Our overall research interests center on how transporter-mediated zinc and manganese mobilization function to regulate diverse cellular processes in health and disease.

1- Zinc is an essential micronutrient which is now recognized as a signaling molecule in addition to its well-characterized regulatory, catalytic, and structural roles. The maintenance of zinc homeostasis and the targeted cellular function of zinc is facilitated by two families of metal transporters, ZIP and ZnT. ZIP14/SLC39A14 is a ZIP family member, which traffics metals into the cytoplasm. Whole-body knockout (KO) of the Zip14 in mice alters zinc homeostasis and creates a phenotype with key features of metabolic endotoxemia (low-grade chronic inflammation). This signature includes increased intestinal permeability, elevated serum endotoxin levels, increased adiposity coupled with up-regulated cytokine expression and insulin insensitivity in adipose tissue, and enlarged pancreatic islets with greater serum insulin. Using both in vitro cell culture systems and in vivo whole-body and tissue-specific conditional (intestine, pancreatic beta-cells, and liver) Zip14 KO mouse models we aim to answer three main questions:

1. What is the role of ZIP14-mediated zinc transport in intestinal barrier function, specifically in the gut microbiota profile and corresponding host response?
2. What is the role of ZIP14-mediated zinc transport in pancreatic insulin biosynthesis and secretion?
3. What is the role of ZIP14-mediated zinc transport in hepatic glucose metabolism?

2- Manganese (Mn) is an essential micronutrient. Impaired Mn homeostasis results in excess Mn and neurotoxicity.  ZIP14/SLC39A14 is a ZIP family transmembrane protein that regulates intracellular manganese and iron in addition to Zn. Recently, it has been shown that humans carrying ZIP14 mutations develop childhood-onset parkinsonism and dystonia. This phenotype was recapitulated in Zip14 knockout (KO) mice. However, the mechanism of  ZIP14-mediated Mn detoxification and how defective ZIP14 function leads to Mn overload, systemic and neuroinflammation have not been well-characterized. Using whole-body and intestine-specific Zip14 KO mouse models, we will investigate the organ/tissue-specific role of ZIP14-mediated Mn transport in Mn homeostasis. The three main aims are:

1. Determine if ZIP14 at the BL membrane of enterocytes provides an alternate route for systemic Mn detoxification.
2. Determine if ZIP14 at the BL membrane of brain endothelial cells regulates Mn detoxification and if defective ZIP14 function leads to neuroinflammation and neurodegeneration.
3. Determine if impaired intestinal barrier function and low-grade chronic inflammation in Zip14 KO mice contribute to ZIP14-associated parkinsonism.