Neuronal regulation of salivary stem cells

描述（由申请人提供）：唾液腺功能障碍是头颈癌放疗后病理损伤的结果，严重影响患者的口腔健康和生活质量。用于恢复唾液功能的潜在再生方法是干细胞疗法，其中自体干/祖细胞被移植到受损器官中或组织内的干细胞被重新激活。然而，人类干细胞/祖细胞的身份以及它们是如何被调控的尚不清楚。在本申请中，我们建议确定小鼠和人类唾液腺中推定的祖细胞对组织修复和再生的贡献，并确定神经元信号对其行为的影响。副交感神经对唾液腺的功能和再生以及上皮祖细胞的维持是必不可少的，并且在放疗后在人唾液腺中严重减少。我们假设，在上皮细胞中， 成年小鼠和人类唾液腺在体内平衡和损伤期间响应神经元信号再生腺泡。因此，本项目的具体目标是：1）确定副交感神经调节祖细胞命运的机制，2）确定唾液祖细胞和神经元信号传导对成人体内平衡和修复的贡献，3）鉴定人类唾液腺中的上皮祖细胞。这些目标将通过结合人类唾液腺和小鼠遗传学以及遗传、生物化学、免疫化学和荧光成像技术来实现。我们研究这一假说的基本原理是，了解唾液腺中祖细胞的特性和调节唾液组织再生的机制将使设计有针对性的再生方法来逆转唾液腺功能障碍。

DESCRIPTION (provided by applicant): Salivary gland dysfunction occurs as a result of pathological injury after radiotherapy for head and neck cancer and significantly compromises the oral health and quality of life of patients. A potential regenerative approach for restoring salivary 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, the identity of human stem/progenitors and how they are regulated are unknown. In this application we propose to determine the contributions of putative progenitors in the mouse and human salivary gland to tissue repair and regeneration and to determine the influence of neuronal signals on their behavior. Parasympathetic nerves are essential to salivary function and regeneration, as well as the maintenance of epithelial progenitor cells, and are severely reduced in human salivary glands after radiotherapy. We hypothesize that discrete epithelial progenitor cells in the adult mouse and human salivary gland regenerate acini during homeostasis and injury in response to neuronal signals. Thus, the Specific Aims of this project are to: 1) Define the mechanisms by which parasympathetic nerves regulate progenitor cell fate, 2) Determine the contribution of salivary progenitor cells and neuronal signaling to adult homeostasis and repair and 3) Identify epithelial progenitor cells in the human salivary gland. These aims will be achieved using a combination of human salivary glands and mouse genetics in conjunction with genetic, biochemical, immunochemical, and fluorescence imaging techniques. Our rationale for investigating this hypothesis is that understanding progenitor cell identity in the salivary gland and the mechanisms that regulate salivary tissue regeneration will enable the design of targeted regenerative approaches to reverse salivary dysfunction.