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

描述（由申请人提供）：味觉是一种重要的感觉，依赖于味觉上皮细胞中的味蕾受体复合物来指导进食和食物选择。味蕾细胞和支持上皮细胞在整个生命过程中不断更新，并且对环境和药理学试剂敏感。因此，味觉器官依赖于严格调控的增殖和分化。Hedgehog（HH）通路调节许多组织中成体干细胞和祖细胞的维持。我们的数据暗示HH信号作为维持和更新味觉受体器官的主要调节器。然而，HH活性不仅调节组织维持，而且不受控制的HH信号传导是基底细胞癌（BCC）（一种常见的皮肤肿瘤）的原因。因此，通过影响HH通路效应物Smoothened来阻断信号传导的HH通路抑制剂（HPI）已被开发为BCC的靶向治疗剂。HPI导致BCC的消退，但患者经常由于包括严重味觉障碍在内的不良反应而停止治疗。我们的初步数据表明，味觉改变是一种靶向效应，反映了味觉功能中对HH信号传导的严格要求。我们假设HH信号传导功能控制味觉器官的更新，并且这种控制的药理学破坏是用HPIs治疗的患者的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）来研究具有改变的HH信号传导的味觉系统。我们的多PI方法包括化学传感和HH信号传导生物学家，以及治疗患有HPI的BCC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的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：Hh途径基因表达模式和整个口腔味觉器官中的信号传导;味蕾受体细胞的维持、更新和功能，在用靶向信号转导组分Smoothened的HPI治疗期间和之后;以及，在遗传模型中，靶向缺失Smoothened对味觉器官的影响。我们研究细胞和组织的影响，以及行为和神经生理味觉功能。在目标2中，我们提出HH信号传导作用于控制BCC患者的味觉器官维持和功能，解释了为什么药理学抑制该途径会导致化学感觉障碍。在接受HPI的患者中，我们在HPI治疗前、治疗期间和治疗后，通过问卷调查和NIH味觉和嗅觉功能测试，对化学感觉中断的程度和时间过程进行了预测;并且，我们量化了菌状乳头的数量和分布，以与味觉测试相关联。该项目致力于HH信号抑制改变味觉器官动力学和功能的机制。这一知识有助于解释在接受HPIs治疗的患者中理解不清的味觉障碍，并最终导致饮食调整或其他方法来改善化学感觉障碍并改善生活质量。

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.