Identification of High Fat Diet Induced Modulations of the Gut-Brain Pathways

高脂肪饮食诱导的肠-脑通路调节的鉴定

基本信息

批准号：
10597789
负责人：
Nahdia S Jones
金额：
$ 8.46万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2022-10-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10597789
关键词：
Address Adipose tissue Adverse effects Affect Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Animal Model Astrocytes Astrocytosis Award Bioinformatics Biological Assay Blood Glucose Brain Cognitive Committee Members Data Dementia Development Diet Disease Doctor of Philosophy Drug Controls Energy Metabolism Environmental Risk Factor Epidemic Event Fatty acid glycerol esters Fellowship Functional disorder Funding Future Gene Expression Gene Expression Profiling Gene Mutation Genes Genetic Risk Genotype Glial Fibrillary Acidic Protein Gliosis Glucose Intolerance Goals High Fat Diet Image Impaired cognition Inflammation Inflammatory Institution Knock-in Mouse Lead Lipids Measures Metabolic Metabolic Pathway Metabolism Metformin Methods Microglia Mus NADH NADP Neuroglia Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Onset of illness Oxidative Stress Pathologic Pathway interactions Peripheral Plasma Population Positioning Attribute Postdoctoral Fellow Professional Organizations Protocols documentation Quantitative Reverse Transcriptase PCR RNA Reactive Oxygen Species Research Research Personnel Research Project Grants Resource Sharing Resources Risk Factors Rodent Model Stains Stimulus Structure Subcellular structure Time Tissues Training Visceral Weight Gain Western Blotting Work brain pathway combinatorial genetic risk factor immunoreactivity innovation interest lipidomics metabolomics microscopic imaging mouse model novel strategies obese person oxidative damage response skills symposium systemic inflammatory response transcriptomics western diet

项目摘要

Project Summary APOE4 is the strongest genetic risk factor for Alzheimer’s Disease (AD) and obesity is one of the most common environmental risk factors for AD. With 14% of the population being APOE4 carriers and 30% of the population suffering from obesity, it is extremely important to understand how these two common AD risk factors interact. We will analyze these interactions in healthy rodent models. Previous studies in mice have shown the combination of obesity and APOE4 further exacerbates AD pathology and cognitive decline; the studies proposed here aim at understanding alterations that occur before AD onset. APOE3 and APOE4 knock-in mice were placed on high fat “western” diets (HFD, 45% fat) for 12 weeks starting at 6 months old. Aim 1a examined the metabolic and cognitive disturbances associated with HFD and we found HFD increased metabolic disturbances in APOE3 and APOE4 mice, with APOE4 mice being more susceptible. Aim 1b examined effects of HFD on glial immunoreactivity, lipid droplet accumulation, and neuronal complexity. We found HFD increased glia immunoreactivity and lipid droplet (LD) accumulation in APOE3 and APOE4 mice. The remainder of my thesis will focus on identifying mechanisms underlying glia immunoreactivity and LD accumulation and reducing HFD induced alterations. Aim 2a will examine parallel peripheral metabolic and inflammatory pathways induced by HFD. We will investigate: 1) With HFD, are specific inflammatory or metabolic genes altered? 2) Is there a correlation between the specific genes altered in the periphery and CNS with HFD? 3) Do the specific genes altered by HFD differ between APOE3 and APOE4 genotypes? Aim 2b will examine whether LD composition differs between genotypes and diets, and if increases in LD accumulation is associated with oxidative stress. We will investigate: 1) Does LD composition differ between APOE genotype and diet? 2) Does LD accumulation correlate with increased oxidative stress? 3) Do LDs colocalize with reactive oxygen species? Aim 2c will examine whether Metformin will ameliorate the LD accumulation and gliosis associated with HFD. We will investigate: 1) Does Metformin reduce gliosis and LD accumulation? 2) Do LDs co-localize with microglia or astrocytes? After completing my PhD, I will continue to build skills in a post-doctoral setting researching the mechanisms underlying diet induced cognitive alterations through metabolomics and transcriptomics. I will be successful in this through first identifying an ideal post-doctoral lab then obtaining the post-doctoral position. My goal is to complete my post-doctoral fellowship at an institution that values rigorous scientific research, innovation, training and professional development. To obtain this fellowship, my sponsor and I have committed to a plan that includes identifying an ideal lab setting. We have agreed to working with my committee members and collaborators, attending multiple conferences and networking events, and inviting speakers. The F99/K00 will greatly assist me in both completing my PhD and obtaining the postdoctoral position I am striving for.

项目摘要 APOE4是阿尔茨海默氏病（AD）的强大遗传危险因素，肥胖是最常见的遗传危险因素之一 AD的环境风险因素。有14％的人口为APOE4载体和30％的人口患有肥胖症，了解这两个常见的AD风险因素如何相互作用非常重要。我们将在健康的啮齿动物模型中分析这些相互作用。以前在小鼠的研究表明肥胖和APOE4的结合进一步加剧了AD病理学和认知能力下降；研究此处提出的旨在理解AD发作之前发生的变化。 APOE3和APOE4敲入小鼠从6个月大时，将其放置在高脂肪“西方”饮食（HFD，45％脂肪）中12周。 AIM 1A检查了与HFD相关的代谢和认知障碍，我们发现HFD增加了代谢 APOE3和APOE4小鼠的紊乱，APOE4小鼠更容易受到影响。 AIM 1B检查了 HFD对神经胶质免疫反应性，脂质液滴积累和神经元复杂性的影响。我们找到了HFD APOE3和APOE4小鼠中的胶质胶质免疫反应性和脂质液滴（LD）的积累增加。这我的论文的其余部分将集中于确定胶质胶质免疫反应性和LD的机制积累和减少HFD诱导的改变。 AIM 2A将检查平行的外周代谢和 HFD诱导的炎症途径。我们将调查：1）使用HFD，是特定的炎症或代谢基因改变了？ 2）在外周的特定基因与HFD中CNS发生变化的特定基因之间是否存在相关性？ 3）在APOE3和APOE4基因型之间，由HFD改变了特定基因？ AIM 2B将检查 LD组成在基因型和饮食之间是否有所不同，以及LD积累的增加是否与带有氧化应激。我们将调查：1）LD的组成基因型和饮食之间的组成差异吗？ 2） LD积累与氧化应激的增加相关吗？ 3）DO LDS与活性氧共定位物种？ AIM 2C将检查二甲双胍是否会改善LD积累和胶质性相关与HFD。我们将调查：1）二甲双胍会降低神经胶质症和LD积累吗？ 2）DO LDS共定位与小胶质细胞或星形胶质细胞？完成博士学位后，我将继续在博士后设置中建立技能研究饮食潜在的机制通过代谢组学和转录组学。我将通过首先确定理想的博士后实验室，然后获得成功，然后获得博士后位置。我的目标是在一个重视的机构中完成我的博士后奖学金严格的科学研究，创新，培训和专业发展。获得这个奖学金，我和我的赞助商致力于一项计划，其中包括确定理想的实验室设置。我们已经同意与我的委员会成员和合作者合作，参加了多次会议和网络活动和邀请发言人。 F99/K00将极大地帮助我完成我的博士学位并获得我正在努力的博士后位置。