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

项目摘要 载脂蛋白E4是阿尔茨海默病(AD)最强的遗传风险因素，肥胖是最常见的因素之一 AD的环境风险因素。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风险因素如何相互作用是极其重要的。 我们将在健康的啮齿动物模型中分析这些相互作用。此前对小鼠的研究表明， 肥胖和载脂蛋白4的结合进一步加剧了AD的病理和认知能力下降；研究 这里提出的建议旨在了解AD发病前发生的变化。APOE3和APOE4基因敲除小鼠 从6个月大开始，将它们放入高脂肪的“西方”饮食(HFD，45%脂肪)12周。审查目标1a 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小鼠中的紊乱，其中APOE4小鼠更容易受到影响。审查目标1b HFD对神经胶质免疫反应性、脂滴堆积和神经元复杂性的影响。我们发现了HFD APOE3和APOE4小鼠的胶质细胞免疫反应性和脂滴(LD)积聚增加。这个 我论文的其余部分将集中于确定神经胶质细胞免疫反应和LD的机制 蓄积和减少高脂蛋白引起的改变。AIM 2a将检查平行的外周代谢和 高脂饲料诱导的炎症途径。我们将调查：1)对于HFD，是特定的炎症或代谢 基因改变？2)外周特异性基因改变与中枢神经系统疾病是否存在相关性？ 3)在APOE3型和APOE4型之间，HFD引起的特异性基因改变是否存在差异？Aim 2b将检查 LD的组成在不同的基因型和饮食中是否不同，以及LD累积的增加是否相关 与氧化应激有关。我们将调查：1)载脂蛋白E基因和饮食中LD的组成是否存在差异？ LD的积累是否与氧化应激增加有关？3)LDS与活性氧共存吗？ 物种？Aim 2c将研究二甲双胍是否会改善LD堆积和相关的胶质细胞增生症 使用HFD。我们将调查：1)二甲双胍是否减少胶质增生和LD积聚？2)LDS是否共定位 是小胶质细胞还是星形胶质细胞？在完成我的博士学位后，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诱导认知改变的潜在机制 转录学。我将通过首先确定一个理想的博士后实验室，然后获得 博士后职位。我的目标是完成我的博士后研究，在一所 严谨的科研、创新、培训和专业发展。为了获得这一点 作为奖学金，我和我的赞助人承诺了一项计划，其中包括确定一个理想的实验室环境。我们 我同意与我的委员会成员和合作者一起工作，参加多个会议 和网络活动，以及邀请演讲者。F99/K00将极大地帮助我完成我的博士学位 并获得我努力争取的博士后职位。

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.