Autonomic regulation of lacrimal stem cells

项目总结/摘要 对于应用新疗法来治疗干眼病存在关键的未满足的需求。一个真正的水- 由于泪腺（LG）功能不足而引起的干眼症是最常见的和使人衰弱的 临床结果。不幸的是，干眼没有治愈的方法，目前的治疗方案针对症状，而不是 而不是解决疾病。一种潜在的恢复泪液功能的再生方法是干细胞治疗， 其中自体干/祖细胞被移植到受损器官或组织内的干细胞中 被重新激活。然而，为了实现这一目标，我们必须识别LG干/祖细胞，并了解 它们是如何受到监管的。我们的第一个目标是解决神经如何调节LG稳态， 通过表征潜在的祖细胞并确定神经如何控制其再生， 分化为功能性腺组织。副交感神经调节上皮祖细胞在 其他腺体系统，是必要的维护泪腺组织。尽管减少了 神经支配是干眼的组成部分，神经改变对泪腺稳态的影响， 修复（或祖细胞）尚不清楚。根据我们的初步数据， 副交感神经源性神经肽Y（NPY）在水缺乏性干眼患者中改变 疾病（GWAS）和控制LG形态发生和组织维持，我们将测试的假设， NPY信号通过控制干/祖细胞调节LG的形成、稳态和再生 细胞行为我们的预测将通过2个具体目标来解决，这些目标旨在：1）定义NPY如何 在发育过程中调节LG祖细胞的信号传导;以及2）确定以下的贡献： 腺泡祖细胞和NPY信号传导到成年LG体内平衡和再生。这些目标将是 使用人类泪腺和小鼠遗传学结合遗传学， 生物化学、免疫化学和转录组学技术。我们研究这一假设的基本原理是 了解祖细胞在器官形成过程中和损伤后的调节方式至关重要， 修复、再生或更换LG，改善患者生活质量。

Project Summary/Abstract There is a critical unmet need for the application of new therapies to treat dry eye disease. A true aqueous- deficient dry eye due to inefficient lacrimal gland (LG) function is among the most common and debilitating clinical outcomes. Unfortunately, dry eye has no cure, and current treatment options target symptoms rather than resolving disease. A potential regenerative approach for restoring lacrimal function is stem cell therapy, where autologous stem/progenitor cells are transplanted into the injured organ or stem cells within the tissue are reactivated. However, to achieve this goal, we must identify LG stem/progenitor cells and understand how they are regulated. Our first objective is to resolve how nerves regulate LG homeostasis and regeneration by characterizing potential progenitor cells and determining how nerves control their differentiation into functional glandular tissue. Parasympathetic nerves regulate epithelial progenitor cells in other glandular systems, and are essential to the maintenance of lacrimal tissue. Yet, despite reduced innervation being a component of dry eye, the impact of nerve alterations on lacrimal gland homeostasis and repair (or on progenitor cells) is not known. Based on our preliminary data strongly suggesting the parasympathetic-nerve derived neuropeptide Y (NPY) is altered in patients with aqueous deficient dry eye disease (GWAS) and controls LG morphogenesis and tissue maintenance, we will test the hypothesis that NPY signaling regulates LG formation, homeostasis and regeneration by controlling stem/progenitor cell behavior. Our prediction will be addressed through 2 specific aims that seek to: 1) Define how NPY signaling regulates LG progenitor cells during development; and to 2) Determine the contribution of acinar progenitors and NPY signaling to adult LG homeostasis and regeneration. These aims will be achieved using a combination of human lacrimal glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and transcriptomic techniques. Our rationale for investigating this hypothesis is that understanding how progenitor cells are regulated during organ formation and after injury is critical if we are to repair, regenerate or replace the LG, and improve patient quality of life.