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

 描述(申请人提供)：口干(口干)是头颈癌(HNC)放射治疗(RT)最常见的并发症。它对患者的生活质量产生不利影响，并使他们面临严重晚期疾病的风险。目前缓解口干症的策略成本高昂且效果不佳。调强放射治疗(IMRT)的目的是保留一个腮腺，虽然它对刺激唾液功能有一定的改善，但由于SMG腺体毗邻引流淋巴结，因此不能保留SMG腺体，因为SMG腺体是全天保持唾液功能的关键部位。最近，我们已经能够从小鼠下颌下腺(SMG)中分离出高度浓缩的成人唾液干细胞(SSC)，并表明只有多达300个细胞在注射到受照射的小鼠SMG后具有恢复唾液功能的能力。基因表达分析表明，这些细胞比它们的非干细胞对应细胞(NSCs)表达明显更多的GNDF，并且在照射前或之后单次注射GDNF的治疗导致GDNF治疗小鼠的唾液产量比赋形剂对照组增加。基于这些初步数据，这项建议的主要目标是：(1)确定挽救唾液功能的GNDF治疗的最佳剂量；(2)确定GNDF是否对于辐射后恢复SMG功能是必不可少的；(3)确定GNDF增加辐射后SSC存活的机制；(4)确定GDNF治疗对头颈部鳞状细胞癌(HNSCC)生存和生长的影响；以及(5)确定其他可能调控SSC存活和增殖的基因，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患者由RT引起的口干症。

 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.