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）：放疗和化学疗法经常破坏癌症患者的味觉系统，使他们几乎没有或根本没有味道食物的能力。这些违规会导致饮食不良，营养不良和从癌症中恢复的预后较差。但是，最近的研究表明，这些疗法破坏了成人味蕾味道细胞的正常细胞更新周期。成人味道感官细胞的寿命为8-12天，并且被连续替换，但尚不清楚负责此细胞替代周期的机制。在胚胎发育过程中，Wnt - ？ - catenin信号途径在细胞分化和成熟中起重要作用。但是，新的证据表明，Wnt - ？ - catenin信号传导也可能在成人味觉细胞替代周期以及受辐射后重新启动此周期中起重要作用。拟议的研究将研究该角色 Wnt - ？ - catenin信号途径在成人味觉细胞替代周期中以及辐射如何影响这一作用。一个实验将将小鼠与Wnt报告基因等位基因一起标记细胞，其中Wnt - ？ - catenin信号传导有效地评估照射后信号传导的变化。 Nguyen and Barlow（2008）报告说，在小鼠的头部和颈部进行了8 Gy剂量后：1）味道芽祖细胞的增殖暂时（1-3天）被捕，中断 新细胞的供应迁移到味蕾中，2）未增殖的细胞在7天后因味蕾而丢失，3）恢复味觉功能后14天后发生。我们将比较正常小鼠和辐照小鼠的味蕾，以确定该信号途径的表达何时通过辐照改变。另一组实验将确定对Wnt的条件抑制 - ？ - catenin途径是否会降低辐射后味觉上皮恢复的能力。我们将在喂食强力霉素的小鼠中使用条件胆汁胆囊系统来驱动Wnt分泌的抑制剂DKK1在舌上皮中的表达。将在14天内比较对照和辐照的临床小鼠，以检验抑制Wnt的假设 - ？ - catenin信号传导将阻止或抑制更新的味觉细胞的恢复。该项目将对味蕾在受伤后的增殖，再生和成熟度的重新植入方式中产生洞察力。这项研究将为未来的研究提供BASI，以研究如何维持正常的成人味蕾系统，如何受到受辐射，化学疗法药物或两种疗法组合的伤害影响，并开发潜在的方法来促进康复，甚至可以保护味觉细胞免受癌症治疗或其他类型的损害的有害影响。 公共卫生相关性：放疗和化学疗法通常使癌症患者无法品尝食物的能力，导致营养不良和从癌症中恢复的预后较差。最近的研究表明，这些疗法破坏了味道感觉细胞的替代。拟议的研究将研究Wnt - ？ - catenin信号通路如何有助于成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途径。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疗法的影响。