Administrative Supplement: Roles for Glucosensors in Taste Function

行政补充：葡萄糖传感器在味觉功能中的作用

• 批准号: 10712541
• 负责人: Lindsey A Schier
• 金额: $ 36.87万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712541
• 关键词: 3xTg-AD mouse; AD transgenic mice; Administrative Supplement; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Behavior; Behavioral; Biological Factors; Biological Markers; Body Composition; Categories; Cells; Central Nervous System; Consumption; Data; Deficiency Diseases; Dementia; Desire for food; Development; Diabetes Mellitus; Diet; Diet Habits; Dietary Factors; Dietary Sugars; Disease; Disease Progression; Eating Behavior; Fatty acid glycerol esters; Food; Functional disorder; Genetic; Genetic Predisposition to Disease; Glucokinase; Glucose; Goals; Human; Immunohistochemistry; Impairment; Inflammation; Inflammatory; Ingestion; Intake; Knock-in; Knowledge; Lead; Link; Liquid substance; Longevity; Measures; Metabolic; Metabolic Diseases; Metabolism; Modernization; Molecular; Molecular Abnormality; Morphology; Motivation; Mus; Nervous System Physiology; Neurocognitive; Neurodegenerative Disorders; Nutrient; Obesity; Oral cavity; Organ; Outcome; Outcome Study; Parents; Peripheral; Pilot Projects; Play; Process; Psychophysics; Publishing; Reporting; Research; Rewards; Risk; Risk Factors; Role; Sensory; Severities; Short-Term Memory; Signal Transduction; Symptoms; System; TNF gene; Taste Bud Cell; Taste Buds; Taste Perception; Taste preferences; Techniques; Testing; Transgenic Mice; Work; age related; apolipoprotein E-4; craving; cytokine; dietary; experience; experimental study; good diet; hedonic; mouse model; novel; novel strategies; pharmacologic; receptor; receptor expression; response; stem; sugar; sweet receptor; sweet taste perception; taste system; western diet; young adult

PROJECT SUMMARY Diets high in sugar are significant risk factors for obesity, diabetes, and neurodegenerative diseases, such as Alzheimer’s. The so called palatable “sweet” taste of these substances play a significant role in promoting their appeal, sometimes at the expense of a balanced diet. In humans, AD progression is marked by a decreased sensitivity to sweet taste, and increased cravings for more intensely sweet foods and fluids. While it is commonly assumed these taste deficits result from impaired central nervous system function, the peripheral conditions associated with the eventual onset of AD may also affect taste processing at its peripheral end organ, the taste bud. In fact, very little is known about how the gustatory abnormalities develop, including if they emerge early and contribute to AD progression. One aim of the parent R01 is to investigate how glucokinase, a glucosensor intermediary, we found to be expressed in murine taste cells, contributes to the hedonic appeal of sugar. To date, we showed that gustatory glucokinase is regulated by metabolic state and dietary sugar, and contributes to the ability to detect glucose-containing sugars in the oral cavity. Although these processes do not require the canonical sweet receptor (T1R2+T1R3), preliminary data included in this administrative supplement now show that glucokinase activity affects sweet receptor expression in mice. Furthermore, in a set of pilot studies, included here, we discovered significant alterations to the taste buds in a transgenic AD mouse model, even in young adulthood. The 3xTg mouse has significantly smaller taste buds, which display high levels of the inflammatory cytokine, TNFα, and less glucokinase, though further testing is needed. Precisely when these morphological and molecular aberrations emerge, whether they are associated with concomitant sweet receptor loss, and how they ultimately affect taste preferences remain unknown. Thus, the goal of this administrative supplement is to extend Aim 1 of the parent R01 to investigate age-dependent changes in the taste bud microenvironment and taste-guided behaviors in familial and sporadic AD. To do this, we will use immunohistochemical techniques and rigorous behavioral taste testing to study two common transgenic mouse lines, 3xTg and APOE4 knock in, which vary in their genetic predisposition to AD, across adulthood. The outcomes of these aims will provide a better understanding of how gustatory glucosensing changes across the lifespan and in response to the underlying metabolic-inflammatory conditions associated with AD. This knowledge will be important for developing new strategies to assess AD symptoms and curb the excess sugar intake exacerbating disease progression.

项目摘要 高糖的饮食是肥胖，糖尿病和神经退行性疾病的重要危险因素， 例如阿尔茨海默氏症。这些物质的所谓的可口的“甜”味在 促进它们的外观，有时以平衡的饮食为代价。在人类中，广告的进展为 对甜味味道的敏感性降低，并增加了对更智能甜食和液体的渴望。尽管 通常认为这些味道定义了中枢神经系统功能受损，周围 与AD事件发作相关的条件也可能会影响其外围末端器官处的味觉处理， 味蕾。实际上，关于味觉异常的发展知之甚少，包括它们是否出现 早期并有助于广告进展。母体R01的目的之一是研究葡萄糖酶如何 葡萄糖传感器中间体，我们发现在鼠味细胞中表达，有助于享乐外观 糖。迄今为止，我们表明味觉葡萄糖酶受代谢状态和饮食糖的调节，以及 有助于检测口腔中含葡萄糖糖的能力。尽管这些过程没有 需要规范的甜蜜接收器（T1R2+T1R3），此管理补充中包含的初步数据 现在表明葡萄糖激酶活性会影响小鼠的甜受体表达。此外，在一组飞行员中 研究，此处包括，我们在转基因AD小鼠模型中发现了对味蕾的重大变化， 即使在年轻的成年中。 3XTG鼠标的味蕾明显较小，显示出高水平的味蕾 炎性细胞因子，TNFα和较少的葡萄糖动物酶，尽管需要进一步测试。恰恰是什么时候 形态和分子畸变出现，是否与伴随的甜接收器相关 损失以及它们最终如何影响口味偏好仍然未知。那是这个行政的目标 补充是扩展母r01的目标1，以研究味蕾的年龄依赖性变化 家庭和零星广告中的微环境和味觉引导的行为。为此，我们将使用 免疫组织化学技术和严格的行为口味测试研究两种常见的转基因小鼠 3xtg和apoE4敲入线，在成年期，它们的遗传易感性易感性各不相同。 这些目标的结果将更好地理解整个味觉的味觉变化 生命周期和对与AD相关的潜在代谢炎症条件的响应。这 知识对于制定新策略来评估广告符号并遏制多余的糖很重要 摄入加剧疾病进展。