Mechanisms of Hedgehog Mediated Rescue of Radiation-induced Hyposalivation

描述（由申请人提供）：本申请是对RFA-DE-12-004，涎腺功能恢复（R 01）的回应。唾液腺功能减退是干燥综合征患者或头颈部肿瘤放疗患者的常见病理状态。目前的治疗只能暂时缓解症状，而基于成体唾液腺干细胞的再生疗法已显示出在动物模型中恢复唾液腺功能的潜力，但受到技术障碍和缺乏分子机制理解的限制。Hedgehog细胞间通路在进化过程中高度保守，调节各种组织损伤后的再生或修复。我们先前发现Hedgehog活性在成年唾液腺中是边缘性的，但在成年唾液腺中显著上调。 在物理损伤后的功能再生过程中;我们的初步数据表明，在雄性和雌性小鼠的唾液腺中，辐射损害唾液干/祖细胞的维持和分化，并且不激活Hedgehog途径，而在雄性小鼠中辐射后的短暂Hedgehog激活显著挽救了唾液流速，可能是通过维持唾液干/祖细胞和它们在辐射后的分化。该项目的目标是了解Hedgehog介导的唾液分泌不足的拯救机制，这将导致这种方法的优化或开发更有效，更安全的方法来恢复唾液功能。为了实现这一目标，我们将：（1）确定瞬时Hedgehog激活对放射后唾液干/祖细胞维持的作用和机制;（2）确定瞬时Hedgehog激活对放射后唾液干/祖细胞分化的作用和机制;（3）确定性别或种属差异对Hedgehog介导的放射诱导的唾液减少的影响。实验的成功将为放射治疗后唾液腺的功能恢复开辟一条新的途径。

DESCRIPTION (provided by applicant): This application is in response to RFA-DE-12-004, Functional Restoration of Salivary Glands (R01). Hypofunction of salivary gland is a common pathological condition in patients with Sjogren's syndrome or treated with radiotherapy for head and neck cancer. Current treatments can only temporarily relieve the symptoms, while regenerative therapies based on adult salivary gland stem cells have shown potential to restore salivary gland function in animal models but limited by technical hurdles and lack of understanding of molecular mechanisms. Hedgehog intercellular pathway is highly conserved during evolution and regulates regeneration or repair of various tissues after injury. We found previously that Hedgehog activity is marginal in adult salivary gland but significantly upregulated during their functional regeneration after physical injury; our preliminary data suggested that in salivary glands of both male and female mice, radiation impairs maintenance and differentiation of salivary stem/progenitor cells, and does not activate Hedgehog pathway, while transient Hedgehog activation after radiation in male mice significantly rescued salivary flow rates, possibly by both maintenance of salivary stem/progenitor cells and their differentiation after radiation. The goal of this project is understanding the mechanisms of Hedgehog-mediated rescue of hyposalivation, which will lead to optimization of this approach or development of more efficient and safer approaches to restore salivary function. To achieve this goal, we will: (1) determine the effects and mechanisms of transient Hedgehog activation on maintenance of salivary stem/progenitor cells after radiation; (2) determine the effects and mechanisms of transient Hedgehog activation on differentiation of salivary stem/progenitor cels after radiation; and (3) determine the effects of gender- or species-differences on Hedgehog mediated resuce of radiation-induced hyposalivation. Success of proposed experiments will open a new avenue for functional restoration of salivary glands after radiotherapy.