Broad Spectrum Bitter Taste Antagonists Discovery

广谱苦味拮抗剂的发现

基本信息

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
项目类别：
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

项目摘要

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

小型企业首席研究员：DiscoveryBioMed, Inc. (DBM) 和 Monell Chemical Senses Center 项目概要摘要食品和药品中的苦味是克服全球公共卫生挑战的障碍：食品不安全感、营养健康状况不佳以及服药依从性差，尤其是儿童和青少年糖和盐是应对这些挑战的支柱，但它们进一步损害了营养健康，目前的替代品有其自身的不良口味属性，我们建议开发一种可靠的、人性化的口味。细胞筛选平台，用于寻找对食品、香料和药品具有商业利益的苦味阻滞剂行业，其最终商业目标是提高营养和可持续的口味和接受度该第二阶段 STTR 提案源自成功的第一阶段 STTR 资助计划。建立原代和永生的人类味蕾源性上皮细胞培养物和细胞系（即 hTBEC 平台）来自具有苦味敏感基因型的捐赠者，以及（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，以产生介质的读出数据提供了初步数据以支持拟议的 MTS 活动。第二阶段 STTR 提案旨在以苦味响应 hTBEC 平台作为关键成分来深化 MTS。该提案的里程碑 1 将由三个具体实验目标支撑，以完成 MTS 和进行化学信息学以实现多种苦味拮抗剂的化学类别。对关键 TAS2R 苦味受体的 qRT-PCR 分析将持续并行进行，以确保稳定性和该提案的里程碑 2 将确定苦味响应 hTBEC 平台的稳健性。具有未来市场实用性的苦味拮抗剂，并将以两个特定的实验为基础目标涉及受体特异性测定中苦味拮抗剂的二次验证，“bitterome” 基因组学和人类味觉行为将测试我们最好的候选苦味拮抗剂。独立地针对其苦味药物（例如活性产品成分或 API）进行严格性和可重复性。该提案的里程碑 3 将侧重于深入表征和选择最佳苦味响应 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以实现苦味药物和苦味食品和饮料的新配方。 DiscoveryBioMed, Inc. 和莫内尔化学感官中心汇集了 (a) 人类文化方面的专业知识味觉细胞、(b) 永生化细胞系的创建、(c) MTS、(d) 遗传学和 (e) 人类感官分析。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，发现新型“苦味阻滞剂” 在异源细胞中发现单独或混合在一起的苦味受体拮抗剂。苦味可以通过减少对盐和糖的依赖来改善健康饮食，并可以通过以下方式提高依从性：因此，我们相信新的苦味阻滞剂将改善人类健康。 PHS 398/2590（修订版 09/04，重新发布 4/2006）页继续格式页