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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' 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

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.

项目概要 APOE4 是阿尔茨海默病 (AD) 最强的遗传风险因素，而肥胖是最常见的遗传风险因素之一 AD 的环境危险因素 14% 的人口是 APOE4 携带者，30% 的人口是 APOE4 携带者。 对于患有肥胖症的人来说，了解这两个常见的 AD 危险因素如何相互作用非常重要。 我们将在健康啮齿动物模型中分析这些相互作用，之前对小鼠的研究已经表明了这一点。 肥胖和 APOE4 的结合进一步加剧了 AD 病理和认知能力下降； 这里提出的目标是在 AD 理解发生之前发生的改变 APOE3 和 APOE4 敲入小鼠。 从 6 个月大时开始进行 12 周的高脂肪“西方”饮食（HFD，45% 脂肪）检查，目标 1a。 与 HFD 相关的代谢和认知障碍，我们发现 HFD 会增加代谢 APOE3 和 APOE4 小鼠中的干扰，其中 APOE4 小鼠更容易受到检查。 HFD 对神经胶质免疫反应性、脂滴积累和神经复杂性的影响。 APOE3 和 APOE4 小鼠的神经胶质细胞免疫反应性和脂滴 (LD) 积累增加。 我论文的其余部分将重点探讨神经胶质细胞免疫反应性和 LD 的潜在机制 目标 2a 将检查平行的外周代谢和变化。 我们将研究 HFD 引起的炎症途径：1) HFD 是特异性炎症或代谢途径。 2) 外周和中枢神经系统的特定基因改变与 HFD 之间是否存在相关性？ 3) Aim 2b 将检查 APOE3 和 APOE4 基因型之间 HFD 改变的特定基因是否不同？ 基因型和饮食之间的 LD 组成是否不同，以及 LD 积累的增加是否相关 我们将研究：1) APOE 基因型和饮食之间的 LD 组成是否不同？ LD 积累与氧化应激增加相关吗 3) LD 与活性氧共定位吗？ 目标 2c 将检查二甲双胍是否会改善 LD 积累和相关神经胶质增生 我们将研究：1) 二甲双胍是否会减少神经胶质增生和 LD 积累？ 完成博士学位后，我将继续在博士后环境中培养技能 通过代谢组学研究饮食引起认知改变的机制 我将通过首先确定一个理想的博士后实验室然后获得转录组学来取得成功。 我的目标是在一个重视的机构完成我的博士后奖学金。 严格的科学研究、创新、培训和专业发展才能获得这一点。 作为奖学金，我和我的赞助商已承诺制定一项计划，其中包括确定理想的实验室环境。 已同意与我的委员会成员和合作者合作，参加多个会议 和社交活动，以及邀请演讲者将极大地帮助我完成我的博士学位。 并获得我正在努力争取的博士后职位。