Mechanisms of Hedgehog Mediated Rescue of Radiation-induced Hyposalivation

描述(申请人提供)：本申请是对RFA-DE-12-004，唾液腺功能恢复(R01)的响应。涎腺功能减退是干燥综合征患者或接受放射治疗的头颈癌患者常见的病理状态。目前的治疗方法只能暂时缓解症状，而基于成人唾液腺干细胞的再生疗法已经显示出在动物模型中恢复唾液腺功能的潜力，但受到技术障碍和对分子机制缺乏了解的限制。Hedgehog细胞间途径在进化过程中高度保守，并调节损伤后各种组织的再生或修复。我们先前发现，刺猬的活动在成人唾液腺中微乎其微，但显著上调 我们的初步数据表明，在雄性和雌性小鼠的唾液腺中，辐射都会损害唾液干/祖细胞的维持和分化，而不会激活Hedgehog途径，而雄性小鼠辐射后短暂的Hedgehog激活显著挽救了唾液流量，这可能是通过维持唾液干/祖细胞及其辐射后的分化来实现的。该项目的目标是了解Hedgehog介导的拯救唾液功能低下的机制，这将导致该方法的优化或开发更有效和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)确定瞬时刺猬激活对辐射后唾液干/祖细胞维持的影响和机制；(2)确定瞬时刺猬激活对辐射后唾液干/祖细胞分化的影响和机制；以及(3)确定性别或物种差异对Hedgehog介导的辐射诱导的低增殖来源的影响。拟议实验的成功将为放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.