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

Hedgehog信号传导在维持味觉器官结构和功能中的作用：基础和临床研究

• 批准号: 9171921
• 负责人: Benjamin Allen
• 金额: $ 65.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171921
• 关键词: Address; Adult; Adverse effects; Affect; Aftercare; Altered Taste; Basal cell carcinoma; Basic Science; Behavioral; Cancer Patient; Cell Cycle; Cell Maintenance; Cells; Clinical; Clinical Research; Collaborations; Complex; Connective Tissue Cells; Data; Development; Diet; Diet Modification; Eating; Electrophysiology (science); Embryonic Development; Epithelial; Epithelium; Erinaceidae; Esthesia; Food; Fungiform Papilla; Gene Expression; Gene Expression Profile; Genetic; Genetic Models; Goals; Histology; Homeostasis; Human; Imaging technology; Knowledge; Lead; Life; Light; Location; Maintenance; Malignant Neoplasms; Maps; Measurement; Measures; Metabolic; Methods; Modeling; Morphology; Mus; Natural regeneration; Oncogenic; Oral cavity; Organ; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Physiological; Population; Process; Quality of life; Questionnaires; Receptor Cell; Regulation; Reporter; Reporting; Role; Scientist; Sensory; Sensory Receptors; Signal Pathway; Signal Transduction; Skin Neoplasms; Smell Perception; Soft Palate; Stem cells; Structure; Taste Bud Cell; Taste Buds; Taste Perception; Testing; Therapeutic; Time; Tissues; Tongue; United States National Institutes of Health; Withholding Treatment; adult stem cell; cell type; chemotherapeutic agent; environmental agent; environmental chemical; experimental study; improved; inhibitor/antagonist; migration; mouse model; neurophysiology; public health relevance; receptor; receptor function; relating to nervous system; response; sensory system; serial imaging; smoothened signaling pathway; targeted treatment; taste system; tongue papilla; transmission process

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.

描述（由申请人提供）：味觉是一种至关重要的意义，它取决于味觉上皮中的味蕾受体复合物，可以直接饮食和食物选择。味蕾细胞和支撑上皮翻转，一生都更新，并且容易受到环境和药理剂的影响。因此，口味器官取决于严格调节的增殖和分化。刺猬（HH）途径调节许多组织中成人茎和祖细胞的维持。我们的数据暗示HH信号是维护和更新味觉受体器官的主要调节剂。但是，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）的原因，这是一种常见的皮肤肿瘤。因此，通过影响HH途径效应子（平滑）的HH途径抑制剂（HPI）已被开发为BCC的靶向治疗方法。 HPI导致BCC的消退，但由于不良效果，包括严重味觉障碍，患者经常停止治疗。我们的初步数据表明，味觉改变是一种目标效应，反映了味觉功能中HH信号的严格要求。我们假设HH信号传导功能可以控制味道器官的更新，并且该控制的药理学破坏是导致用HPI治疗的患者的化学感应障碍。我们使用遗传模型（小鼠）和药理治疗（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方法包括化学感应和HH信号生物学家，以及治疗BCC患者HPI的临床医生/科学家。在AIM 1中，我们假设HH信号传导通过在上皮组织更新中的重要作用来调节味蕾和/或乳头状的维护和功能。在小鼠中，我们分析了：HH途径基因表达模式和整个口腔味道内脏中的信号传导；味蕾受体细胞维持，更新和功能，在用HPI处理期间和之后，靶向信号转导分量平稳的HPI；并且，在遗传模型中，靶向删除对口味器官的靶向缺失的影响。我们研究细胞和组织效应，以及行为和神经生理的味道功能。在AIM 2中，我们建议HH信号传导可以控制BCC患者的味觉维持和功能，从而解释了为什么对该途径的药理抑制会导致化学感应障碍。在接受HPI的患者中，我们在HPI治疗前，期间和之后，通过问卷调查和NIH工具箱测试味道和气味感官功能测试，在HPI治疗前，期间和之后的化学感觉破坏程度和时间过程中进行预测；而且，我们量化了真菌乳头的数量和分布，以与味觉测试相关。该项目解决了HH信号传导抑制的机制，以改变口味器官动力学和功能。这些知识有助于解释接受HPI治疗的患者的知识不足，味觉障碍，并最终可能导致饮食改造或其他改善化学感应破坏并改善生活质量的方法。