Decoding the Brain-Liver Axis: Uncovering mechanisms of host defense

This research proposal seeks to uncover neuronal mechanisms orchestrating metabolic adaptations to bacterial infections, specifically delineating the pivotal role of the brain-liver axis in modulating metabolic responses. By combining the methods of neuroscience and immunology, the research aims to better understand neuronal and hepatic responses to infections. I showed earlier that housing infected mice at thermoneutrality instead of ambient room temperature better mimics human bacterial infections. For example, infected mice at thermoneutrality develop severe hyperlipidemia, compromising survival. Here, I hypothesize that circulating lipids are regulated by neuronal and hepatic mechanisms. In Goal 1, I will look for neurocircuits in the hypothalamus that might monitor circulating lipoproteins and trigger counterregulatory responses. To do this, I will use genetic mouse models and chemogenetics to stimulate and inhibit candidate neuronal clusters during infections. In Goal 2, I will perform an unbiased screen to elucidate hepatic secretome using TurboID, followed by targeted proteomics. I will target these hepatic factors in vivo to test their role in improving host survival during bacterial infections. My approaches defining the molecular basis of hyperlipidemia in mouse models are highly innovative and likely to provide novel insights into how circulating lipid levels determine host survival.