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.