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Co-opting Lef-1 and miR-26b activities to regulate dental stem cells and their progeny

共同选择 Lef-1 和 miR-26b 活性来调节牙齿干细胞及其后代

基本信息

批准号：
10664967
负责人：
BRAD A AMENDT
金额：
$ 40.68万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664967
关键词：
Adult Affect Architecture Artificial Organs Binding Bioinformatics Biological Assay Biomedical Engineering Bromodeoxyuridine Cell Compartmentation Cell Differentiation process Cell Line Cell Maintenance Cell Proliferation Cell division Cells Cervical ChIP-seq Complex Daughter Defect Dental Dental Enamel Development Disease Embryo Embryonic Development Enhancers Epigenetic Process Epithelial Cells Epithelium Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genomics Glean Goals Growth Human In Situ Hybridization Incisor Injury Knockout Mice Knowledge Life Lung Mesenchyme MicroRNAs Molecular Mus Natural regeneration Odontoblasts Odontogenesis Oral Organ Outcome Pathway interactions Pattern Phenotype Pluripotent Stem Cells Population Process Production Proliferating Regulation Regulatory Pathway Reporter Repression Role Signal Pathway Signal Transduction Stains Stem Cell Factor Testing Tissues Tooth regeneration Tooth structure Trachea Western Blotting Work cell behavior cell injury cell type craniofacial daughter cell epithelial stem cell experimental study in vivo injured knock-down morphogens mouse model novel therapeutics oral cavity epithelium oral tissue overexpression progenitor programs regenerative repaired single-cell RNA sequencing stem stem cell differentiation stem cell expansion stem cell function stem cell niche stem cell proliferation stem cells tissue regeneration tool transcription factor transcriptome transcriptome sequencing

项目摘要

Project Summary Tissue specific regeneration requires the function of progenitor cells that can differentiate to repair diseased or injured tissues. Affected tissues can contain stem cells and their growth and patterning are controlled by transcription factors and signaling pathways. Stem cells derived from stem cell niches contribute to the regeneration of mature tissue types in many different organs, including the trachea, lungs and teeth, amongst others. These niches are formed in developing embryos, and must be maintained throughout life by symmetric cellular divisions that produce daughter pluripotent stem cells. Another equally important behavior of the cells in a stem cell niche is the production of differentiated daughter cells by asymmetric cell division, which then take the place of damaged cells in regenerative organs, in order to allow the organ to continue to function. However, the roles of specific microRNAs (miRs) in these processes are unclear. miRs have become appreciated as playing a role in stem cell differentiation. The ability to coopt miR expression in order to reprogram and control the differentiation of naive cells into different cell types will be an important tool required to create artificial organs and repair diseased tissues, saving millions of lives and public dollars. We hypothesize that miR-26b is acting in part to regulate the stem cell niche of the lower and upper incisor by regulating Lef-1 expression, and that this mechanism may be common to many tissues that house stem cell niches. Thus, the absence of miR-26b expression prior to E14.5 allows Lef-1 expression in the oral epithelium (placode) and LaCL (stem cell niche) during development. However, after E14.5, miR-26b expression in the dental epithelium restricts Lef-1 expression and then other factors (Sox2) regulate stem cell maintenance. In order to determine how Lef-1 and miR-26b is affecting gene expression during development and cells we will pursue three aims: 1) to use our murine models to understand in vivo stem cell proliferation and differentiation by Lef-1 and miR-26b OE; and use miR-26b OE to rescue the Lef-1 OE phenotype and define the role of miR-26b OE in dental development; 2) validate molecular interactions between miR-26b, Lef- 1 and known factors involved in DESC proliferation and differentiation; 3) isolate the dental epithelial cells from WT, Lef-1 OE, miR-26b OE and rescue mice to identify new genetic pathways using RNA-Seq, ChIP-Seq. and Single cell Seq.

项目摘要组织特异性再生需要祖细胞的功能，祖细胞可以分化以修复病变或损伤。受伤的组织受影响的组织可以包含干细胞，它们的生长和模式由转录因子和信号通路。来源于干细胞小生境的干细胞有助于许多不同器官中成熟组织类型的再生，包括气管，肺和牙齿，他人这些生态位在发育中的胚胎中形成，并且必须通过对称的产生子多能干细胞的细胞分裂。细胞的另一个同样重要的行为在干细胞小生境中，通过不对称细胞分裂产生分化的子细胞，取代再生器官中受损的细胞，以使器官继续发挥功能。然而，特定的microRNAs（miRs）在这些过程中的作用尚不清楚。miR已经成为被认为在干细胞分化中起作用。利用miR表达的能力，重新编程和控制幼稚细胞分化为不同的细胞类型将是一个重要的工具，制造人造器官和修复病变组织，挽救了数百万人的生命和公共资金。我们假设miR-26 b通过以下方式部分调节上下切牙的干细胞生态位：调节Lef-1表达，这种机制可能是许多容纳干细胞的组织所共有的。壁龛因此，在E14.5之前miR-26 b表达的缺乏允许Lef-1在口腔中表达。上皮（基板）和LaCL（干细胞龛）。然而，在E14.5之后，miR-26 b 在牙上皮中的表达限制Lef-1的表达，然后其他因子（Sox 2）调节干细胞上维护为了确定Lef-1和miR-26 b在发育过程中如何影响基因表达，我们将追求三个目标：1）使用我们的小鼠模型来了解体内干细胞增殖和分化;并使用miR-26 b OE拯救Lef-1 OE表型，确定miR-26 b OE在牙齿发育中的作用; 2）验证miR-26 b、Lef-1和Lef-2之间的分子相互作用。 1和已知的参与DESC增殖和分化的因子; 3）分离牙上皮细胞， WT、Lef-1 OE、miR-26 b OE和拯救小鼠，以使用RNA-Seq、ChIP-Seq鉴定新的遗传途径。和单细胞测序

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HMGN2 represses gene transcription via interaction with transcription factors Lef-1 and Pitx2 during amelogenesis.

DOI：
10.1016/j.jbc.2022.102295
发表时间：
2022-09
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Eliason, Steven;Su, Dan;Pinho, Flavia;Sun, Zhao;Zhang, Zichao;Li, Xiao;Sweat, Mason;Venugopalan, Shankar R.;He, Bing;Bustin, Michael;Amendt, Brad A.
通讯作者：
Amendt, Brad A.

Wolf-Hirschhorn syndrome candidate 1 (Whsc1) methyltransferase signals via a Pitx2-miR-23/24 axis to effect tooth development.