Autonomic regulation of lacrimal stem cells

项目摘要/摘要 应用新疗法治疗干眼病的需求尚未得到满足。一种真正的水性- 由于泪腺(LG)功能低下而导致的干眼症是最常见的和使人衰弱的疾病之一。 临床结果。不幸的是，干眼症无法治愈，目前的治疗选择是针对症状 而不是解决疾病。干细胞治疗是恢复泪液功能的一种潜在的再生方法， 将自体干细胞/祖细胞移植到受损器官或组织内的干细胞 被重新激活。然而，为了实现这一目标，我们必须鉴定LG干细胞/祖细胞，并了解 他们是如何被监管的。我们的第一个目标是解决神经如何调节LG动态平衡和 通过表征潜在的祖细胞和确定神经如何控制它们的再生 分化为功能性腺体组织。副交感神经对上皮祖细胞的调节作用 其他腺体系统，对泪腺组织的维持是必不可少的。然而，尽管减少了 神经支配是干眼的一个组成部分，神经改变对泪腺动态平衡和 修复(或在祖细胞上)尚不清楚。根据我们的初步数据有力地表明 缺水干眼患者副交感神经源性神经肽Y(NPY)的变化 疾病(GWAS)和控制LG的形态发生和组织维持，我们将检验以下假设 NPY信号通过调控干/祖细胞调控LG的形成、动态平衡和再生 细胞行为。我们的预测将通过寻求以下两个具体目标来实现：1)如何定义NPY 信号在发育过程中调节LG祖细胞；2)确定 腺泡前体细胞和NPY信号转导成年LG动态平衡和再生。这些目标将是 通过结合人类泪腺和小鼠的遗传基因， 生化、免疫化学和转录学技术。我们研究这一假说的基本原理是 了解祖细胞在器官形成期间和损伤后是如何调节的是至关重要的，如果我们是 修复、再生或更换LG，提高患者的生活质量。

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.