Dissecting Sex-Specific Metabolic Responses to Inflammation

剖析性别特异性对炎症的代谢反应

基本信息

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
项目类别：
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

项目摘要

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.

项目概要性别是影响危及生命的感染生存的主要因素，但目前的治疗方案并不能为了发现治疗严重感染的新策略，我希望阐明性别特异性的护理。我的主要观点是肝脏在感染期间改善宿主健康的机制。肝脏因素影响受感染小鼠的生存，我希望针对这些因素来提高生存率费率。在博士后培训期间，我开发了可以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热中性温度下比将受感染的小鼠更好地反映了受感染的人类我最近的研究表明，将受感染的小鼠饲养在室温下。与雄性小鼠相比，热中性会损害雌性小鼠的生存，这是由于我的进一步数据表明，这是由肝脏转录调节的。因子 BCL6，靶向肝脂蛋白代谢，介导其在全身脂质中的关键功能在我的 K99 Aim1 中，我将开始测试在 BCL6 下游发挥作用且新颖的候选因子。病原体感染期间宿主健康的调节因子，我将继续研究全身脂质处理。感染我的 K99 Aim 2 并进行 VLDL 合成和清除测定，以了解其机制感染引起的小鼠高脂血症。 K99培训阶段结束后，我希望在其中一个专业建立一个独立的研究实验室美国的机构研究影响结果的肝脏中性别特异性代谢适应我的目标是在独立 R00 阶段扩展这个问题，并确定影响感染的肝脏因素。我令人兴奋的新研究表明，虽然肝脏 BCL6 可以在男性患病期间发挥保护作用。感染，而当雄性小鼠喂食高脂肪饮食时，则会发生相反的情况，其中，肝脏 BCL6 使雄性小鼠易感。在我的 R00 目标中，我希望作为一名独立研究者来研究这一点，但我需要在独立之前接受性类固醇代谢和肝脏基因操作的进一步培训。独立奖将使我能够在霍利博士那里接受两年的关键培训来发展这些技能在英格拉汉姆的实验室中，我将培养我的独立职业所需的技能以及她对工作的热情。在建立独立研究小组之前，指导对于我的培训非常宝贵。