The candidate's research interests center around metal toxicology and physiology-based pharmacokinetic-pharmacodynamic (PBPK) modeling. The goals are to further investigate the relationship between pharmacokinetics of metal absorption and metal-induced toxicity in the context of environmental exposure and genetic susceptibility (gene-environment interactions). The major underlying hypothesis of this research proposal is that absorption of ingested and inhaled metals is up-regulated upon HFE-deficiency such that patients with mutations in HFE (C282Y;H62D) are more vulnerable to neurotoxicity induced by environmental metal exposure. Mentored phase: During the mentored phase of this grant at the Harvard School of Public Health, the candidate will gain knowledge and expertise in new areas of research that complement their past training and that are essential for my future studies as an independent investigator. The research areas are: i) biochemical assays for expression of DMT1 and its regulation by iron status and ii) pharmacokinetics of metal absorption from various routes of exposure, and inhalation in particular.
The specific aims are: 1) To determine protein levels of DMT1 in duodenal, respiratory and olfactory epithelium from 3, 6, and 10 wk-old Hfe-/- and Hfe+/+ mice fed iron-deficient, basal and iron-loaded diets. 2) To determine and compare the pharmacokinetics and tissue distribution of 59Fe and 54Mn administered to Hfe-/- and Hfe+/+ """"""""wild-type"""""""" control mice by intravenous injection and by intragastric gavage. 3) To determine and compare the pharmacokinetics and tissue distribution of 54Mn administered to Hfe-/- and Hfe+/+ mice by intranasal and intra-tracheal instillation. Independent phase: The candidate's long-term career goal is to obtain a tenure-track faculty position at an academic institution where they will be able to expand their area of research, train and instruct graduate and undergraduate students, and collaborate with and learn from my academic peers. Utilizing the training and results obtained during the mentored phase, the hypothesis that HFE-deficiency enhances manganese neurotoxicity will be tested. 4) To test motor coordination and learning/memory capacity of Hfe-/- and Hfe+/+ mice after Mn exposure. 5) To examine CNS damage in Hfe-/- and Hfe+/+ mice due to Mn intoxication. 6) To develop a physiology-based pharmacokinetic/pharmacodynamic model to describe the role of Hfe on metal pharmacokinetics and toxicity. By directly examining the influence of HFE on the uptake and disposition of metals and their associated neurotoxicity, this investigation will provide the groundwork to assess the future risk of health effects due to metal absorption from environmental sources and genetic vulnerability. The research has broad relevance to the management of HFE-associated hemochromatosis and iron-overload. Public Health Relevance: This investigation will provide the groundwork to assess the future risk of health effects due to metal absorption from environmental sources and genetic vulnerability. The research has broad relevance to the management of HFE-associated hemochromatosis and iron-overload.

Public Health Relevance

This investigation will provide the groundwork to assess the future risk of health effects due to metal absorption from environmental sources and genetic vulnerability. The research has broad relevance to the management of HFE-associated hemochromatosis and iron-overload.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Career Transition Award (K99)
Project #
5K99ES017781-02
Application #
8019097
Study Section
Special Emphasis Panel (ZES1-LKB-J (K6))
Program Officer
Shreffler, Carol K
Project Start
2010-02-01
Project End
2012-08-31
Budget Start
2011-02-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$89,711
Indirect Cost
Name
Harvard University
Department
Genetics
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Ye, Qi; Kim, Jonghan (2016) Mutation in HFE gene decreases manganese accumulation and oxidative stress in the brain after olfactory manganese exposure. Metallomics 8:618-27
Han, Murui; Chang, JuOae; Kim, Jonghan (2016) Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity. J Neurochem 138:918-28
Menon, Archita Venugopal; Chang, JuOae; Kim, Jonghan (2016) Mechanisms of divalent metal toxicity in affective disorders. Toxicology 339:58-72
Ye, Qi; Kim, Jonghan (2015) Effect of olfactory manganese exposure on anxiety-related behavior in a mouse model of iron overload hemochromatosis. Environ Toxicol Pharmacol 40:333-41
Kim, Jonghan; Buckett, Peter D; Wessling-Resnick, Marianne (2013) Absorption of manganese and iron in a mouse model of hemochromatosis. PLoS One 8:e64944
Kim, Jonghan; Li, Yuan; Buckett, Peter D et al. (2012) Iron-responsive olfactory uptake of manganese improves motor function deficits associated with iron deficiency. PLoS One 7:e33533
Claus Henn, Birgit; Kim, Jonghan; Wessling-Resnick, Marianne et al. (2011) Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models. Environ Health 10:97