Mechanisms of Adult Taste Bud Regeneration

成人味蕾再生的机制

基本信息

批准号：
9021623
负责人：
Linda A Barlow
金额：
$ 31.45万
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 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9021623
关键词：
Adopted Adult Affect Cell Cycle Cell Cycle Kinetics Cell Differentiation process Cell Lineage Cell Proliferation Cells Complement 3 Cytokeratin Data Development Diet Eating Embryo Epidermis Epithelial Epithelial Cells Epithelium Figs - dietary Functional disorder Genetic Goals Health Homeostasis Human Individual Life Longevity Mammals Maps Mediating Mitotic Modeling Molecular Molecular Genetics Mus Natural regeneration Nature Neurons Obesity Pathway interactions Patients Population Process Proliferating Radiation therapy Receptor Cell Recovery Regulation Reporter Series Signal Transduction Staging Stem cells Surface System Taste Bud Cell Taste Buds Taste Perception Testing Tetracyclines Tissues Tongue Transgenic Organisms cancer therapy cell type chemotherapy daughter cell experience genetic manipulation head and neck cancer patient insight keratinocyte precursor cell progenitor regenerative self-renewal sensory system taste system tongue papilla tool

项目摘要

DESCRIPTION (provided by applicant): Taste is a fundamental sense, which increasingly has been implicated in dietary choices that contribute to obesity and thus to human health. The sense of taste is mediated by taste buds comprising aggregates of heterogeneous receptor cells within specialized papillae on the tongue. In adult mammals, taste receptor cells, despite their functional similarities to neurons, are continually renewed throughout life, like epithelial cells.It is likely due to this continual turnover, however, that the taste system is exceptionally prone to disruption by agents that affect cell proliferation. In particular, head and neck cancer patients receiving radiotherapy virtually always experience loss or distortion of their sense of taste that can persist for years. Numerous chemotherapies also interrupt taste function, again presumably because of the regenerative nature of taste buds. To ascertain how these treatments cause taste dysfunction, it is important to have a clear understanding of the fundamental mechanisms of taste bud cell renewal. The current model of taste bud regeneration has been adopted primarily from studies of epidermis: presumed taste bud stem cells self-renew and generate transit amplifying cells, which together comprise the proliferating taste progenitor population tha gives rise to post-mitotic taste precursor cells which in turn differentiate into mature taste receptor cells. The model is limited in detail and only partially supported by current data, but nonetheless provides an excellent framework for our efforts to define the taste progenitor pool, and elucidate how it continually produces the correct complement of ~3 differentiated taste cell types. While we have some understanding of the cellular underpinnings of taste cell renewal, molecular regulation of this process is largely unexplored. Using conditional molecular genetics in mice, we have shown that the Wnt/ß-catenin pathway, a key regulator of development and homeostasis in multiple tissues is required for taste bud formation in embryos. Our new data suggest that this pathway also regulates adult taste cell renewal. Thus, in the following 2 specific aims, we will used conditional, tissue specific molecular genetic tools to test the hypothesis that: Taste buds continually renew from a specialized set of progenitor cells via processes that are distinct from the surrounding epithelium, and regulated by Wnt/ß-catenin signaling. Aim 1. Define the cell lineage and kinetics of taste receptor cell renewal in adult mice Aim 2. Define Wnt/ß-catenin function in discrete stages of taste cell renewal. In elucidating these mechanisms, we will gain crucial insight into cellular and molecular mechanisms of taste bud regeneration. In the long term, we will leverage these advances to explore how this process is disrupted in patients receiving conventional cancer therapies.

描述（由适用提供）：口味是一种基本意义，越来越多地在饮食选择中实施，从而有助于肥胖，从而有助于人类健康。味道介导的味蕾是通过在舌头上专门的乳头状乳头内完成异质受体细胞聚集体的介导的。在成年哺乳动物中，味觉受体细胞与它们与神经元的功能相似之处呈现，像上皮细胞一样不断更新。特别是，接受放射治疗的头和颈癌患者几乎总是会持续多年的味觉丧失或失真。许多化学疗法也中断了味觉功能，大概是由于味蕾的再生性质。为了确定这些治疗方法如何引起味道功能障碍，重要的是要清楚了解味蕾细胞更新的基本机制。当前的味蕾再生模型是从表皮研究中采用的：假定的味蕾干细胞自我更新并产生过境扩增的细胞，这些细胞共同完成了增生的味觉祖细胞的祖细胞，从而引起了麦素化味前体细胞，从而又可以分化为成熟的味觉受体细胞。该模型受到详细限制，仅由当前数据部分支持，但是尽管如此，我们还是为我们努力定义味觉祖细胞池的努力提供了一个绝佳的框架，并阐明了它如何连续产生〜3种差异化的味觉细胞类型的正确完成。尽管我们对味觉细胞更新的细胞基础有一些了解，但该过程的分子调节在很大程度上是意外的。使用小鼠中的条件分子遗传学，我们表明Wnt/ß-catenin途径是胚胎中味蕾形成的多个时序中发育和稳态的关键调节剂。我们的新数据表明，该途径还调节了成人味觉细胞的更新。在以下两个特定目的中，我们将使用条件，组织特定的分子遗传工具来测试以下假设：味蕾通过与周围上皮不同的过程不断从专业的祖细胞中恢复，并由Wnt/ß-catenin信号调节。 AIM 1。定义成年小鼠味觉受体细胞更新的细胞谱系和动力学目标2。在味觉细胞更新的离散阶段定义Wnt/ß-catenin功能。在阐明这些机制时，我们将对味蕾再生的细胞和分子机制获得至关重要的见解。从长远来看，我们将利用这些进步来探讨接受常规癌症疗法的患者如何残疾。