Defining the role of NPY signaling during lacrimal gland development and regeneration

 描述(申请人提供)：泪膜对整体眼睛健康和视力是必不可少的。干眼病(DED)是一种泪液和眼表的多因素疾病，以干涩和刺激症状为特征。真正的缺水干眼，临床上称为干性角结膜炎(KCS)，是最常见的并发症之一(约400万)，是由于泪腺(LG)功能低下所致。尽管在理解KCS进展过程中的腺体衰竭方面取得了重大进展，但目前还没有修复/再生LG以恢复泪液产生的疗法。DED患者LG功能障碍的一个指标是副交感神经支配的丧失，这是LG功能和副交感神经衍生神经递质Y(NPY)下调所必需的。然而，神经支配和NPY在LG发育、动态平衡和再生中的作用尚不清楚。我推测副交感神经来源的NPY调节LG上皮的形态发生和再生。在这个提案中，我建议定义NPY及其受体在LG发育和再生过程中的作用。因此，本研究的具体目的是：1)确定NPY信号在LG发育过程中对上皮细胞和间充质细胞的影响；2)确定NPY信号在LG再生中的作用。这些目标将利用小鼠遗传学与遗传学、体外器官、生化、免疫化学和荧光成像技术相结合来实现。我研究这一假说的基本原理是，了解神经支配对泪腺形态发生和再生的影响以及调节这些过程的机制，将有助于设计有针对性的再生方法来逆转泪腺功能障碍。

 DESCRIPTION (provided by applicant): Tear film is essential for overall eye health and visual acuity. Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. A true aqueous- deficient dry eye, known clinically as keratoconjunctivitis sicca (KCS) is among the most common (~4 million) complications and is due to inefficient lacrimal gland (LG) function. Despite significant progress in understanding glandular failure during KCS progression, there is currently no therapy for repairing/regenerating the LG to restore tear production. An indicator of LG dysfunction in patients with DED is the loss of parasympathetic innervation, which is essential for LG function and the downregulation of the parasympathetic- derived neurotransmitter neuropeptide Y (NPY). However, the function of innervation and NPY in LG development, homeostasis and regeneration is not known. I hypothesize that parasympathetic nerve-derived NPY regulates LG epithelial morphogenesis and regeneration. In this proposal, I propose to define the role of NPY and its receptors during LG development and regeneration. Thus the Specific Aims of this proposal are to 1) Determine the influence of NPY signaling on epithelial and mesenchymal cells during LG development; and 2) Determine the effects of NPY signaling on LG regeneration. These aims will be achieved using a combination of mouse genetics in conjunction with genetic, ex vivo organ, biochemical, immunochemical, and fluorescence imaging techniques. My rationale for investigating this hypothesis is that understanding the effects of innervation on lacrimal gland morphogenesis and regeneration and the mechanisms that regulate these processes will enable the design of targeted regenerative approaches to reverse lacrimal dysfunction.