Rob Dowen, PhD

EMAIL: dowen@email.unc.edu

PERSONAL WEBSITE: https://robdowenlab.web.unc.edu/

PUBLICATIONS: Publications Link

Proper regulation of cellular lipid stores is paramount to maintaining organismal energy homeostasis and is coordinated by a network of multi-tissue endocrine signals. We aim to elucidate the molecular mechanisms that govern the storage, metabolism, and intercellular transport of lipids; as well as understand how these circuits interface with other cellular homeostatic pathways (e.g., growth and aging). We utilize C. elegans and mammalian cells as model systems to interrogate these evolutionarily conserved pathways, combining genetic approaches (forward and reverse genetic screens, CRISPR) with genomic methodologies (ChIP-Seq, mRNA-Seq, DNA-Seq) to identify new components and mechanisms of metabolic regulation. Our ultimate goal is to perform basic research that advances the mechanistic understanding of lipid regulation and to uncover the underlying molecular pathologies of human metabolic disease to yield new therapeutic approaches. Two rotation projects are available in the lab:

1. How do pro-growth signaling pathways control lipid homeostasis? We have previously demonstrated that a developmentally-regulated inter-tissue signaling pathway regulates fat storage in C. elegans. We recently discovered that a classic regulator of tissue patterning and development, the Hedgehog morphogen, is the responsible for this inter-tissue comxmunication and governs metabolic programs by controlling the mTOR signaling pathway. We found that regulation of mTOR by Hedgehog is conserved in mammalian liver cells. Rotation projects will be aimed at uncovering how Hedgehog signals to mTOR to maintain metabolic homeostasis, which is currently unknown.

We have also discovered that a mitogen-activated protein kinase (MAPK) pathway acts in concert with mTOR signaling to regulate lipid levels in the C. elegans intestine. This MAPK pathway promotes the uptake of nutrients from the lumen of the intestine, which is a novel role for MAPK proteins. We are investigating whether MAPK signaling governs the activity of intestinal ion channels, which are required for transport of nutrients across membranes. Rotation projects will be aimed at identifying the mechanisms by which MAPK signaling regulates nutrient absorption.

References:
https://pubmed.ncbi.nlm.nih.gov/38766075/
https://pubmed.ncbi.nlm.nih.gov/38766028/
https://pubmed.ncbi.nlm.nih.gov/38712300/
https://pubmed.ncbi.nlm.nih.gov/37773960/
https://pubmed.ncbi.nlm.nih.gov/30956009/
https://pubmed.ncbi.nlm.nih.gov/27401555/

2. How does the gut microbiome govern lipid homeostasis and organismal aging? We use C. elegans to elucidate the molecular mechanisms by which intestinal microbes reconfigure host metabolic and aging pathways. Employing metabolomic and genetic approaches in C. elegans, we aim to identify pro-longevity metabolites that tune host signaling pathways to restrict lipid accumulation and extend lifespan. This rotation project is aimed at determining the host response to probiotic microbes, including evaluation of specific intestinal nutrient sensing pathways that may respond to the composition of the gut microbiome. This interdisciplinary project will offer an opportunity to integrate biochemical, genetic, and genomic approaches.

Reference:
https://pubmed.ncbi.nlm.nih.gov/38547054/