Diets rich in palmitate increase Alzheimers disease risk by activating CHOP gene

富含棕榈酸酯的饮食通过激活 CHOP 基因增加阿尔茨海默病风险

• 批准号: 9264957
• 负责人: OTHMAN GHRIBI
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264957
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animal Model; Apoptotic; Autopsy; Brain; CREB1 gene; Cell Death; Complex; Crossbreeding; Cytoplasm; Data; Dementia; Development; Diet; Dietary intake; Disease; Disease Progression; Drug Targeting; Endoplasmic Reticulum; Epigenetic Process; Etiology; Functional disorder; Gene Proteins; Generations; Genes; Genetic; Glutathione; Glycogen Synthase Kinase 3; Hippocampus (Brain); Human; Incubated; Inflammation; Inherited; Knowledge; Link; Memory; Memory impairment; Mouse Protein; Mus; Mutation; Nature; New Agents; Nonesterified Fatty Acids; Oxidative Stress; Palmitates; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Plasma; Production; Public Health; Publishing; Risk; Role; Saturated Fatty Acids; Signal Pathway; Slice; Stress; Symptoms; Testing; Transcriptional Activation; Transgenic Mice; Wild Type Mouse; Work; activating transcription factor; baicalein; base; beta-site APP cleaving enzyme 1; brain tissue; design; drug discovery; endoplasmic reticulum stress; environmental chemical; factor C; feeding; human tissue; in vivo; inflammatory marker; mouse model; novel; novel therapeutics; offspring; overexpression; oxidative damage; phenylmethylpyrazolone; prevent; pro-apoptotic protein; protein activation; protein expression; public health relevance; tau Proteins; tau phosphorylation; transcription factor; transcription factor CHOP

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a complex disorder that affects memory and progresses to a debilitating dementia. Evidence shows that the nature of our dietary intake influences both epigenetic changes and disease-related genes, thus potentially increasing or reducing our risks of developing diseases such as AD. This application examines novel mechanisms that link a specific dietary agent (palmitate) to a specific transcription factor (CHOP) that may work in concert to cause AD-like pathology in mice. Characterization of such mechanisms may help identify new etiological factors and targets for drug discovery for AD in humans. CHOP (C/EBP-homologous protein) is expressed in the cytoplasm at low levels in normal conditions and is specifically overexpressed following sustained stress to the endoplasmic reticulum (ER). Various agents including environmental (chemical or dietary), genetic, and pathological factors can induce ER stress. The objective of this proposal is to test the hypothesis that the saturated free fatty acid palmitate triggers or exacerbates AD-like pathology by mechanisms involving the activation of the transcription factor CHOP; inhibiting CHOP precludes palmitate-induced AD-like pathology. Our hypothesis is formulated based on our recently published data and preliminary results showing that (i) a palmitate-enriched diet triggers AD hallmarks in wild type mice and exacerbates AD-like pathology in the triple transgenic mouse model for AD (3xTg-AD); (ii) CHOP levels are increased in postmortem brain tissue from humans with AD, in vivo in the 3xTg-AD, and ex vivo in mouse hippocampal slices incubated with palmitate; and that (iii) deleting CHOP gene abrogates palmitate-induced AD hallmarks. In the light of our postmortem, in vivo, and ex vivo results, we propose that determining the particular functional link between the common dietary agent palmitate and the transcription factor CHOP is extremely important to the continuing effort of identifying new etiological agents and genes that may be relevant to the pathogenesis of AD. We propose the following Specific Aims to test our hypothesis: Aim 1: Characterize the functional relationship between palmitate feeding and the triggering of AD-like pathology in mouse models. Aim 2: Determine the role of CHOP in the progression of AD-like pathology in mouse models. Aim 3: Determine the extent to which available drugs that inhibit CHOP prevent or delay AD-like pathology in mice. Completion of the proposed studies may show that the saturated free fatty acid palmitate promotes AD- like pathology in mice through CHOP activation. This is important to identifying etiological factors and genes related to the pathogenesis of AD in humans. Using existing drugs or designing new agents that inhibit CHOP might be promising targets for determining their translational potential in reducing the progression of AD.

描述（由申请人提供）：阿尔茨海默病（AD）是一种影响记忆并发展为衰弱性痴呆的复杂疾病。有证据表明，我们饮食摄入的性质影响表观遗传变化和疾病相关基因，从而可能增加或减少我们患AD等疾病的风险。本申请研究了将特定的饮食剂（棕榈酸酯）与特定的转录因子（CHOP）联系起来的新机制，该转录因子可能共同作用导致小鼠AD样病理学。这些机制的表征可能有助于确定新的病因因素和药物发现的目标，在人类AD。 CHOP（C/EBP同源蛋白）在正常条件下在细胞质中以低水平表达，并且在持续应激至内质网（ER）后特异性过表达。包括环境（化学或饮食）、遗传和病理因素在内的各种因素都可以诱导ER应激。本提案的目的是检验以下假设：饱和游离脂肪酸棕榈酸酯通过涉及转录因子CHOP激活的机制触发或加重AD样病理;抑制CHOP可排除棕榈酸酯诱导的AD样病理。我们的假设是基于我们最近发表的数据和初步结果，表明（i）富含棕榈酸酯的饮食在野生型小鼠中触发AD标志，并在AD的三重转基因小鼠模型（3xTg-AD）中加重AD样病理;（ii）在来自患有AD的人的死后脑组织中，在体内在3xTg-AD中，和离体与棕榈酸孵育的小鼠海马切片;和（iii）删除CHOP基因消除棕榈酸诱导的AD标志。根据我们的尸检，在体内和体外的结果，我们建议，确定特定的功能之间的联系，共同的饮食剂棕榈酸酯和转录因子CHOP是非常重要的持续努力，以确定新的病原体和基因，可能是相关的发病机制的AD。我们提出了以下具体目标来检验我们的假设：目标1：在小鼠模型中表征棕榈酸酯喂养与AD样病理触发之间的功能关系。目的2：确定CHOP在小鼠模型中AD样病理学进展中的作用。目的3：确定抑制CHOP的可用药物预防或延迟小鼠AD样病理的程度。 所提出的研究的完成可显示饱和游离脂肪酸棕榈酸酯通过CHOP活化促进小鼠中的AD样病理。这对于确定人类AD发病机制相关的致病因素和基因具有重要意义。使用现有的药物或设计新的药物，抑制CHOP可能是有前途的目标，以确定其翻译潜力，在减少AD的进展。