Convergence of Cellular and Molecular Pathways in Appetitive Taste

 描述（由申请人提供）适当的食物选择对于获得生长、能量消耗和繁殖所需的营养至关重要。味觉是鉴别营养化合物（如碳水化合物、蛋白质、盐和脂肪）以及有害和有毒化合物（如生物碱、萜类化合物和酚类化合物、被人类感知为苦味的化学物质）的主要感觉模态。果蝇作为一个重要的模型系统来剖析许多感觉过程的分子基础，包括味觉。基因组/遗传资源是优秀的，研究人员有一个令人印象深刻的阵列的分子遗传，电生理和成像工具在他们的处置，而该系统也适合优雅的行为分析。尽管哺乳动物和昆虫表达了进化上不同的味觉受体，但味觉感觉系统的整体组织，特别是味觉编码的逻辑是相似的。因此，苍蝇提供了一个机会，揭示味觉的基本机制，以及他们的神经回路的组织原则。果蝇基因组含有68个味觉受体（Gr）基因，其中8个亚家族被认为编码所有假定的糖受体。然而，在过去几年中出现了一种模型，该模型假定只有两种异二聚体糖受体（Gr 5a/Gr 64 a和Gr 5a/Gr 64 f）介导大部分或全部甜味。我们已经测试了这一假设，使用特定的敲入/表达等位基因，以及“糖盲”果蝇品系。 这些研究让我们得出结论，该模型的两个主要前提需要修改：第一，Gr 64 a不是甜味的主要介质，第二，所有糖Gr蛋白都作为功能性甜味受体的单位参与。此外，虽然糖受体作为多聚体复合物发挥作用，但大多数味觉受体的Gr组成是未知的。这种知识上的差距将被有条不紊的救援战略系统地填补。我们还将在我们最近发现的基础上进一步研究，即果蝇的甜味细胞不仅对糖有反应，而且对脂肪酸也有反应，脂肪酸是几乎所有动物（包括果蝇）的另一种重要营养成分。在初步研究中，我们已经确定了第一个脂肪酸味觉所必需的受体基因，它是离子型受体基因家族的一员。我们将通过研究该基因家族的其他成员的表达以及它们在脂肪酸味觉中的功能来研究它们的作用。最后，我们发现了一种全新的味觉形态，它被调整为羧酸，而不是一般的酸。羧酸是存在于许多水果中的通用组分。我们将确定味觉细胞的反应谱，这些味觉细胞对这些食物成分有特异性反应，可能对氨基酸也有反应，并使用靶向候选基因方法寻找识别这些化合物的受体。

 DESCRIPTION (provided by applicant) Appropriate food choices are critical for the acquisition of nutrients for growth, energy expenditure and reproduction. Taste perception is the primary sensory modality for the identification of nutritious compounds, such as carbohydrates, proteins, salts and fats, as well as harmful and toxic compounds, such as alkaloids, terpenoids and phenols, chemicals perceived as bitter by humans. Drosophila has served as an important model system to dissect the molecular basis of many sensory processes, including taste perception. The genomic/genetic resources are excellent and researchers have an impressive array of molecular-genetic, electrophysiological and imaging tools at their disposal, while the system is also amenable to elegant behavioral assays. Even though mammals and insects express evolutionarily distinct sets of taste receptors, the overall organization of taste sensory systems and especially the logic of taste coding are similar. Thus, the fly provides an opportunity to uncover basic mechanisms of taste perception, as well as organizing principle of their neural circuits. The Drosophila genome harbors 68 Gustatory receptor (Gr) genes, a subfamily of eight is thought to encode all putative sugar receptors. However, a model has emerged over the last few years that posits that only two heterodimeric sugar receptors (Gr5a/Gr64a and Gr5a/Gr64f) mediate most or all of sweet taste. We have tested this hypothesis using specific knock-in/expression alleles, as well as `sugar blind' Drosophila strains. These studies let us conclude that two major premises of this model need revision: First, Gr64a is not a major mediator of sweet taste and second, all sugar Gr proteins participate as units of functional sweet taste receptors. Moreover, while sugar receptors do function as multimeric complexes, Gr composition for most taste receptors is unknown. This gap in knowledge will be systematically filled with a methodical rescue strategy. We will also build on our recent discovery that sweet taste cells in the fly are not exclusively tuned to sugars, but also respond t fatty acids, another important nutritional component for almost all animals, including fruit flies.In preliminary studies, we have identified the first receptor gene necessary for fatty acid taste, a member of the Ionotropic receptor gene family. We will investigate the role of other members if this gene family by studying both their expression, as well as their function in fatty acid taste. Lastly, we discovered an entirely new taste modality, tuned to carboxylic acids but not acid in general. Carboxylic acids are generic components present in many fruits. We will determine the response profile of taste cells that specifically respond to these food components, and possibly to amino acids, and search for the receptors that recognize these compounds using a targeted candidate gene approach.