Dissecting Sex-Specific Metabolic Responses to Inflammation

剖析性别特异性对炎症的代谢反应

• 批准号: 10449694
• 负责人: Joni Nikkanen
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449694
• 关键词: Accounting; Affect; Award; BCL6 gene; Basal metabolic rate; Binding Sites; Biological Assay; CRISPR/Cas technology; Caring; ChIP-seq; Communicable Diseases; Data; Data Set; Escherichia coli Infections; Exhibits; Fatty Liver; Fatty acid glycerol esters; Female; Genes; Genetic Transcription; Genomics; Goals; Gonadal Steroid Hormones; Hepatic; High Fat Diet; Holly; Host Defense Mechanism; Housing; Human; Hyperlipidemia; Infection; Inflammation; Institution; Laboratory Research; Life; Lipase; Lipids; Lipoproteins; Liver; Masks; Mediating; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Obesity; Outcome; Overnutrition; Pathogenicity; Pathway interactions; Pharmacology; Phase; Phenotype; Plasma; Postdoctoral Fellow; Predisposing Factor; Predisposition; Regulation; Research; Research Personnel; Risk Factors; Role; Sampling; Scintillation Counting; Sepsis; Sex Bias; Sex Differences; Survival Rate; System; Temperature; Testing; Tracer; Training; Triglycerides; United States; United States National Institutes of Health; Very low density lipoprotein; Viral; alternative treatment; career; feeding; fitness; gallin; genetic manipulation; human model; improved; insight; knock-down; lipid metabolism; liver function; liver metabolism; male; men; mortality; mouse model; non-alcoholic fatty liver disease; novel; novel strategies; overexpression; particle; pathogen; post-doctoral training; programs; promoter; response; sex; sexual dimorphism; skills; steroid metabolism; thermal stress; transcription factor; transcriptome sequencing; treatment strategy

Project Summary Sex is a major factor affecting survival from life-threatening infections, but current treatment alternatives do not provide sex-specific care. To discover novel strategies to treat severe infections, I wish to unravel sex-specific mechanisms of the liver that improve host fitness during infections. My central hypothesize is that sex-specific factors of the liver impact the survival of infected mice, and I wish to target these factors to improve survival rates. During my postdoctoral training, I have developed mouse models that replicate human responses to infections and found that housing infected mice at their thermoneutral temperature better mirrors infected humans than housing mice at ambient room temperature. My recent studies demonstrate that housing infected mice at thermoneutrality compromises the survival of female mice as compared to males, and this is due to a dramatic accumulation of plasma triglycerides. My further data demonstrate that this is regulated by a hepatic transcription factor, BCL6, which targets hepatic lipoprotein metabolism to mediate its critical function in systemic lipid handling. In my K99 Aim1, I will start testing candidate factors that function downstream of BCL6 and are novel regulators of host fitness during pathogenic infections. I will continue studying systemic lipid handling following infection in my K99 Aim 2 and perform VLDL synthesis and clearance assays to understand the mechanism of infection-induced hyperlipidemia in mice. After the K99 training phase, I wish to establish an independent research laboratory in one of the major institutions in the United States to study sex-specific metabolic adaptations in the liver that impact the outcome of infections. I aim to expand this question during the independent R00 phase and identify hepatic factors that predispose men to NAFLD. My exciting new studies suggest that while hepatic BCL6 protects males during infection, the opposite occurs when male mice are fed with high-fat diet. There, hepatic BCL6 predisposes males to fatty liver and hepatic steatosis. In my R00 Aim, I wish to study this as an independent investigator, but I need further training in sex steroid metabolism and hepatic gene manipulation before independence. The NIH Pathway to Independence Award will allow me the two years of critical training to develop these skills in Dr. Holly Ingraham’s lab. In her lab, I will develop the skills needed for my independent career, and her passion in mentorship will be invaluable for my training before establishing my independent research group.

项目摘要 性行为是影响患者从危及生命的感染中存活下来的一个主要因素，但目前的治疗方案并不是这样。 提供针对性别的护理。为了发现治疗严重感染的新策略，我希望揭开性别的差异 肝脏在感染期间改善宿主健康的机制。我的中心假设是特定性别 肝脏的因素影响感染小鼠的存活率，我希望针对这些因素来提高存活率 费率。 在我的博士后培训期间，我开发了复制人类对感染反应的小鼠模型 并发现，将受感染的小鼠安置在温度中等的环境中，比将其置于受感染的人类体内更能反映出受感染的人类 在室温下饲养小鼠。我最近的研究表明，将受感染的老鼠安置在 与雄鼠相比，中温性降低了雌鼠的存活率，这是由于戏剧性的 血浆甘油三酯积聚。我的进一步数据表明，这是由肝脏转录调控的。 BCL6因子，以肝脂蛋白代谢为靶点，介导其在全身脂质中的关键作用 正在处理。在我的K99Aim1中，我将开始测试在BCL6下游起作用且新颖的候选因子 病原性感染期间寄主适合度的调节器。接下来我会继续研究全身脂肪的处理。 感染My K99的目的2并进行极低密度脂蛋白的合成和清除试验，以了解其机制 感染所致小鼠高脂血症。 在K99培训阶段结束后，我希望建立一个独立的研究实验室，在专业之一 美国机构研究肝脏中影响结局的性别特异性代谢适应 感染的可能性。我的目标是在独立的R00阶段扩大这个问题，并确定肝脏因素 使男性易患非酒精性脂肪肝。我令人兴奋的新研究表明，虽然肝脏BCL6在 感染，当雄性小鼠喂食高脂肪食物时，情况正好相反。在那里，肝脏BCL6先于男性 脂肪肝和肝脏脂肪变性。在我的R00 Aim中，我希望以独立调查员的身份研究这一问题，但我需要 在独立前对性激素代谢和肝脏基因操作进行进一步的培训。美国国立卫生研究院的途径 独立奖将让我在两年的批判性培训中发展霍莉博士的这些技能 英格拉汉姆的实验室。在她的实验室里，我将培养我独立职业生涯所需的技能，以及她对 在建立我的独立研究小组之前，导师对我的培训将是无价的。