Dissecting Sex-Specific Metabolic Responses to Inflammation

项目摘要 性别是影响危及生命的感染存活率的一个主要因素，但目前的治疗替代方案并没有 提供针对性的护理。为了发现治疗严重感染的新策略，我希望解开性别特异性 在感染期间改善宿主适应性的肝脏机制。我的主要假设是， 肝脏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 rates. 在我的博士后培训期间，我已经开发出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置于其热中性温度下更能反映受感染的人类， 在环境室温下饲养小鼠。我最近的研究表明， 与雄性相比，热中性损害了雌性小鼠的生存，这是由于一个戏剧性的 血浆甘油三酯蓄积。我进一步的数据表明，这是由肝脏转录调节， 因子BCL 6，其靶向肝脂蛋白代谢以介导其在全身脂质中的关键功能 装卸.在我的K99 Aim 1中，我将开始测试在BCL 6下游发挥作用的候选因子，这些因子是新的 病原体感染期间宿主适应性的调节器。我将继续研究全身脂质处理， 感染我的K99 Aim 2，并进行VLDL合成和清除试验，以了解 感染诱导的小鼠高脂血症。 在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。 研究性别特异性的肝脏代谢适应，影响结果 感染。我的目标是在独立R00阶段扩展这个问题，并确定 使男性易患NAFLD。我令人兴奋的新研究表明，虽然肝脏BCL6保护男性， 当雄性小鼠被喂食高脂肪食物时，情况正好相反。在那里，肝BCL 6倾向于男性 脂肪肝和肝性脂肪变性。在我的R00目标中，我希望作为一名独立调查员研究这一点，但我需要 在独立之前接受过性类固醇代谢和肝脏基因操作方面的进一步培训。NIH Pathway 独立奖将使我有两年的关键训练，以发展这些技能，在博士冬青 英格拉哈姆的实验室。在她的实验室里，我将培养我独立职业所需的技能，以及她对工作的热情。 在我成立独立的研究小组之前，导师对我的培训将是非常宝贵的。

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.