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 该提案研究了成纤维细胞的基本分子和细胞机制， 控制泪腺（LG）干细胞和祖细胞功能的生长因子（FGF）信号传导和LG 生长和再生。这些机制很少被研究和了解。定义因素， 可以在受损/发炎的LG中维持干细胞/祖细胞功能， 治疗由于水性缺乏性干眼（ADDE）引起的LG功能障碍的疗法。我们的研究和最近 出版物表明慢性炎症损害上皮干细胞龛， 上皮干细胞功能[1-3]。尽管许多研究人员（包括我们的团队）正在采用 干细胞移植用于组织修复的策略，这种治疗的替代方法是， 操纵干细胞微环境或小生境，以促进内源性干细胞对LG的修复。 通过克隆细胞命运作图研究，使用一种新的CCRre报告基因结合体内 组蛋白2B绿色荧光蛋白脉冲追踪策略，我们首次证明， 导管基底层中存在多能LG上皮干细胞以及不同的长寿命细胞。 祖细胞我们的初步研究描述了支持Fgf 10的新上皮小生境的存在。 表达细胞，能够维持干/祖细胞的存活和生长。这些导管FGF 10- 表达细胞具有独特的形态并表达上皮标记物E-钙粘蛋白。此外，委员会认为， 它们与导管的基底细胞层内的干/祖细胞形成密切的相互作用。我们 假设FGF-Fgfr 2b信号传导是维持上皮干细胞和祖细胞 人口。 在拟议的研究中，我们将确定FGF 10表达细胞和FGF-Fgfr 2b的具体作用， 信号在泪腺稳态和再生，将测试假设，基础 干/祖细胞通过产生表达FGF 10的上皮细胞来维持和限制它们的细胞库。 最后，我们还将测试FGF 10在LG消退中的治疗效果 炎症和改善干细胞功能。 我们的目标是确定能够减少慢性炎症患者炎症的机制/治疗方法。 LG和保护干/祖细胞，因此LG的功能。拟议的研究将 更好地定义FGF信号在LG稳态和炎症中的作用，并确定新的治疗方法， 改善LG和角膜表面长期健康的策略。