Mechanisms of adult taste bud regeneration

成人味蕾再生机制

• 批准号: 9247545
• 负责人: Linda A Barlow
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247545
• 关键词: Adult; Adverse effects; Affect; Afferent Neurons; Ageusia; Altered Taste; Antineoplastic Agents; Basal cell carcinoma; Body Weight; Brain; Cancer Patient; Cell Differentiation process; Cells; Cellular biology; Data; Desire for food; Development; Drug Targeting; Dysgeusia; Eating; Ectopic Expression; Embryo; Enterobacteria phage P1 Cre recombinase; Epithelial; Epithelial Cells; Epithelium; Erinaceidae; Failure; Feeding behaviors; Functional disorder; Gene Targeting; Genes; Goals; Health; Homeostasis; Human; Individual; Injection of therapeutic agent; Injury; Knowledge; Life; Ligands; Longevity; Maintenance; Mediating; Mental Depression; Molecular; Molecular Genetics; Morphology; Mus; Natural regeneration; Nerve; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Process; Proliferating; Publishing; Quality of life; RNA; Receptor Cell; Reporting; SHH gene; Signal Transduction; Skin Neoplasms; Sonic Hedgehog Pathway; Source; Stem cells; Stimulus; Supporting Cell; Surface; Taste Bud Cell; Taste Buds; Taste Perception; Testing; Time; Tissues; Tongue; Type I Epithelial Receptor Cell; Viral; base; cancer therapy; cell type; cellular transduction; chemotherapy; experience; genetic manipulation; keratinocyte; mouse model; nerve supply; novel; progenitor; relating to nervous system; response; sensory system; smoothened signaling pathway; transcriptome

Taste is a fundamental sense and is crucial for human health. Like our other primary senses, we consider our ability to appreciate sweet, sour, salty, bitter and umami tastes to be relatively constant, even though the taste bud cells that transduce these stimuli are renewed rapidly and regularly. The importance of the sense of taste is particularly evident for cancer patients receiving a range of chemotherapies, as these individuals often experience significant taste loss (ageusia) or dysfunction (dysgeusia). For patients with perturbed taste, simply eating a meal can be unpleasant or impossible; patients have significantly reduced quality of life including depression, lack of appetite and failure to maintain body weight, as well as poorer outcomes with cancer treatment. In particular, Basal Cell Carcinoma patients treated with drugs that target the Hedgehog (Hh) signaling pathway frequently experience dysgeusia. Interestingly Hh antagonists cause taste bud loss in mice, suggesting that functional taste loss in patients given these drugs is due to an effect on taste buds. Yet a mechanistic understanding of how taste bud homeostasis is impacted by Hh inhibition remains unexplored. And hence treatments to mitigate taste loss for cancer patients are yet to be imagined. Sonic hedgehog (Shh), one of 3 secreted Hh ligands, is implicated in taste bud cell renewal based on its expression pattern and that of its target gene, Gli1. A subset of taste bud cells is Shh+, while Gli1 expression is restricted to proliferating progenitor cells outside of buds, suggesting that Shh from within buds signals to adjacent progenitors to control taste cell turnover. However, the cellular and molecular processes regulated by Hh signaling are unknown, representing a significant gap in our knowledge of taste bud cell biology, and further limits our understanding of how Hh antagonists alter taste. Here, based on published reports and our pilot data, we propose the novel hypothesis that: Hedgehog signaling is required for taste receptor cell (TRC) differentiation and taste bud maintenance. We will test this overarching hypothesis using mouse models in 3 aims, and in completing these, greatly expand understanding of basic cellular and molecular mechanisms responsible for taste cell renewal, as well as define mechanistically how Hh pathway-targeted chemotherapy disrupts this process. Aim 1 Determine if Shh promotes TRC differentiation from taste progenitor cells. Aim 2 Identify the tissue source(s) of Shh required for TRC differentiation. Aim 3 Define cellular mechanisms underlying loss of differentiated TRCs in mice treated with Hh antagonist.

味道是一种基本意义，对人类健康至关重要。像我们的其他主要感官一样，我们认为我们的 即使味道 转导这些刺激的芽细胞会迅速和定期更新。品味感的重要性 对于接受一系列化学疗法的癌症患者而言，这一点尤其明显，因为这些人经常 经历大量的味觉丧失（年龄）或功能障碍（dysgeusia）。对于患有扰动味觉的患者，只需 吃饭可能是不愉快的或不可能的；患者的生活质量大大降低了，包括 抑郁症，食欲不足和无法保持体重，以及癌症的结果较差 治疗。特别是，基底细胞癌患者接受了针对刺猬（HH）的药物治疗的药物 信号通路经常经历病变。有趣的是，HH拮抗剂会导致小鼠的味蕾丧失， 表明鉴于这些药物的患者的功能味道丧失是由于对味蕾的影响。但是 对HH抑制作用影响如何影响味蕾稳定的机械理解尚未得到探索。 因此，尚未想象为减轻癌症患者的味觉丧失的治疗方法。 Sonic刺猬（SHH）是三种分泌的HH配体之一，与味蕾更新有关 表达模式及其靶基因Gli1的模式。味蕾细胞的一个子集为SHH+，而Gli1表达为 仅限于芽外的祖细胞增殖，这表明SHH从芽信号内到 邻近的祖细胞控制味觉细胞更新。但是，由 HH信号是未知的 限制了我们对HH拮抗剂如何改变口味的理解。在这里，根据已发布的报告和我们的试验数据， 我们提出了一个新的假设，即刺激器信号是味觉受体细胞（TRC）所必需的 分化和味蕾维护。 我们将使用3个目标中的鼠标模型来测试这个总体假设，并在完成这些假设中，很大程度上 也扩展对负责味觉细胞更新的基本细胞和分子机制的了解 因为从机械上定义了HH途径靶向化学疗法如何破坏这一过程。 AIM 1确定SHH是否促进了TRC从味觉祖细胞中分化。 AIM 2确定TRC分化所需的SHH的组织来源。 AIM 3定义了用HH拮抗剂治疗的小鼠分化TRC损失的细胞机制。