Functional restoration through salivary progenitor label retaining cells

描述（由申请人提供）：唾液腺生物学和再生领域由于缺乏关于干细胞或祖细胞的鉴定以及唾液腺损伤后该群体的命运的知识而受到严重阻碍。细胞标记保留方法可以客观地鉴定假设为干细胞和/或祖细胞的长寿命和非增殖细胞。该提案将在两种已建立的唾液腺恢复模型中利用标记保留细胞（LRC）技术，即放射后注射胰岛素样生长因子（IGF 1）[3]和导管结扎/脱结扎[4]，以便对损伤后唾液腺再生有更全面的了解。该建议的中心假设是标记保留细胞通过重建顶端-基底极性在协调唾液腺再生中起重要作用。具体目标1将证明唾液BrdU标记保留细胞（LRC）的再生潜力。特异性目的2将评估标记保留细胞内的顶部-基底极性在恢复细胞凋亡中的内在作用。 细胞分化具体目标3将确定极性丧失对标记保留细胞的补偿性增殖反应的非细胞自主效应。本提案的总体目标是确定标记保留细胞再生分化的唾液腺结构的能力，并确定极性信号传导机制在促进分化和功能重建中的作用。该提案的长期目标是评估促进唾液干/祖细胞及其各自小生境内的顶-底极性的新疗法是否可以改善头颈癌放射治疗后慢性唾液腺功能障碍和口干症的临床治疗。

DESCRIPTION (provided by applicant): The field of salivary gland biology and regeneration is severely hampered by a lack of knowledge regarding the identification of stem or progenitor cells and the fate of this population following salivary gland damage. The cell label retaining approach can objectively identify long living and non-proliferative cells that are hypothesized to be stem and/or progenitor cells. This proposal will utilize the label retaining cell (LRC) techniqu within two established models of salivary gland restoration, post-radiation injections of insulin-like growth factor (IGF1) [3] and ductal ligation/deligation [4], in order to create a more universl understanding of salivary gland regeneration following injury. The central hypothesis of this proposal is label retaining cells play an important role in orchestrating salivary gland regeneration through reestablishment of apical- basal polarity. Specific Aim 1 will demonstrate the regenerative potential of salivary BrdU label retaining cells (LRC). Specific Aim 2 will evaluate the intrinsic role of apical-basal polarity within label retaining cells in restoration of cellular differentiation. Specific Aim 3 will determine the non-cell autonomous effect of loss of polarity on the compensatory proliferation response of label retaining cells. The general goal of this proposal is to identify the capacity of label retaining cells to regenerate differentiated salivary gland structures, and to identify the role of polarity signaling mechanism in promoting differentiation and functional reconstitution. The long-term goal of this proposal is to evaluate whether novel therapies that promote apical-basal polarity within salivary stem/progenitor cells and their respective niches could improve clinical therapeutics for chronic salivary gland dysfunction and xerostomia following radiation therapy for head and neck cancer.