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Elucidating the role of p63 and transcriptional control mechanisms in progenitor cells of the salivary gland

阐明 p63 和转录控制机制在唾液腺祖细胞中的作用

基本信息

批准号：
9243483
负责人：
Rose-Anne Romano
金额：
$ 11.91万
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：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243483
关键词：
Address Adult Animals Area Automobile Driving Biological Assay Biological Markers Biological Models Biology Cell Culture Techniques Cell Lineage Cell physiology Cells ChIP-seq Characteristics Clinical Critical Pathways DNA Development Disease Embryonic Development Ensure Epithelial Epithelial Cells Equilibrium Foundations Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Profiling Gene Targeting Genes Genetic Genetic Transcription Genomic approach Genomics Gland Goals Head and neck structure Homeostasis Human Injury Knockout Mice Knowledge Label Light Mammary gland Maps Molecular Molecular Profiling Morphogenesis Mus Natural regeneration Normal tissue morphology Organ Organogenesis Pathway interactions Patients Phenotype Play Population Process Property Protein Isoforms Regulator Genes Role Salivary Glands Signal Pathway Signal Transduction Sjogren&apos s Syndrome Skin Squamous cell carcinoma Stem cells Submandibular gland Systems Biology Techniques Technology Therapeutic Time Tissue Engineering Tissues Transcriptional Regulation Transgenic Mice Xerostomia base cell type epigenomics experimental study genetic approach genome-wide gland development in vivo injured injury and repair insight interest irradiation mRNA Expression mouse model next generation sequencing novel novel therapeutic intervention progenitor prospective regenerative stem stem cell biology stem cell division tissue regeneration tool transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY The delicate balance between proliferation and differentiation of stem/progenitor cells of the salivary gland (SG) must be tightly regulated to ensure proper morphogenesis, homeostasis and regeneration. Alterations to normal SG function, clinically often manifested with hyposalivation, are associated with diseases such as Sjögren’s Syndrome and with γ-irradiation therapy of Head and Neck Squamous Carcinoma patients. Currently, treatment options for hyposalivation and mechanisms for restoring normal SG function remain limited. Therefore, the development of new tools and strategies directed at identifying transcriptional and signaling networks underlying stem/progenitor cell function of the SG with the ultimate goal for use in stem cell regenerative-based therapies and tissue engineering approaches, are critical. Hence, our goal is to examine the transcriptome landscape of the stem/progenitor cells of the SG and identify and characterize the regulatory networks of this cell population. It is well established that ΔNp63, plays a critical role in epithelial regenerative function as ΔNp63-null animals fail to develop several epithelial-rich organs including the SG. However, our current knowledge of how ΔNp63 regulates gene expression in the stem/progenitor cells of the SG is lacking. Thus examining the p63-driven regulatory networks is a key step towards a better understanding of the biology of the SG progenitor cells and in directing new strategies in treating SG dysfunction. To address these knowledge gaps, we will utilize SG stem/progenitor cells obtained from novel ΔNp63-GFP transgenic mice to study two major areas of interest. First, we will perform functional assays to compare the abilities of ΔNp63- GFPhi and ΔNp63-GFPlow SG cells to retain both their progenitor capacity and their ability to differentiate into mature cell lineages in SG organospheres (Aim1A). Furthermore, we will perform in vivo transcriptomic profiling (RNA-seq) to generate the mRNA expression profile in a pure population of ΔNp63-GFPhi SG progenitor cells and ΔNp63-GFPlow SG cells (Aim 1B). Such in vivo studies are important, since they will identify for the first time the gene expression profile of SG progenitor cells on a broad and dynamic scale. Second, we will perform in vivo ChIP-seq studies to identify key regulatory networks and pathways regulated by ΔNp63 in SG cells. Collectively, our approach using a genetically-defined model system and cutting-edge next generation sequencing technology will better elucidate the transcriptomic landscape of SG progenitor cells and shed light on the ΔNp63-governed transcriptional regulatory network and signaling pathways. Since such genomic studies are particularly lacking for SG cells, our proposed experiments will likely reveal new biomarkers and important regulators and drivers of stem cell function in this organ. Long term, such knowledge will have clinical and therapeutic implications for human patients who suffer from SG dysfunction diseases.

项目总结