Wnt/B-catenin function in irradiated taste epithelium

Wnt/B-连环蛋白在辐照味觉上皮中的功能

• 批准号: 8300381
• 负责人: Eugene R Delay
• 金额: $ 6.04万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300381
• 关键词: Adult; Affect; Alleles; Cancer Patient; Cell Differentiation process; Cell Maturation; Cells; Circumvallate Papilla; Complement; Data; Development; Dietary intake; Dose; Doxycycline; Embryo; Embryonic Development; Epithelium; Food; Fungiform Papilla; Future; Genes; Genetic; Head and neck structure; Human; Injury; Interruption; K-18 conjugate; Lead; Left; Longevity; Malignant Neoplasms; Malnutrition; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Natural regeneration; Normal Cell; Pathway interactions; Pharmaceutical Preparations; Play; Process; Radiation Injuries; Radiation therapy; Recovery; Reporter; Reporting; Research; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Stem cells; Stream; System; Taste Buds; Taste Perception; Testing; Therapeutic; Time; Training Activity; Training Programs; Walkers; base; cancer therapy; cell type; chemotherapy; experience; feeding; gastrointestinal epithelium; inhibitor/antagonist; insight; irradiation; outcome forecast; repaired; research study; restoration

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.

描述（由申请人提供）：放射治疗和化学治疗通常会破坏癌症患者的味觉系统，使他们几乎没有或没有品尝食物的能力。这些缺陷会导致饮食摄入不足，营养不良和癌症康复预后不良。然而，最近的研究表明，这些疗法破坏了成年味蕾中味觉细胞的正常细胞更新周期。成年味觉细胞的寿命为8-12天，并不断更换，但这种细胞更换周期的机制还不清楚。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重要作用。然而，新的证据表明，Wnt-？-连环蛋白信号传导也可能在成年味觉细胞替换周期中以及在辐射损伤后重新启动该周期中起重要作用。拟议中的研究将审查 的Wnt-？-连环蛋白信号通路在成人味觉细胞更换周期和辐射如何影响这一作用。一个实验将使用具有Wnt报告基因等位基因的小鼠来标记其中Wnt-？连环蛋白信号传导是活跃的，以评估照射后信号传导的变化。Nguyen和Barlow（2008）报道，在对小鼠的头部和颈部单次给予8戈伊剂量后：1）味蕾祖细胞的增殖被暂时（1-3天）抑制，中断了味蕾祖细胞的增殖。 迁移到味蕾中的新细胞的供应，2）7天后非增殖细胞从味蕾中丢失，和3）14天后味觉功能恢复。我们将比较正常和辐射小鼠的味蕾，以确定何时该信号通路的表达被辐射改变。另一组实验将确定是否有条件抑制Wnt-？连环蛋白途径降低了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性双基因系统来驱动舌上皮中Wnt分泌抑制剂Dkk 1的表达。将在14天内比较对照和辐照双基因小鼠，以检验抑制Wnt-？-连环蛋白信号传导将延迟或抑制味觉细胞更新的恢复。这个项目将产生新的见解如何味蕾是通过增殖，再生和成熟的成年味觉细胞损伤后重新填充的过程。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如何维持，如何受到辐射，化疗药物或两种疗法组合的影响，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损伤的有害影响的潜在方法。 公共卫生关系：放疗和化疗往往使癌症患者无法品尝食物，导致营养不良和癌症康复预后不良。最近的研究表明，这些疗法破坏了味觉细胞的替代。拟议的研究将研究如何Wnt-？-连环蛋白信号通路有助于成年人味觉系统的味觉细胞更新和再生周期，以及辐射如何破坏这一通路。它最终可能有助于确定如何促进恢复，甚至保护该系统免受这些治疗的影响。