Regulation of lacrimal gland development and regeneration

泪腺发育和再生的调节

• 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
• 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' 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

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(申请人提供)：干眼综合症是一种慢性缺乏足够的润滑剂在眼睛中由于故障或泪腺受损。干眼可能是自然衰老过程的一部分，可能是许多药物的副作用，也可能是环境原因(干燥的气候或污染)的影响，或者是自身免疫性疾病(干燥综合征)的结果。虽然泪腺功能已经得到了很好的研究，但对泪腺发育的调控机制却知之甚少。我们的长期目标是确定这些机制，并创建一个全面的泪腺发育模型，这可能对设计泪腺疾病患者的替代治疗方案至关重要。我们先前的研究表明，成纤维细胞生长因子家族的成员是泪腺形态发生的重要调节因子。特别是，我们发现成纤维细胞生长因子-10是泪腺和哈德氏腺发育所必需的。此外，最近的研究发现，在泪腺和唾液腺发育不全(ALSG)患者和泪耳-齿-指综合征(LAD)患者中，FGF10基因突变。这些研究共同证实了成纤维细胞生长因子信号在泪腺发育中的重要作用。在过去的两年里，我们在理解不同FGFs的结构差异如何融入其功能特性方面取得了重大进展。因此，我们表明，Fgf7和FGF10与细胞外基质中硫酸乙酰肝素(HS)结合的不同导致了不同梯度的形成，这些梯度决定了这些FGFs在分支形态发生过程中的不同功能活性。这些数据首次将FGFs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，FGFs与规范的Wnt/2-catenin信号和同源结构域转录因子Barx2在泪腺形态发生调控中具有协同作用。我们现在建议集中精力定义不同FGFs在LG分支形态发生中不同功能的结构基础(目标1)。为此，我们将对FGF3和FGF10结构的突变进行全面的功能研究。此外，我们还将评估成纤维细胞生长因子和Wnt信号通路与转录因子Barx2在控制泪腺细胞增殖和分化中的调控关系(目标2)。了解成纤维细胞生长因子信号在泪腺形态发生中的作用机制，将在发育生物学领域具有广泛的意义，从长远来看，将有助于开发治疗干眼症患者的新的治疗方法。 公共卫生相关性：在本应用中，我们将重点了解控制泪腺分支和修复的调节机制。我们的长期目标是确定这些机制，并创建一个全面的泪腺发育模型，这可能对设计泪腺疾病患者的替代治疗方案至关重要。