Mechanisms of Adult Taste Bud Regeneration

描述(申请人提供)：味觉是一种基本的感觉，它越来越多地与导致肥胖的饮食选择有关，从而对人类健康产生影响。味觉是由味蕾调节的，味蕾由舌头上特殊乳突内的异种受体细胞聚集而成。在成年哺乳动物中，味觉感受器细胞尽管在功能上与神经元相似，但在整个生命过程中都会像上皮细胞一样不断更新。然而，很可能是由于这种持续的更替，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丧失或扭曲，这种感觉可能会持续多年。许多化疗也会干扰味觉功能，想必也是因为味蕾的再生性质。要弄清这些治疗方法是如何导致味觉功能障碍的，重要的是要清楚地了解味蕾细胞更新的基本机制。目前味蕾再生的模式主要来自于对表皮的研究：推测味蕾干细胞自我更新并产生运输放大细胞，这些细胞共同组成增殖的味觉前体细胞群，从而产生有丝分裂后的味觉前体细胞，这些细胞又分化为成熟的味觉受体细胞。该模型在细节上是有限的，仅部分地得到了当前数据的支持，但仍然为我们定义味觉祖细胞池提供了一个很好的框架，并阐明了它是如何持续产生~3种分化的味觉细胞类型的正确补充。虽然我们对味觉细胞更新的细胞基础有了一些了解，但这一过程的分子调控在很大程度上还没有被探索。利用小鼠的条件分子遗传学，我们已经证明Wnt/ss-catenin途径是胚胎味蕾形成所必需的，Wnt/ss-catenin途径是多个组织中发育和动态平衡的关键调节因子。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，在以下两个特定的目标中，我们将使用条件性的、组织特异性的分子遗传学工具来检验这一假设：味蕾通过与周围上皮不同的过程从一组专门的前体细胞持续更新，并受Wnt/ss-catenin信号调节。目的1.明确成年小鼠味觉感受器细胞更新的细胞谱系和动力学。目的2.明确Wnt/ss-catenin在味觉细胞更新不同阶段的功能。在阐明这些机制的过程中，我们将对味蕾再生的细胞和分子机制有重要的了解。从长远来看，我们将利用这些进展来探索在接受传统癌症治疗的患者中这一过程是如何被破坏的。

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.