Mechanisms of adult taste bud regeneration

成人味蕾再生机制

基本信息

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
项目类别：
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

项目摘要

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.

味觉是一种基本感觉，对人类健康至关重要。就像我们的其他主要感官一样，我们认为我们的鉴赏甜、酸、咸、苦和鲜味的能力相对恒定，即使味道转导这些刺激的芽细胞会快速且有规律地更新。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明显的味觉丧失（味觉丧失）或功能障碍（味觉障碍）。对于味觉失调的患者，只需吃饭可能会令人不愉快或不可能；患者的生活质量显着下降，包括抑郁、食欲不振、无法维持体重以及癌症预后较差治疗。特别是接受针对 Hedgehog 药物治疗的基底细胞癌患者 (Hh) 信号通路经常出现味觉障碍。有趣的是，Hh 拮抗剂会导致小鼠味蕾丧失，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所致。还有一个关于 Hh 抑制如何影响味蕾稳态的机制仍有待探索。因此，减轻癌症患者味觉丧失的治疗方法尚不可想象。声波刺猬 (Shh) 是 3 种分泌型 Hh 配体之一，基于其功能，与味蕾细胞更新有关。表达模式及其靶基因 Gli1 的表达模式。味蕾细胞的一个子集是 Shh+，而 Gli1 的表达是仅限于芽外的增殖祖细胞，这表明芽内的Shh信号邻近的祖细胞控制味觉细胞的更新。然而，细胞和分子过程受 Hh 信号传导尚不清楚，这代表了我们对味蕾细胞生物学知识的巨大差距，并且进一步限制了我们对 Hh 拮抗剂如何改变味觉的理解。在这里，根据已发布的报告和我们的试点数据，我们提出新的假设：味觉受体细胞 (TRC) 需要 Hedgehog 信号传导分化和味蕾维护。我们将使用小鼠模型来测试这一总体假设的三个目标，并在完成这些目标的过程中，极大地扩大对负责味觉细胞更新的基本细胞和分子机制的理解从机制上定义 Hh 通路靶向化疗如何破坏这一过程。目标 1 确定 Shh 是否促进味觉祖细胞向 TRC 分化。目标 2 确定 TRC 分化所需的 Shh 组织来源。目标 3 明确用 Hh 拮抗剂治疗的小鼠中分化 TRC 丢失的细胞机制。