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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要在美国，超过10％的婴儿出生时患有牙齿异常，包括产生牙齿，畸形，和搪瓷发育不良（ed）。对牙齿发育的研究对于理解这些先天性至关重要疾病和发展新颖的疗法和治疗方法，因此对口腔健康具有影响。然而，控制牙齿发育的转录和表观遗传机制尚不清楚。长期术语目标是识别和表征作为重要调节剂的转录因子健康和疾病的发展。该提议的目的是了解转录和牙釉质发育太大的表观遗传调节机制，并解决了为什么功能丧失 p63基因的突变引起牙齿异常，包括Ed。 p63是外胚层的主转录因子发育和稳态，如p63突变个体外胚层发育不良所证明的那样，通常涉及ED和其他牙科异常。然而，ΔNP63的作用，p63的主要同工型和 ΔNP63调节牙齿中染色质和转录调节环境的机制由于缺乏目标遗传系统，发展是完全未知的。为了应对这一需求，一个很好的生成定义的ΔNP63敲除小鼠模型以执行可鲁棒的，可诱导的ΔNP63缺失开发搪瓷器官。基于其他人的初步数据和重新分析其他人的作品，这是假设p63通过全面激活来充当牙釉质发育的主要调节剂其靶基因，这对于驱动较早的细胞命运规格和较晚的细胞分化事件至关重要在搪瓷器官细胞中。使用基因组学和表观基因组学方法以及新开发的小鼠模型 ED在外胚层发育不良中，其中ΔNP63敲除在牙齿发育过程中诱导，三个重要问题将被解决。 AIM 1将定义在需要p63行动的发展机制牙齿发育。 AIM 2将定义p63指导牙齿发育的分子机制。最后， AIM 3将确定细胞状态过渡动力学和受基本的表观遗传机制牙齿发育中的ΔNP63。总的来说，这些实验将定义在广泛而动态的规模上控制牙釉质的开发，这将提供基本信息开发更好的方法来诊断，治疗和预防先天性和获得的牙科疾病至关重要。