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 高糖饮食是肥胖、糖尿病和神经退行性疾病的重要风险因素， 比如老年痴呆症这些物质的所谓可口的“甜”味在以下方面起着重要作用： 为了提高他们的吸引力，有时会牺牲均衡的饮食。在人类中，AD进展的标志是 对甜味的敏感性降低，对更强烈的甜味食物和液体的渴望增加。而 通常认为这些味觉缺陷是由受损的中枢神经系统功能、外周神经系统功能、神经系统功能 与AD的最终发作相关的病症也可能影响其外周末端器官的味觉加工， 味蕾事实上，我们对味觉异常是如何发展的，包括它们是否出现， 早期并促进AD进展。亲本R01的一个目的是研究葡萄糖激酶， 葡萄糖传感器中间体，我们发现在小鼠味觉细胞中表达，有助于 糖到目前为止，我们发现味觉葡萄糖激酶受代谢状态和膳食糖的调节， 有助于检测口腔中含葡萄糖的糖的能力。虽然这些过程不 需要典型的甜味受体（T1R2+T1R3），初步数据包括在本行政补充 现在表明葡萄糖激酶活性影响小鼠甜味受体的表达。此外，在一组试点中， 研究，包括在这里，我们发现了显着的改变，味蕾在转基因AD小鼠模型， 即使是在年轻的成年人。3xTg小鼠具有明显较小的味蕾，其显示高水平的 炎性细胞因子TNFα和较少的葡萄糖激酶，但需要进一步测试。正是当这些 出现形态和分子畸变，无论它们是否与伴随的甜味受体相关， 损失，以及它们最终如何影响口味偏好仍然未知。因此，本行政 补充是为了扩展亲本R01的目标1，以研究味蕾的年龄依赖性变化 微环境和口味引导的行为在家族性和散发性AD。为此，我们将使用 免疫组织化学技术和严格行为味觉测试研究两种常见转基因小鼠 品系，3xTg和APOE 4敲入，其在整个成年期内对AD的遗传易感性不同。的 这些目标的结果将提供更好的理解味觉葡萄糖传感如何在整个过程中变化。 寿命和响应与AD相关的潜在代谢炎症状况。这 知识对于开发新的策略来评估AD症状和抑制过量的糖将是重要的。 摄入会加剧疾病进展。