Cross sensitization of diet and alcohol on binge behaviors and metabolic dysfunction

饮食和酒精对暴饮暴食行为和代谢功能障碍的交叉敏感性

基本信息

批准号：
10501123
负责人：
Yuval Silberman
金额：
$ 41.74万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
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：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10501123
关键词：
Adopted Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid deposition Apolipoprotein E Behavior Behavioral Behavioral Model Blood Vessels Brain Cell Surface Receptors Cerebrospinal Fluid Cerebrovascular Disorders Cerebrum Chronic Clinical Complement Consumption Development Diet Disease Progression Disease susceptibility Enzymes Ethanol Genotype Glucose Goals Heterogeneity High Density Lipoproteins High Fat Diet Hippocampus (Brain)Histologic Homeostasis Human Human body Immune response Impaired cognition Impairment Inflammation Insulin Link Lipids Lipoprotein (a)Lipoproteins Memory Metabolic Metabolic Pathway Metabolic dysfunction Metabolism Modeling Molecular Molecular Conformation Monitor Mus Neurofibrillary Tangles Neuroimmune Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Study Oxidative Stress Parents Pathologic Pathway interactions Peripheral Plasma Protein Isoforms Proteins Proteome Proteomics Resolution Risk Risk Factors Role Scaffolding Protein Senile Plaques Severities Short-Term Memory Surface System Technology Testing Tissues Transgenic Mice Vascular Dementia Vascular Diseases Water alcohol use disorder binge drinking binge type behavior blood glucose regulation cerebrovascular chronic alcohol ingestion clinically relevant cognitive development comorbidity disease phenotype early onset glucose metabolism glucose tolerance human model improved insulin signaling insulin tolerance lipid metabolism lipid transport lipidomics liquid chromatography mass spectrometry morris water maze mouse model nanosized neuroinflammation new therapeutic target novel novel therapeutic intervention particle pleiotropism protein complex response scaffold

项目摘要

Summary Cerebrovascular dysfunction is tightly linked to the deposition of amyloid plaques and neurofibrillary tangles in the brain; hallmarks of Alzheimer’s disease (AD). High fat diets (HFD) and chronic over-consumption of alcohol independently result in aberrant lipid metabolism which underlies the vascular dysfunction associated with obesity, type II diabetes, vascular dementia, and AD. While HFD and alcohol are both linked to the development of AD, there is limited information on how binge co-consumption of HFD and alcohol impact AD progression and associated cognitive decline. Our parent R01 utilizes a novel behavioral mouse model of binge co-consumption of HFD and alcohol which recapitulates clinical findings showing HFD increases alcohol intake and vice versa, providing a unique behavioral model to dissect the pathways that go awry with over-consumption of HFD and alcohol and how they impact the development of AD. HFD and chronic alcohol consumption have a profound impact on the speciation, composition, and function of plasma lipoproteins which modulate multiple metabolic pathways including systemic immune response, inflammation, glucose metabolism and oxidative stress. Lipoprotein function are mostly dominated by a handful of dynamic “scaffold” proteins that reside at the water- lipid interface, in particular apolipoprotein E (APOE) which has three isoforms—APOE2, APOE3, and APOE4. APOE4 is associated with elevated neuroinflammation and lower rates of cerebral glucose metabolism and carriers of APOE4 are at substantially elevated risk for early onset and increased severity of AD. We hypothesize that HFD and chronic alcohol consumption alter the speciation and compositional signatures of APOE-containing lipoproteins which exacerbates the neuroimmune response and accelerates cognitive decline and development of AD. Our specific aim is to characterize the impact of binge co-consumption of HFD and alcohol on the speciation and composition of APOE3 and APOE4-containing lipoproteins and how they modulate the development of AD. Utilizing transgenic mouse lines susceptible to Alzheimer’s Disease phenotypes with humanize APOE isoforms, we will determine how co-morbid high fat diet and alcohol binge consumption modulates memory function, insulin and glucose function, hippocampal neuroinflammation, and plasma lipoprotein speciation.

概括脑血管功能障碍与淀粉样斑块和神经原纤维缠结的沉积密切相关大脑；阿尔茨海默氏病（AD）的特征；高脂肪饮食（HFD）和长期过度饮酒。独立导致异常的脂质代谢，这是与血管功能障碍相关的基础肥胖、二型糖尿病、血管性痴呆和阿尔茨海默氏症（AD），而 HFD 和酒精都与该病的发生有关。对于 AD 的治疗，关于同时摄入 HFD 和酒精如何影响 AD 进展的信息有限，我们的母体 R01 采用了一种新型的暴饮暴食行为小鼠模型。 HFD 和酒精的关系概括了临床结果，表明 HFD 会增加酒精摄入量，反之亦然，提供独特的行为模型来剖析因过度消费 HFD 而出错的途径酒精以及它们如何影响 HFD 和长期饮酒有着深远的影响。对调节多种代谢的血浆脂蛋白的形态、组成和功能的影响途径包括全身免疫反应、炎症、葡萄糖代谢和氧化应激。脂蛋白的功能主要由驻留在水中的少数动态“支架”蛋白主导。脂质界面，特别是载脂蛋白 E (APOE)，它具有三种亚型：APOE2、APOE3 和 APOE4。 APOE4 与神经炎症升高和脑葡萄糖代谢率降低有关 APOE4 携带者 AD 早发和严重程度增加的风险显着升高。 HFD 和长期饮酒会改变含 APOE 的形态和成分特征脂蛋白会加剧神经免疫反应并加速认知能力下降和发展我们的具体目标是描述同时食用 HFD 和酒精对 AD 的影响。含有 APOE3 和 APOE4 的脂蛋白的形态和组成以及它们如何调节利用易患阿尔茨海默病表型的转基因小鼠品系来开发 AD。将 APOE 亚型人性化，我们将确定高脂肪饮食和酗酒如何共存调节记忆功能、胰岛素和葡萄糖功能、海马神经炎症和血浆脂蛋白形态。