Manipulating Stem Cells to Provide Long Term Regeneration of Irradiated Salivary Glands

项目摘要/摘要 在世界范围内，每年有50多万存活的头颈部癌症患者的生活质量是 由于健康的唾液分泌腺体的共同照射，大大减少了。目前的治疗方法是 抢救唾液过少只能暂时缓解；因此，永久组织修复的新疗法是 需要的。在小鼠模型中，我们通过移植KIT+成功地修复了受辐射的唾液腺 干细胞/祖细胞。然而，这种干细胞/祖细胞的数量随着年龄的增长而减少， 异质性；因此，目前损害了我们有效利用这些细胞进行治疗的能力。近期 我们实验室的发现表明，转录因子Sox10严格调控细胞的增殖和 胎儿KIT+细胞的分化。在这个提议中，我们假设只有成体KIT+细胞亚群， 其中表达Sox10，保留干细胞自我更新能力。因此，我们的目标是：(1)刻画多能性 KIT+细胞群中的干细胞，(2)定义转录因子Sox10在维持成体中的作用 KIT+细胞，以及(3)鉴定人类KIT+细胞的分子异质性和Sox10特征。 总体而言，这里提出的科学想法将扩大我们对唾液腺干细胞群体的了解， 并将显著改善未来以干细胞为基础的疗法拯救唾液过少的情况。

PROJECT SUMMARY/ABSTRACT Worldwide, the quality of life of over half a million surviving head-and-neck cancer patients per year is drastically decreased due to co-irradiation of healthy saliva-secreting salivary glands. Current therapies to rescue hypo-salivation only provide temporary relief; hence new therapies for permanent tissue repair are needed. In a mouse model, we induced successful repair of irradiated salivary glands by transplanting KIT+ stem/progenitor cells. However, this population of stem/progenitor cells decreases with age and is heterogeneous; hence, currently compromising our ability to efficiently use these cells for therapy. Recent discoveries in our lab have shown that transcription factor SOX10 tightly regulates proliferation and differentiation in fetal KIT+ cells. In this proposal we hypothesize that only a subpopulation of adult KIT+ cells, which express SOX10, retain stem cell self-renewal capacity. Thus, we aim to: (1) characterize the multipotent stem cells within the KIT+ cell population, (2) define the role of transcription factor SOX10 in maintaining adult KIT+ cells, and (3) characterize the molecular heterogeneity and SOX10 signature in human KIT+ cells. Overall, the scientific ideas proposed here will expand our knowledge of salivary gland stem cell populations, and will significantly improve future hypo-salivation rescuing by stem cell-based therapies.