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

 描述（由申请人提供）：泪膜是必不可少的整体眼睛健康和视力。干眼症（DED）是一种多因素的泪液和眼表疾病，其特征是干燥和刺激症状。真正的水缺乏性干眼症，临床上称为干燥性角膜结膜炎（KCS），是最常见的（约400万）并发症之一，并且是由于泪腺（LG）功能低下。尽管在了解KCS进展期间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患者中LG功能障碍的指标是副交感神经支配的丧失，这对于LG功能和副交感神经源性神经递质神经肽Y（NPY）的下调是必不可少的。然而，神经支配和神经肽Y在LG的发展，稳态和再生的功能是未知的。我推测，副交感神经源性神经肽Y调节LG上皮形态发生和再生。在这个建议中，我建议定义的作用，神经肽Y及其受体在LG的发展和再生。因此，本提案的具体目的是1）确定在LG发育期间NPY信号传导对上皮细胞和间充质细胞的影响;和2）确定NPY信号传导对LG再生的影响。这些目标将使用小鼠遗传学与遗传、离体器官、生物化学、免疫化学和荧光成像技术的组合来实现。我调查这一假说的理由是，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，将使有针对性的再生方法，以扭转泪腺功能障碍的设计。

 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.