knockout mouse model was generated to perform robust, inducible deletion of ΔNp63 in the developing enamel organ. Based on preliminary data and re-analysis of published work by others, it is hypothesized that p63 functions as a major regulator of tooth enamel development by comprehensively activating its target genes, which are essential for driving earlier cell fate specification and later cell differentiation events in the enamel organ cells. Using genomics and epigenomics approaches and a newly developed mouse model of ED in ectodermal dysplasia, in which ΔNp63 knockout is induced during tooth development, three important questions will be addressed. Aim 1 will define the developmental mechanisms that require p63 action during tooth development. Aim 2 willdefine the molecular mechanisms by which p63 directs tooth development. Finally, Aim 3 will identify the cell-state transition dynamics and the underlying epigenetic mechanism governed by ΔNp63 in tooth development. Collectively, these experiments will define the fundamental mechanisms that govern tooth enamel development on a broad and dynamic scale, which will provide foundational information essential for developing better ways to diagnose, treat, and prevent congenital and acquired dental disorders.

项目总结/摘要 在美国，超过10%的婴儿出生时有牙齿异常，包括牙齿发育不全，畸形， 和釉质发育不良（艾德）。牙齿发育的研究对于了解这些先天性的 因此，它对口腔健康具有重要意义。然而，在这方面， 控制牙齿发育的转录和表观遗传机制还不清楚。很长的- 术语的目标是鉴定和表征作为牙齿重要调节因子的转录因子， 健康和疾病的发展。这项建议的目的是了解转录和 牙釉质发育的表观遗传调控机制，并解决功能丧失的原因 p63基因的突变导致牙齿异常，包括ED。p63是外胚层的主要转录因子， 发育和稳态，如p63突变个体的外胚层发育不良所证明的，通常 包括艾德和其他牙齿异常。然而，Δ Np 63（p63的主要亚型）和 Δ Np 63调控牙齿染色质和转录调控环境的机制 由于缺乏有针对性的遗传系统，发育完全未知。为了满足这一需求，一个良好的- 产生了定义的Δ Np 63敲除小鼠模型，以在小鼠中进行Δ Np 63的稳健的、可诱导的缺失。 发育中的釉质器根据初步数据和对其他人发表的工作的重新分析， 假设p63通过全面激活， 它的靶基因是驱动早期细胞命运特化和后期细胞分化事件所必需的 在釉质器官细胞中。利用基因组学和表观基因组学方法以及新开发的小鼠模型 外胚层发育不良中艾德的发育异常，其中Δ Np 63敲除在牙齿发育过程中被诱导，三个重要的 问题将得到解决。目的1将定义在发育过程中需要p63作用的发育机制。 牙齿发育目的二是明确p63基因调控牙齿发育的分子机制。最后， 目标3将确定细胞状态转换动力学和潜在的表观遗传机制， Δ Np 63在牙齿发育中的作用总的来说，这些实验将确定基本的机制， 在广泛和动态的范围内控制牙釉质发育，这将提供基础信息 对于开发更好的方法来诊断，治疗和预防先天性和后天性牙科疾病至关重要。