Regulation of lacrimal gland development and regeneration

泪腺发育和再生的调节

基本信息

批准号：
8217219
负责人：
Helen P. Makarenkova
金额：
$ 23.74万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8217219
关键词：
Adverse effects Aging-Related Process Autoimmune Diseases Binding Biological Biological Process Cell Differentiation process Cell Proliferation Chronic Climate Data Development Developmental Biology Diffusion Disease Dry Eye Syndromes Epithelial Epithelial Cells Extracellular Matrix Eye FGF10 gene FGF3 gene FGF7 gene Family Fibroblast Growth Factor Functional disorder Gene Expression Gene Expression Regulation Gene Family Genes Goals Harderian Gland Heparitin Sulfate Hospitals Laboratories Lacrimal gland structure Lead Letters Los Angeles Lubrication Mediating Mediator of activation protein Medical center Mesenchymal Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Modeling Modification Molecular Structure Morphogenesis Mutation Natural regeneration Organ Pathway interactions Patients Pharmaceutical Preparations Pollution Process Property Publications Reagent Regulation Salivary Glands Signal Pathway Signal Transduction Signaling Molecule Sjogren&apos s Syndrome Specificity Structure Syndrome System Time Tissues Translating Work alternative treatment base cell motility computerized data processing design digital eye dryness fibroblast growth factor 10 fibroblast growth factor receptor 2b fibroblast growth factor receptor 2c gland development homeodomain member migration novel therapeutic intervention proto-oncogene protein kfgf public health relevance repaired research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dry eye syndrome is a chronic lack of sufficient lubrication in the eye due to malfunction or damage to the lacrimal gland. Dry eye may occur as a part of the natural aging process, as a side effect of many medications, as an effect of environmental causes (dry climate or pollution), or as result of an autoimmune disease (Sjogren's syndrome). Though lacrimal gland function has been well studied, relatively little is known about the mechanisms that regulate lacrimal gland development. Our long-term goal is to define these mechanisms and to create a comprehensive model of lacrimal gland development that could be critical for designing alternative treatments for patients with lacrimal gland disorders. Our previous studies showed that members of the fibroblast growth factor (FGF) family are important regulators of lacrimal gland morphogenesis. In particular we found that FGF-10 was necessary for lacrimal and Harderian gland development. Moreover, recent studies have identified mutations in FGF10 in patients with aplasia of the lacrimal and salivary glands (ALSG) and in lacrimo-auriculo-dento-digital (LADD) syndrome. Together these studies established that FGF signaling is important for lacrimal gland development. Over the past two years, we have made significant advances in understanding how structural differences in various FGFs are incorporated into their functional properties. Thus we showed that differences in the binding of FGF7 and FGF10 to heparan sulfate (HS) within the extracellular matrix result in the formation of different gradients that dictate distinct functional activities of these FGFs during branching morphogenesis. These data for the first time connected the structural differences of FGFs with their biological function in LG branching morphogenesis. Our preliminary studies have also shown that FGFs cooperate with canonical Wnt/2-catenin signaling and the homeodomain transcription factor Barx2 in regulating of lacrimal gland morphogenesis. We now propose to focus our efforts on defining structural basis for distinct functions of different FGFs in LG branching morphogenesis (Aim 1). In this aim we will perform a comprehensive functional study of mutations in FGF3 and FGF10 structure. In addition, we will evaluate the regulatory connections between FGF and Wnt signaling pathways and the transcription factor Barx2 in controlling lacrimal gland cell proliferation and differentiation (Aim 2). Understanding the mechanistic details of the FGF signaling in lacrimal gland morphogenesis will have broad significance in the field of developmental biology and will, in the long-term, help the development of novel therapeutic approaches for treatment of patients with dry eye conditions. PUBLIC HEALTH RELEVANCE: In this application we will focus on understanding the regulatory mechanisms that control lacrimal gland branching and repair. Our long-term goal is to define these mechanisms and to create a comprehensive model of lacrimal gland development that could be critical for designing alternative treatments for patients with lacrimal gland disorders.

描述（由申请人提供）：干眼症综合症是由于故障或泪腺损害而慢性缺乏足够的润滑性。干眼症可能是自然衰老过程的一部分，作为许多药物的副作用，作为环境原因（干燥气候或污染）的作用，也可能是由于自身免疫性疾病（Sjogren's综合征）的结果。尽管对泪腺功能进行了充分的研究，但对调节富富富腺发育的机制知之甚少。我们的长期目标是定义这些机制，并创建一个详细的泪腺发育模型，这对于为泪腺疾病患者设计替代治疗至关重要。我们以前的研究表明，成纤维细胞生长因子（FGF）家族的成员是富富腺形态发生的重要调节剂。特别是，我们发现FGF-10对于泪腺和硬腺发育是必不可少的。此外，最近的研究已经确定了富集腺和唾液腺（ALSG）以及曲limo-auriculo-dento-digital（LADD）综合征患者的FGF10突变。这些研究共同确定了FGF信号对于泪腺发育很重要。在过去的两年中，我们在了解如何将各种FGF的结构差异纳入其功能属性方面取得了重大进步。因此，我们表明，在细胞外基质中FGF7和FGF10与硫酸乙酰肝素（HS）的结合差异导致不同梯度的形成，这些梯度在分支形态发生过程中决定了这些FGF的不同功能活性。这些数据首次将FGF的结构差异与其在LG分支形态发生中的生物学功能联系起来。我们的初步研究还表明，FGF与规范的Wnt/2-catenin信号传导和同源域转录因子BARX2合作，以调节泪腺形态发生。现在，我们建议将精力集中在定义结构基础上，以在LG分支形态发生中不同FGF的不同功能（AIM 1）。在此目标中，我们将对FGF3和FGF10结构中的突变进行全面的功能研究。此外，我们将评估FGF和Wnt信号通路与转录因子BARX2之间的调节连接，以控制泪腺细胞增殖和分化（AIM 2）。了解泪腺形态发生中FGF信号传导的机理细节将在发育生物学领域具有广泛的意义，并将长期帮助开发新型的治疗方法，以治疗干眼症患者的患者。公共卫生相关性：在本应用程序中，我们将专注于理解控制泪腺分支和修复的监管机制。我们的长期目标是定义这些机制，并创建一个详细的泪腺发育模型，这对于为泪腺疾病患者设计替代治疗至关重要。