Wnt/B-catenin function in irradiated taste epithelium

描述(申请人提供)：放疗和化疗经常扰乱癌症患者的味觉系统，使他们几乎没有品尝食物的能力。这些缺陷会导致饮食摄入不足，营养不良，癌症康复的预后更差。然而，最近的研究表明，这些疗法扰乱了成人味蕾中味觉细胞的正常细胞更新周期。成人味觉感觉细胞的寿命为8-12天，并不断被更换，但负责这一细胞更换周期的机制尚不清楚。在胚胎发育过程中，Wnt-？-catenin信号通路在细胞分化和成熟过程中起着重要作用。然而，新的证据表明，Wnt-？-catenin信号也可能在成人味觉细胞替换周期中发挥重要作用，并在辐射损伤后重新启动这一周期。拟议中的研究将检验这一角色 Wnt-？-catenin信号通路在成人味觉细胞替换周期中的作用以及辐射如何影响这一作用。一项实验将使用带有Wnt报告等位基因的小鼠来标记Wnt-？-catenin信号活跃的细胞，以评估辐射后信号的变化。Nguyen和Barlow(2008)报道，在对小鼠头部和颈部进行单次8Gy射线照射后：1)味蕾前体细胞的增殖暂时停止(1-3天)，中断 2)非增殖细胞在7天后从味蕾中消失，3)味觉功能在14天后恢复。我们将比较正常和辐射小鼠的味蕾，以确定这一信号通路的表达何时会因辐射而改变。另一组实验将确定条件抑制Wnt-？-catenin途径是否会降低味觉上皮在辐射后恢复的能力。我们将在喂食多西环素的小鼠中使用条件双基因系统来驱动舌上皮细胞中Wnt分泌抑制物Dkk1的表达。对照和辐射后的双基因小鼠将在14天内进行比较，以检验Wnt-？-catenin信号的抑制将延缓或抑制味觉细胞更新的恢复的假设。这个项目将对味蕾如何在受伤后通过成年味觉细胞的增殖、再生和成熟而重新繁殖的过程产生新的见解。这项研究将为未来的研究提供基础，以研究正常成人味蕾系统是如何维持的，它是如何受到辐射、化疗药物或两种疗法联合作用的影响的，并开发促进恢复甚至保护味觉细胞免受癌症治疗或其他类型伤害的潜在方法。 与公共卫生相关：放疗和化疗往往使癌症患者无法品尝食物，导致营养不良，癌症康复的预后更差。最近的研究表明，这些疗法扰乱了味觉感觉细胞的替换。这项拟议的研究将研究Wnt-？-catenin信号通路如何促进成人味觉系统的味觉细胞更新和再生周期，以及辐射如何扰乱这一途径。它最终可能有助于确定如何促进康复，甚至保护这个系统免受这些疗法的影响。

DESCRIPTION (provided by applicant): Radiotherapy and chemotherapy often disrupt the taste system of cancer patients, leaving them with little or no ability to taste foods. These deficts can cause poor dietary intake, malnutrition and a poorer prognosis for recovery from cancer. However, recent studies suggest that these therapies disrupt the normal cell renewal cycle of taste cells in adult taste buds. Adult taste sensory cells have a life span of 8-12 days and are continuously replaced but the mechanisms responsible for this cell replacement cycle are not well understood. During embryonic development, the Wnt-?-catenin signal pathway plays an important role in cell differentiation and maturation. However, new evidence suggests that Wnt-?-catenin signaling may also play an important part in the adult taste cell replacement cycle and in restarting this cycle after injury from irradiation. The proposed research will examine the role of the Wnt-?-catenin signal pathway in the adult taste cell replacement cycle and how irradiation affects this role. One experiment will use mice with a Wnt reporter allele to mark cell in which Wnt-?-catenin signaling is active to assess changes in signaling after irradiation. Nguyen and Barlow (2008) reported that after a single 8 Gy dose to the head and neck of mice: 1) proliferation of taste bud progenitor cells is temporarily (1-3 days) arrested, interrupting the supply of new cells migrating into taste buds, 2) non-proliferating cells are lost from taste buds after 7 days, and 3) restoration of taste function occurs after 14 days. We will compare the taste buds of normal and irradiated mice to determine when expression of this signal pathway is altered by irradiation. Another set of experiments will determine if conditional inhibition of the Wnt-?-catenin pathway decreases the ability of the taste epithelium to recover following irradiation. We will use a conditional bigenic system in mice fed doxycycline to drive the expression of the Wnt secreted inhibitor, Dkk1 in lingual epithelium. Control and irradiated bigenic mice will be compared over 14 days to test the hypothesis that inhibition of Wnt-?-catenin signaling will retard or repress recovery of taste cell renewal. This project will yield ne insights into the processes underlying how taste buds are repopulated through proliferation, regeneration, and maturation of adult taste cells after injury. This research will provide the basi for future research to study how the normal adult taste bud system is maintained, how it is affected by injury from irradiation, chemotherapy drugs, or the combination of the two therapies, and to develop potential ways of facilitating recovery or even protecting taste cells from the deleterious effects of cancer treatments or from other types of injury. PUBLIC HEALTH RELEVANCE: Radiotherapy and chemotherapy often leaves the cancer patient without the ability to taste foods, leading to malnutrition and a poorer prognosis for recovery from cancer. Recent studies suggest that these therapies disrupt the replacement of taste sensory cells. The proposed research will study how the Wnt-?-catenin signaling pathway contributes to the taste cell renewal and regeneration cycle of the adult taste system and how irradiation disrupts this pathway. It may eventually help determine how to facilitate recovery or even protect this system from the effects of these therapies.