Development of the Sense of Taste

描述(申请人提供)：味觉领域已经确定了几个指导菌状乳头发育的调节分子：味蕾在舌前部的感觉器官。然而，乳头味觉器官的复杂性被忽视了，它由特定的信号间隔组成，包括上皮组织和结缔组织。此外，菌状乳头形成舌区和无乳头舌区的基因表达的具体差异还没有被探索。这项应用侧重于这样一个概念，即只有了解舌头和真菌状乳头的特定区域的基因表达和蛋白质定位，才能清楚地了解乳头发育是如何调节的。舌区和乳头间隔是整合信号以平衡细胞增殖或分化反应的生理单位。因此，细胞信号在特定间隔的范围内进行，然后这些间隔来回发送信号以定义乳头的诱导、发育和分化。工作假设是，重要的形态原，Sonic hedgehog，以浓度依赖的方式控制真菌状乳头的发育，通过：(A)信号调节特定隔室和舌区的细胞增殖；以及(B)与信号其他分子家族的相互作用。检验这一假设的方法包括使用报告和转基因小鼠；舌器官培养；基因阵列；以及通过转基因和电穿孔用siRNAs敲除基因。三个特定的目标是：探索重要的形态原Sonic hedgehog(Shh)在细胞增殖和分化中的阶段和隔室特定的作用。定义并探索舌腔特定基因在发育中的舌体和舌体文化中的作用，比较乳头充盈、乳头过多、乳头抑制或无乳头条件下的舌组织。确定Shh、无翼(Wnt)和骨形成蛋白(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；这一深度对于了解乳头和味觉细胞特有的隔间是如何产生的至关重要。反过来，对乳头分化中信号间隔的了解是探索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的基础。这些知识对于获取味觉如何产生的基本信息，最终指导我们的饮食和食物选择是必不可少的。与公共健康相关：味觉在指导识别和摄取或拒绝营养方面是生命所必需的。味蕾位于舌头中的味觉乳头中，而味觉乳头是一种复杂的感官器官。因此，发育中的乳头包含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，以及基因构成或早期食物经验在多大程度上决定了人们对食物的偏好和厌恶，需要了解味觉乳头感觉器官如何发展的基本知识。有必要知道乳头发育的哪些时期是严格确定的，哪些时期容易受到孕妇摄入或进入胎盘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，这一相互作用建立了味觉的神经回路。

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.