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.

味觉是一种基本的感觉，对人体健康至关重要。就像我们的其他主要感官一样，我们认为我们的 能够欣赏甜，酸，咸，苦和鲜味的味道是相对恒定的，即使味道 吸收这些刺激的芽细胞迅速而有规律地更新。味觉的重要性 对于接受一系列化疗的癌症患者来说尤其明显，因为这些人经常 经历显著的味觉丧失（味觉丧失）或功能障碍（味觉障碍）。对于味觉紊乱的患者，只需 吃饭可能令人不快或无法进食;患者的生活质量显著降低， 抑郁，食欲不振，无法保持体重，以及癌症的预后较差 治疗特别是，用靶向Hedgehog（Hh）的药物治疗的基底细胞癌患者 信号通路经常经历味觉障碍。有趣的是，Hh拮抗剂导致小鼠味蕾丧失， 这表明服用这些药物的患者的功能性味觉丧失是由于对味蕾的影响。然而 味蕾内稳态如何受到Hh抑制的影响的机制理解仍然未被探索。 因此，减轻癌症患者味觉丧失的治疗方法还有待想象。 Sonic hedgehog（Shh）是3种分泌型Hh配体之一，基于其在味蕾细胞中的表达， 表达模式及其靶基因Gli 1的表达模式。味蕾细胞的一个子集是Shh+，而Gli 1表达是 仅限于芽外的增殖祖细胞，这表明芽内的Shh信号， 相邻的祖细胞来控制味觉细胞更新。然而，细胞和分子过程调节的 Hh信号是未知的，代表了我们对味蕾细胞生物学知识的重大空白， 限制了我们对Hh拮抗剂如何改变味觉的理解。在这里，根据已发表的报告和我们的试点数据， 我们提出了一个新的假说：Hedgehog信号是味觉受体细胞（TRC）所必需的， 分化和味蕾维持。 我们将在3个目标中使用小鼠模型来测试这一总体假设，在完成这些目标时， 扩大对负责味觉细胞更新的基本细胞和分子机制的理解，以及 如机械地定义Hh通路靶向化疗如何破坏这一过程。 目的1确定Shh是否促进TRC从味觉祖细胞分化。 目的2鉴定TRC分化所需Shh的组织来源。 目的3明确Hh拮抗剂诱导小鼠TRCs分化缺失的细胞机制。