FGF signaling in lacrimal gland homeostasis, regeneration and disease

FGF 信号在泪腺稳态、再生和疾病中的作用

• 批准号: 9891063
• 负责人: Helen P. Makarenkova
• 金额: $ 46.82万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891063
• 关键词: Ablation; Adopted; Adult; Apoptosis; Basal Cell; Cell Lineage; Cell Proliferation; Cell Survival; Cell physiology; Cell surface; Cells; Chronic; Clone Cells; Complex; Cornea; Development; Diphtheria Toxin; Disease; Duct (organ) structure; Ductal Epithelium; E-Cadherin; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix; FGF10 gene; Fibroblast Growth Factor; Film; Fluorescein; Functional disorder; Gel; Genetic Transcription; Gland; Goals; Green Fluorescent Proteins; Growth; Health; Homeostasis; Human; Impairment; Inbred NOD Mice; Individual; Inflammation; Injections; Injury; Label; Lacrimal gland structure; Mediating; Mesenchymal; Mesenchyme; Molecular; Morphogenesis; Morphology; Mus; Mutation Analysis; Natural regeneration; Pain; Physiologic pulse; Population; Proliferating; Publications; Recombinants; Reporter; Research; Research Personnel; Role; Salivary Glands; Signal Transduction; Stains; Stem cell transplant; Stratum Basale; Supporting Cell; Surface; Tamoxifen; Testing; Thrombospondin 1; Time; Treatment Efficacy; Vimentin; aqueous; cell injury; cell regeneration; corneal epithelium; diphtheria toxin receptor; effective therapy; epithelial stem cell; experimental study; eye dryness; fibroblast growth factor receptor 2b; improved; in vivo; knockout gene; mRNA sequencing; novel; novel strategies; novel therapeutic intervention; ocular surface; postnatal; postnatal development; receptor; repaired; response; stem; stem cell niche; stem cells; therapeutic evaluation; tissue repair

Summary This proposal investigates the fundamental molecular and cellular mechanisms of the fibroblast growth factor (FGF) signaling that controls lacrimal gland (LG) stem and progenitor cell function and LG growth and regeneration. These mechanisms are little studied and poorly understood. Defining factors that can maintain stem/progenitor cell function in the damaged/inflamed LG will help us develop effective therapies to treat LG dysfunction due to aqueous deficiency dry eye (ADDE). Our studies and recent publications suggest that chronic inflammation impairs the epithelial stem cell niche and therefore epithelial stem cell function [1-3]. Although many researchers (including our group) are adopting the strategy of stem cell transplantation for tissue repair, an alternative approach to this therapy is to manipulate the stem cell microenvironment, or niche, to facilitate LG repair by endogenous stem cells. Through clonal cell-fate mapping studies using a multicolor Cre reporter combined with an in vivo histone2B green fluorescent protein pulse chase strategy, we demonstrated for the first time, the existence of multipotent LG epithelial stem cells in the basal layer of the duct as well as distinct long-lived progenitor cells. Our preliminary studies describe the existence of novel epithelial niche supporting Fgf10- expressing cells, able to maintain the survival and growth of stem/progenitor cells. These ductal FGF10- expressing cells have a distinctive morphology and express the epithelial marker E-cadherin. Moreover, they form an intimate interaction with the stem/progenitor cells within the basal cell layer of ducts. We hypothesize that FGF-Fgfr2b signaling is required to maintain the epithelial stem and progenitor cell populations. In the proposed research, we will determine specific roles for FGF10 expressing cells and FGF-Fgfr2b signaling in lacrimal gland homeostasis and regeneration, will test the hypothesis that basal stem/progenitor cells maintain and restrict their cell pool by generating the epithelial FGF10-expressing niche-supporting cells, finally we will also test the therapeutic efficacy of FGF10 in resolving of LG inflammation and improving the stem cell function. Our goal is to define the mechanisms/treatments able to reduce inflammation in chronically inflamed LGs and protect stem/progenitor cells and therefore the function of the LG. The proposed studies will better define the role of FGF signaling in LG homeostasis and inflammation and identify new therapeutic strategies to improve the long-term health of LG and corneal surface.

总结