Mechanisms of Adult Taste Bud Regeneration

描述（由申请人提供）：味觉是一种基本感觉，其越来越多地涉及导致肥胖并因此影响人类健康的饮食选择。味觉由味蕾介导，味蕾包括舌头上特化乳头内的异质受体细胞的聚集体。在成年哺乳动物中，味觉感受器细胞尽管功能与神经元相似，但在整个生命过程中会不断更新，就像上皮细胞一样。然而，可能是由于这种持续的更新，味觉系统特别容易受到影响细胞增殖的因素的破坏。特别是，接受放射治疗的头颈部癌症患者几乎总是会经历味觉的丧失或扭曲，这种感觉可能持续多年。许多化疗也会中断味觉功能，这也可能是因为味蕾的再生性质。为了确定这些治疗如何导致味觉功能障碍，重要的是要清楚地了解味蕾细胞更新的基本机制。目前的味蕾再生模型主要是从表皮的研究中采用的：假定的味蕾干细胞自我更新并产生转运放大细胞，其共同构成增殖的味觉祖细胞群，其产生有丝分裂后的味觉前体细胞，其继而分化成成熟的味觉受体细胞。该模型的细节有限，并且仅得到当前数据的部分支持，但尽管如此，它为我们定义味觉祖细胞库并阐明它如何不断产生~3种分化味觉细胞类型的正确补充提供了一个很好的框架。虽然我们对味觉细胞更新的细胞基础有一些了解，但这一过程的分子调控在很大程度上尚未探索。在小鼠中使用条件分子遗传学，我们已经表明，Wnt/β-catenin途径，在多个组织中的发育和稳态的关键调节因子是味蕾形成所需的胚胎。我们的新数据表明，这一途径也调节成人味觉细胞的更新。因此，在以下2个具体目标中，我们将使用条件性的、组织特异性的分子遗传学工具来测试以下假设：味蕾通过与周围上皮不同的过程从一组专门的祖细胞持续更新，并由Wnt/β-连环蛋白信号调节。目标1.确定成年小鼠味觉感受器细胞更新的细胞谱系和动力学.定义Wnt/β-连环蛋白在味觉细胞更新的离散阶段中的功能。在阐明这些机制，我们将获得至关重要的洞察味蕾再生的细胞和分子机制。从长远来看，我们将利用这些进展来探索如何在接受常规癌症治疗的患者中破坏这一过程。

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.