Role of DMT in Manganese Transport and Neurotoxicity

Harvard University (Sch Of Public Hlth), Boston MA

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Abstract

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the role of DMT1 (Divalent Metal Transporter 1) in Mn neurotoxicity in correlation with iron-deficiency. The Belgrade rat has been chosen for these studies since its DMT1 gene contains a gly-to-arg substitution (G185R). This defective allele encodes a protein with little or no activity in iron uptake assays and transfection studies suggest that the mutant protein is rapidly degraded. Functionally, DMT1 mediates the uptake of many different divalent metal cations. These animals display profoundly impaired iron metabolism, they also have significant defects in manganese metabolism. The animals will be grouped into three categories based on diet and genotype. The control animals will be heterozygote (b/+) fed a standard diet, b/+ mice fed an iron deficient diet and homozygotes (b/b). Aim 1 is to characterize the expression of metal transporters in the lungs of the animals in comparison to the gastrointestinal tract. Aim 2 is to instill 54MnC1 into the lungs of the animals such that the distribution and the time course for delivery and distribution of Mn to body (particularly, the brain) is measured to assess the role of DMT1.