Development of the Sense of Taste

描述（由申请人提供）：味觉领域已经鉴定了几种指导菌状乳头发育的调节分子：舌前部味蕾的感觉器官。然而，乳头味觉器官的复杂性被忽视了，乳头味觉器官由特定的信号室组成并包含上皮组织和结缔组织。此外，尚未探索形成菌状乳头的舌头区域与无乳头的舌头区域的基因表达的具体差异。该应用的重点是这样一个概念：只有了解舌头特定区域和菌状乳头区室的基因表达和蛋白质定位，才能清楚地了解如何调节乳头发育。舌头区域和乳头区是整合信号以平衡增殖或分化的细胞反应的生理单位。因此，细胞信号传导在特定区室的范围内进行，然后来回发出信号以定义乳头的诱导、发育和分化。工作假设是，重要的形态发生素 Sonic hedgehog 以浓度依赖的方式控制菌状乳头的发育，通过： (a) 信号传导调节特定区室和舌头区域的细胞增殖； (b) 与其他信号分子家族的相互作用。检验该假设的方法包括使用报告小鼠和转基因小鼠；舌器官培养；基因阵列；以及通过转染和电穿孔使用 siRNA 进行基因敲除。三个具体目标是： 探测重要的形态发生素 Sonic Hedgehog (Shh) 在细胞增殖与分化中的阶段和区室特定作用。定义并探索区室特异性基因在发育中的舌头和舌头培养物中的作用，比较乳头丰富、乳头过多、乳头抑制或无乳头条件下的舌组织。确定 Shh、Wingless (Wnt) 和骨形态发生蛋白 (Bmp) 家族之间的相互作用。研究将为理解菌状乳头的形成增加至关重要的深度；深度对于了解乳头和味觉细胞特异性区室如何产生至关重要。反过来，有关乳头分化中信号区室的知识对于探究特定味觉细胞构成的起源、乳头和味觉细胞更新的控制以及发育过程中乳头和味觉细胞可塑性等问题至关重要。这些知识对于获取味觉如何产生的基本信息至关重要，从而最终指导我们的饮食和食物选择。公共健康相关性：味觉对于生命至关重要，可以指导营养物质的识别和摄入或排斥。味蕾存在于舌头的味觉乳头中，味觉乳头是复杂的感觉器官。因此，发育中的乳头含有最终决定味蕾形成的细胞和分子信息。为了了解营养选择的发育起源，以及基因组成或早期食物经验在多大程度上可以决定食物的偏好和厌恶，需要了解味觉乳头感觉器官如何发育的基本知识。有必要了解哪些时期的乳头发育是严格确定的，哪些时期容易受到母亲摄入或进入后穿过胎盘的物质的影响。了解味觉乳头的基本发育生物学也将有助于深入了解味蕾-感觉神经相互作用的形成，从而建立味觉的神经回路。

DESCRIPTION (provided by applicant): The field of taste has identified several regulatory molecules that direct development of the fungiform papilla: the sense organ residence of taste buds on the anterior tongue. However, the complexity of the papilla taste organ, composed of specific signaling compartments and encompassing both epithelial and connective tissues, has been ignored. Furthermore, specific differences in gene expression in fungiform papilla-forming versus papilla-free tongue regions have not been explored. This application focuses on the concept that only with knowledge about gene expression and protein localization in particular regions of the tongue and compartments of the fungiform papilla can a clear understanding emerge about how papilla development is regulated. Tongue regions and papilla compartments are physiological units that integrate signals to balance cell responses of proliferation or differentiation. Thus, cell signaling proceeds in the confines of particular compartments that then signal back and forth to define papilla induction, development and differentiation. The working hypothesis is that the important morphogen, Sonic hedgehog controls fungiform papilla development, in a concentration dependent manner, through: (a) signaling to regulate cell proliferation in specific compartments and tongue regions; and, (b) interactions with signaling other molecular families. Approaches to test the hypothesis include use of reporter and transgenic mice; tongue organ cultures; gene arrays; and gene knockdown with siRNAs via transfection and electroporation. Three specifc aims are to: Probe stage and compartment specific roles for the important morphogen, Sonic hedgehog (Shh), in cell proliferation versus differentiation. Define, and explore roles for, compartment specific genes in the developing tongue and tongue cultures, comparing lingual tissues in conditions that are papilla-replete, papilla-superabundant, papilla-suppressed, or papilla-free. Determine interactions among Shh, Wingless (Wnt) and Bone morphogenetic protein (Bmp) families. Studies will add crucial depth to understanding fungiform papilla formation; depth that is essential to knowing how papilla- and taste cell- specific compartments arise. In turn knowledge about signaling compartments in papilla differentiation is fundamental to pursuing questions about the origins of specific taste cell constitution, control of papilla and taste cell renewal, and papilla and taste cell plasticity during development. This knowledge is essential for acquiring basic information about how taste sensation emerges, to ultimately direct our diet and food choices. PUBLIC HEALTH RELEVANCE: The sense of taste is life-essential, in directing identification and ingestion or rejection of nutrients. Taste buds reside, in the tongue, in taste papillae which are complex sensory organs. Thus developing papillae contain cell and molecular information that ultimately determines taste bud formation. To understand the developmental origins of nutrient selection, and the extent to which genetic makeup or early food experience can determine food preferences and aversions, basic knowledge is needed about how the taste papilla sense organs develop. It is necessary to know what periods of papilla development are rigidly determined and what periods are vulnerable to influence from substances that cross the placenta after maternal ingestion or access. Understanding the basic developmental biology of taste papillae also will provide insight into formation of taste bud-sensory nerve interactions that set up the neural circuits for taste sensation.