Hedgehog signaling in maintaining taste organ structure and function: basic and clinical studies

描述(申请人提供)：味觉是一种重要的感觉，它依赖味觉上皮中的味蕾受体复合体来指导饮食和食物选择。味蕾细胞和支持上皮翻转，在整个生命过程中更新，并对环境和药物敏感。因此，味觉器官依赖于严格调控的增殖和分化。Hedgehog(HH)途径调节许多组织中成体干细胞和祖细胞的维持。我们的数据表明，HH信号是味觉感受器器官维持和更新的主要调节因素。然而，HH活性不仅调节组织的维持，而且不受控制的HH信号是基底细胞癌(BCC)的原因，基底细胞癌是一种常见的皮肤肿瘤。因此，通过影响HH通路效应来阻断信号转导的HH通路抑制物(HPI)已被开发为治疗基底细胞癌的靶向药物。HPI可导致基底细胞癌的消退，但患者经常因不良反应(包括严重的味觉障碍)而停止治疗。我们的初步数据表明，味觉变化是一种靶向效应，反映了味觉功能中对HH信号的严格要求。我们假设HH信号功能控制味觉器官的更新，这种控制的药物干扰是使用HPI治疗的患者化学感觉障碍的原因。我们使用遗传模型(小鼠)和药物治疗(小鼠和人类癌症患者)来研究HH信号改变的味觉系统。我们的多PI方法包括化学感觉和HH信号生物学家，以及治疗患有HPI的基底细胞癌患者的临床医生/科学家。在目标1中，我们假设HH信号通过在上皮组织更新中起重要作用来调节味蕾和/或乳头的维持和功能。在小鼠中，我们分析了：HH途径基因在整个口腔味觉器官中的表达模式和信号；味蕾受体细胞在HPI治疗期间和治疗后的维持、更新和功能；以及，在遗传模型中，靶向缺失Smoothed对味觉器官的影响。我们研究细胞和组织效应，以及行为和神经生理味觉功能。在目标2中，我们提出HH信号对基底细胞癌患者味觉器官的维持和功能起控制作用，解释了为什么药物抑制这一途径会导致化学感觉障碍。在接受HPI治疗的患者中，我们通过问卷调查和NIH味觉和嗅觉感觉功能工具箱测试来测试对HPI治疗前、中和后化学感觉破坏的程度和时间进程的预测；我们还量化了真菌样乳头的数量和分布，以与味觉测试相关联。该项目阐述了HH信号抑制在改变味觉、器官动力学和功能方面的机制。这一知识有助于解释接受HPI治疗的患者中知之甚少的味觉障碍，并最终可能导致改变饮食或其他方法，以改善化学感觉障碍和提高生活质量。

DESCRIPTION (provided by applicant): Taste is a vital sense that depends on taste bud receptor complexes in the gustatory epithelia to direct eating and food choices. Taste bud cells and supporting epithelia turn over, are renewed throughout life, and are susceptible to environmental and pharmacological agents. Taste organs therefore depend on tightly regulated proliferation and differentiation. The Hedgehog (HH) pathway regulates maintenance of adult stem and progenitor cells in many tissues. Our data implicate HH signaling as a principal regulator of maintenance and renewal of taste receptor organs. However, HH activity not only regulates tissue maintenance, but also uncontrolled HH signaling is the cause of basal cell carcinoma (BCC), a common skin tumor. Therefore, HH Pathway Inhibitors (HPIs) that block signaling by affecting the HH pathway effector, Smoothened, have been developed as targeted therapeutics for BCC. HPIs lead to regression of BCCs, but patients often discontinue treatment due to adverse effects including severe taste disturbances. Our preliminary data suggest that the taste alterations are an on-target effect reflecting a strict requirement for HH signaling in taste function. We hypothesize that HH signaling functions to control renewal of taste organs and that pharmacological disruption of this control is responsible for chemosensory disturbances in patients treated with HPIs. We use genetic models (mouse) and pharmacological treatment (mouse and human cancer patients) to study the taste system with altered HH signaling. Our Multi PI approach includes chemosensory and HH signaling biologists, and a clinician/scientist treating BCC patients with HPIs. In Aim 1 we hypothesize that HH signaling regulates taste bud and/or papilla maintenance and function through an essential role in epithelial tissue renewal. In mouse we analyze: Hh pathway gene expression pattern and signaling in taste organs throughout the oral cavity; taste bud receptor cell maintenance, renewal and function, during and after treatment with HPIs that target the signal transduction component Smoothened; and, in genetic models, effects of targeted deletion of Smoothened on taste organs. We study cell and tissue effects, and behavioral and neurophysiological taste function. In Aim 2 we propose that HH signaling acts to control taste organ maintenance and function in BCC patients, explaining why pharmacological inhibition of this pathway causes chemosensory disturbance. In patients receiving HPIs, we test predictions about the extent and time course of chemosensory disruption, before, during and after HPI treatment, with questionnaires and NIH Toolbox tests of taste and smell sensory function; and, we quantify the number and distribution of fungiform papillae to correlate with taste sensation tests. The project addresses mechanisms of HH signaling inhibition in altering taste organ dynamics and function. This knowledge contributes to explaining the poorly understood, taste disturbances in patients treated with HPIs, and could ultimately lead to dietary modifications or other approaches to ameliorate chemosensory disruption and improve quality of life.