Regulation of lacrimal gland development and regeneration

描述（由申请人提供）：干眼综合征是由于泪腺功能障碍或损伤导致眼睛长期缺乏足够润滑。干眼症可能作为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）的影响，或作为自身免疫性疾病（干燥综合征）的结果而发生。虽然泪腺的功能已经得到了很好的研究，但相对而言，对调节泪腺发育的机制知之甚少。我们的长期目标是确定这些机制，并建立一个全面的泪腺发育模型，这对设计泪腺疾病患者的替代治疗方案至关重要。我们以前的研究表明，成纤维细胞生长因子（FGF）家族成员是泪腺形态发生的重要调节因子。特别是，我们发现FGF-10是泪腺和哈氏腺发育所必需的。此外，最近的研究已经确定了患有泪腺和唾液腺发育不全（ALSG）和泪-耳-牙-指（拉德）综合征的患者中FGF 10的突变。总之，这些研究确定FGF信号传导对泪腺发育很重要。在过去的两年中，我们在理解各种FGF的结构差异如何纳入其功能特性方面取得了重大进展。因此，我们表明，在细胞外基质内的FGF 7和FGF 10的硫酸乙酰肝素（HS）的结合的差异，导致在形成不同的梯度，决定不同的功能活动，这些FGF在分支形态发生。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与经典的Wnt/2-catenin信号传导和同源域转录因子Barx 2在泪腺形态发生中起协同调节作用。我们现在建议集中精力定义不同FGF在LG分支形态发生中的不同功能的结构基础（目的1）。在这个目标中，我们将进行全面的功能研究的突变FGF 3和FGF 10的结构。此外，我们将评估FGF和Wnt信号通路和转录因子Barx 2在控制泪腺细胞增殖和分化（目标2）之间的调节联系。了解泪腺形态发生中FGF信号传导的机制细节将在发育生物学领域具有广泛的意义，并且从长远来看，将有助于开发用于治疗干眼症患者的新治疗方法。 公共卫生相关性：在这个应用程序中，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，并建立一个全面的泪腺发育模型，这对设计泪腺疾病患者的替代治疗方案至关重要。

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.