权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Bidirectional control of keratinocyte differentiation and proliferation by transcription factor FOXQ1

转录因子FOXQ1对角质形成细胞分化和增殖的双向控制

基本信息

批准号：
10717982
负责人：
Mikhail Nikiforov
金额：
$ 51.31万
依托单位：
DUKE UNIVERSITY
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：
2023-08-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717982
关键词：
Affect Atopic Dermatitis Automobile Driving Biological Calcineurin Calcium Cell Maintenance Cell Proliferation Cells Chemicals Dehydration Differentiation Antigens Disease Epidermis Equilibrium Event FOXQ1 gene Gene Expression Genes Genetic Transcription Histone Deacetylase Homeostasis Human Hyperplasia Imiquimod Impairment Inflammatory Knock-out Knockout Mice Large Keratinocyte Lesion Mediating Messenger RNA Mus Pattern Persons Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Prevention Process Proliferating Protein Dephosphorylation Protein Family Proteins Psoriasis Regulation Role STAT3 gene Signal Transduction Skin Testing Transcriptional Regulation Wild Type Mouse cofactor constitutive expression cytokine extracellular gene repression histone demethylase in vivo intercellular communication interleukin-22 keratinocyte keratinocyte differentiation member novel overexpression programs response skin barrier skin disorder transcription factor treatment response

项目摘要

The skin forms the first barrier against physical, biological and chemical insults and is essential for prevention of dehydration. To maintain this function epidermal keratinocytes undergo differentiation. During differentiation, the gene expression programs in keratinocytes switch from maintenance of cell proliferation to terminal differentiation. Calcium gradient formed between the basal and upper epidermal layers is a major factor underlying induction of terminal differentiation in keratinocytes. In addition, skin homeostasis relies on well- orchestrated intercellular communications mediated by cytokines that are produced by keratinocytes and other skin resident cells. We have identified that transcription factor FOXQ1 (a member of the Forkhead Box family of proteins) utilizes a novel, rheostat-like mechanism of transcriptional regulation of keratinocyte differentiation. Thus, in presence of low extracellular calcium, FOXQ1 repressed genes associated with epidermal differentiation in normal human keratinocytes (NHKs) and immortalized human keratinocytes (HaCaT). On the contrary, in calcium-treated (i.e. differentiation-induced) NHK and HaCaT cells, FOXQ1 activated the same set of genes. Therefore, in Specific Aim 1, we will identify the mechanisms underlying transcriptional regulation by FOXQ1 of keratinocyte differentiation. In addition, we demonstrated that under normal conditions, depletion of FOXQ1 in cultured keratinocytes decreased whereas its overexpression increased cell proliferation. Moreover, Foxq1-/- mice demonstrated decreased epidermal hyperplasia in response to treatment with imiquimod which induces psoriasis-like phenotypes in mouse epidermis. Therefore, in Specific Aim 2, we will generate keratinocyte-specific Foxq1 knock-out mice and identify the mechanisms of FOXQ1 regulation by pro-inflammatory cytokines and the role of Foxq1 in regulation of keratinocyte hyper-proliferation.

皮肤是抵御物理、生物和化学侵害的第一道屏障，对预防至关重要