Characterization and Targeting the GDNF and Other Pathways in Salivary Stem Cells

 描述（由申请人提供）：口干（口干）是头颈癌（HNC）放疗（RT）最常见的并发症。它对患者的生活质量产生不利影响，并使他们面临重大晚期发病率的风险。目前缓解口干症的策略是昂贵且无效的。调强放疗（IMRT），其目的是节省一个腮腺，导致刺激唾液功能的一些改善，但它不能节省SMG腺体，这是至关重要的休息唾液功能的一天，因为它们的位置邻近引流淋巴结。最近，我们已经能够从小鼠下颌下腺（SMG）中分离出高度富集的成体唾液干细胞（SSC），并显示当注射到照射的小鼠SMG中时，只有300个细胞具有恢复唾液功能的能力。基因表达分析表明，这些细胞表达显着更多的GNDF比他们的非干细胞对应物（NSC）和治疗与单次注射GDNF之前或之后照射导致增强的唾液产生GDNF治疗小鼠相比，车辆控制。根据这些初步数据，本提案的主要目标是：（1）确定GNDF治疗挽救唾液功能的最佳剂量，（2）确定GNDF是否是放射后恢复SMG功能所必需的，（3）确定GNDF增加放射后SSC存活的机制，（4）确定GDNF治疗对头颈部鳞状细胞癌（HNSCC）的存活和生长的影响，和（5）鉴定可能调节SSC存活和增殖的其他基因，用于未来的干细胞治疗。我们的最终目标是设计新的GNDF或其他策略来减轻HNC患者中RT诱导的口干症。

 DESCRIPTION (provided by applicant): Xerostomia (dry mouth) is the most common complication of radiotherapy (RT) in head and neck cancer (HNC). It adversely impacts patients' quality of life and places them at risk for significant late morbidities. Current strategies to mitigate xerostomia are costly and ineffective. Intensity modulated radiotherapy (IMRT), which aims to spare one parotid gland, has resulted in some improvement of stimulatory salivary function, but it cannot spare the SMG glands, which are crucial for resting salivary function throughout the day, because of their locations adjacent to the draining lymph nodes. Recently, we have been able to isolate a highly enriched population of adult salivary stem cells (SSC) from murine submandibular gland (SMG) and showed that as few as 300 cells had the ability restore salivary function when injected into irradiated murine SMG. Gene expression analysis showed that these cells expressed significantly more GNDF than their non-stem-cell counterparts (NSCs) and treatment with a single injection of GDNF either before or after irradiation resulted in enhanced saliva production in GDNF treated mice compared to vehicle controls. Based on these preliminary data, the main objectives of this proposal are: (1) to identify the best dose of GNDF treatment to rescue saliva function, (2) to determine whether GNDF is essential for restoring SMG function after radiation, (3) to determine the mechanism by which GNDF increased SSC survival after radiation, (4) to determine the effect of GDNF treatment on survival and growth of head and neck squamous cell carcinoma (HNSCC), and (5) to identify other genes that may regulate SSC survival and proliferation for future stem cell therapy. Our ultimate goal is to devise novel GNDF or other strategies to mitigate RT-induced xerostomia in HNC patients.