Molecular Basis of Mammalian Manganese Homeostasis

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Metals are essential for human health yet potentially toxic in excess. Our understanding of the regulation of metal levels in the body stems prominently from studies of inherited diseases of metal deficiency and excess. Our understanding of manganese (Mn) homeostasis is limited by the fact that inherited forms of Mn excess and deficiency were only recently identified. In 2012, mutations in a membrane protein SLC30A10 were reported in patients with Mn excess, increased red blood cell counts, liver disease and Parkinson-like neurologic deficits. These characteristics, together with our preliminary data that murine Slc30a10 deficiency recapitulates the human disease, indicate that SLC30A10 is essential for Mn homeostasis. Our long-term objective is to establish a mechanistic model of Mn homeostasis with which we can explore the interplay of nutrition and genetics in Mn biology in states of health and disease. Our immediate goal is to determine the mechanisms by which SLC30A10 deficiency leads to disease. This will be accomplished in three aims. The first aim will determine if the diverse characteristics of Slc30a10 deficiency—broader than the Parkinson-like neurologic deficits observed in acquired Mn excess—are consequences of Mn excess or represent Mn-independent functions of Slc30a10. The second aim will establish the relative contribution of hepatic and neuronal Slc30a10 function to overall Mn homeostasis. This aim is relevant as both liver and brain function can be severely compromised by SLC30A10 deficiency. The third aim will interrogate the role of hypoxia signaling in disease pathophysiology. The hematologic defects of SLC30A10 deficiency and our preliminary data suggest that SLC30A10 deficiency leads to upregulation of hypoxia-responsive gene expression in the absence of hypoxia. This aim is relevant as hypoxia signaling has known or putative roles in hematologic, hepatic and neurologic disorders. Overall, this work will establish pathways of Mn homeostasis that may be exploited for treatment or prevention of disease and for identification of diagnostic markers for use before or after disease onset. These studies will also help us understand how genetic variability and nutritional status contribute to susceptibility to Mn-related disease. Funding of this grant will enable us to perform these studies and will represent a key step in Dr. Bartnikas' early research career.