Broad Spectrum Bitter Taste Antagonists Discovery

广谱苦味拮抗剂的发现

• 批准号: 10017488
• 负责人: DANIELLE Renee REED
• 金额: $ 81.67万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017488
• 关键词: Address; Affect; Applied Research; Behavior; Beverages; Biological Assay; Businesses; Cell Culture Techniques; Cell Line; Cells; Chemicals; Child; Client; Collaborations; Data; Diet; Drug Industry; Elderly; Epithelial Cells; Food; Food Industry; Formulation; Foundations; Funding; Fungiform Papilla; Future; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Healthy Eating; Human; Individual; Industry; Industry Collaboration; Institutes; Intellectual Property; International; Joints; Lead; Ligands; Masks; Medicine; Messenger RNA; Methods; Nutritional; Organic Chemicals; Output; Palate; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Philadelphia; Physiological; Phytochemical; Primary Cell Cultures; Principal Investigator; Proteins; Public Health; Quantitative Reverse Transcriptase PCR; Recommendation; Reporter; Reproducibility; Research; Research Contracts; Research Personnel; Science; Sensory; Signal Transduction; Small Business Technology Transfer Research; Sodium Chloride; Structure-Activity Relationship; Target Populations; Taste Bud Cell; Taste Buds; Taste Perception; Technology; Testing; Tongue; Validation; base; behavior test; cell immortalization; cheminformatics; clinically relevant; compliance behavior; cytotoxicity; design; drug discovery; ethnic diversity; experimental study; food challenge; food flavor; food insecurity; genetic variant; human subject; improved; innovation; interest; novel; overexpression; programs; public health relevance; receptor; receptor function; reduced food intake; response; salt intake; screening; small molecule; sugar; transcriptome sequencing; validation studies

Principal Investigators for Small Business: DiscoveryBioMed, Inc. (DBM) and Monell Chemical Senses Center Project Summary Abstract Bitter taste in foods and medicines presents a barrier to overcoming global public health challenges: food insecurity, poor nutritional health, and poor compliance with medication use, particularly among children and the elderly. Sugar and salt, the mainstays to address these challenges, further erode nutritional health, and current alternatives have adverse taste attributes of their own. We propose to develop a reliable, human taste- cell screening platform to find bitter blockers of commercial interest to the food, flavor, and pharmaceutical industries, with the ultimate commercial aim to improve the taste and acceptance of nutritious and sustainable foods and medicines. This Phase 2 STTR proposal evolves from a successful Phase 1 STTR funded program to establish primary and immortal human taste-bud-derived epithelial cell cultures and lines (i.e., hTBEC platforms) from donors with bitter-sensitive genotypes and (b) to design, optimize, and implement hTBEC- based bioassays of bitter taste receptor function and other key end points to produce readout data for medium- throughput screening (MTS). Preliminary data is presented in support of the proposed MTS campaign. This Phase 2 STTR proposal seeks to deepen MTS with bitter-responsive hTBEC platforms as the key ingredient. Milestone 1 of the proposal will be underpinned by three specific experimental aims to complete MTS and perform cheminformatics to realize multiple chemical classes that are bitter taste antagonists. Genomic and qRT-PCR analysis of key TAS2R bitter receptors will be performed continually in parallel to insure stability and robustness of the bitter-responsive hTBEC platforms. Milestone 2 of the proposal will identify ‘broad spectrum’ bitter taste antagonists with future marketplace utility and will be underpinned by two specific experimental aims involving secondary validation of bitter taste antagonists in receptor-specific assays, ‘bitterome’ genomics, and human taste behavior. Industry collaborators will test our best candidate bitter taste antagonists independently for rigor and reproducibility against their bitter drugs (e.g., active product ingredients or APIs). Milestone 3 of the proposal will focus on characterizing deeply and selecting the best bitter-responsive hTBEC platforms and bioassays for clients and to optimize and partner bitter taste antagonists with industry to realize new formulations for bitter-tasting drugs and bitter-tasting foods and beverages. This collaboration between DiscoveryBioMed, Inc. and Monell Chemical Senses Center brings together expertise in (a) culture of human taste cells, (b) the creation of immortalized cell lines, (c) MTS, (d) genetics and (e) human sensory analysis. The guiding hypothesis is that hTBEC-platform-based bioassays will provide a more relevant robust way to discover novel ‘bitter blockers’, given the imperfect current methods of overexpressing known taste receptors in heterologous cells. The discovery of bitter taste receptor antagonists that alone or blended together block bitter taste can improve healthy eating by reducing reliance on salt and sugar and can improve compliance by patients taking medicines. Thus, we are confident that new bitter blockers will improve human health. PHS 398/2590 (Rev. 09/04, re-issued 4/2006) Page Continuation Format Page

小型企业的主要研究者：DiscoveryBioMed，Inc. (DBM)Monell化学感官中心 项目摘要 食品和药品的苦味是克服全球公共卫生挑战的障碍：食品 不安全、营养不良和不遵守用药规定，特别是儿童， 老人糖和盐是应对这些挑战的主要支柱，它们进一步侵蚀了营养健康， 目前的替代品本身具有不利的味道属性。我们建议发展一种可靠的，人性化的品味- 细胞筛选平台，以寻找具有商业利益的食品，香料和制药苦味阻断剂 工业，最终的商业目标是提高营养和可持续的口味和接受度， 食品和药品。本第2阶段STTR提案是从成功的第1阶段STTR资助计划演变而来的 为了建立原代和永生的人味蕾衍生的上皮细胞培养物和细胞系（即，hTBEC 平台），和（B）设计、优化和实施hTBEC- 基于苦味受体功能和其他关键终点的生物测定， 通量筛选（MTS）。初步数据支持拟议的MTS运动。这 第2阶段STTR提案旨在深化MTS，其中将可响应的hTBEC平台作为关键成分。 该提案的里程碑1将以三个具体的实验目标为基础，以完成MTS， 执行化学信息学以实现作为苦味拮抗剂的多种化学类别。基因组和 关键TAS 2 R苦味受体的qRT-PCR分析将连续平行进行，以确保稳定性， 这是对hTBEC平台的稳定性的评估。该提案的里程碑2将确定“广谱” 苦味拮抗剂具有未来的市场效用，并将通过两个具体的实验来支持。 在受体特异性试验中对苦味拮抗剂进行二次验证的目的， 基因组学和人类味觉行为。行业合作者将测试我们最好的候选苦味拮抗剂 独立于其苦味药物的严谨性和再现性（例如，活性产品成分或API）。 该提案的第三个里程碑将集中于深入表征和选择最佳的抗肿瘤响应性hTBEC 为客户提供平台和生物测定，并与行业合作优化苦味拮抗剂， 新配方的口味的药物和口味的食品和饮料。之间的这种合作 Discovery BioMed，Inc. Monell化学感官中心汇集了（a）人类文化的专业知识 味觉细胞，（B）永生化细胞系的产生，（c）MTS，（d）遗传学和（e）人类感觉分析。 指导性假设是基于hTBEC平台的生物测定将提供一种更相关的稳健方法， 鉴于目前过度表达已知味觉受体的方法不完善， 在异源细胞中。苦味受体拮抗剂的发现，单独或混合在一起， 苦味可以通过减少对盐和糖的依赖来改善健康饮食， 病人吃药。因此，我们相信新的苦味阻断剂将改善人类健康。 PHS 398/2590（2004年9月修订，2006年4月重新印发）