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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目概要高糖饮食是肥胖、糖尿病和神经退行性疾病的重要危险因素，这些物质所谓的“甜味”在老年痴呆症中发挥着重要作用。提高它们的吸引力，有时以牺牲均衡饮食为代价。在人类中，AD 进展的特点是。对甜味的敏感性降低，对更甜的食物和液体的渴望增加。人们普遍认为这些味觉缺陷是由于中枢神经系统功能受损造成的与AD最终发作相关的条件也可能影响其外周终末器官的味觉处理，事实上，人们对味觉异常是如何发生的，包括它们是否出现，知之甚少。母体 R01 的一个目标是研究葡萄糖激酶（一种我们发现葡萄糖传感器中介在小鼠味觉细胞中表达，有助于增强享乐吸引力迄今为止，我们发现味觉葡萄糖激酶受代谢状态和膳食糖的调节，并且有助于检测口腔中含葡萄糖的糖的能力，尽管这些过程不会。需要规范的甜味受体（T1R2+T1R3），初步数据包含在本行政补充中现在，在一组试验中表明，葡萄糖激酶活性会影响小鼠中的甜味受体表达。我们在转基因 AD 小鼠模型中发现了味蕾的显着改变，即使在成年初期，3xTg 小鼠的味蕾也明显较小，显示出高水平的味蕾。炎症细胞因子、TNFα 和较少的葡萄糖激酶，但具体何时需要进一步测试。形态和分子畸变的出现是否与伴随的甜味受体有关损失，以及它们最终如何影响口味偏好仍然未知。因此，这一行政管理的目标仍然未知。补充是扩展母体 R01 的目标 1，以研究味蕾的年龄依赖性变化为了做到这一点，我们将使用家族性和散发性 AD 中的微环境和味觉引导行为。免疫组织化学技术和严格的行为味觉测试研究两种常见的转基因小鼠 3xTg 和 APOE4 基因敲入，在整个成年期对 AD 的遗传易感性各不相同。这些目标的结果将有助于更好地理解味觉葡萄糖感受如何在整个过程中发生变化。寿命以及对与 AD 相关的潜在代谢炎症状况的反应。这些知识对于制定评估 AD 症状和抑制过量糖分的新策略非常重要摄入加剧疾病进展。