Progress 10/01/13 to 09/30/14
Outputs
Target Audience: Our target audiences are health professionals involved in the prevention and treatment of iron deficiency and iron overload as well as researchers in the field of iron metabolism. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? This project has provided training opportunities for a post-doctoral fellow who has been primarily responsible for supervising the project. She has presented her work at multiple national conferences which has provided her with training in scientific presentation. She has also had to coordinate a large project and interface with multiple collaborators which has provided important training in project coordination. In addition, multiple undergraduate students have worked closely with the post-doctoral fellow on all aspects of the project. They received hands on training in experimental design, research methods, data interpretation, and presentation to a scientific audience. How have the results been disseminated to communities of interest? We have continued to communicate our results to the scientific community through presentations at scientific meetings. Special efforts has also been taken to present our data to government policy makers by presenting at the Society of Toxicology (SOT) annual meeting, , and Northern California SOT Regional Chapter meetings. What do you plan to do during the next reporting period to accomplish the goals? We are now expanding our efforts to an expanded set of 110 inbred and recombinant inbred strains. We will measure iron status in multiple tissues in female mice on two defined iron diets.
Impacts
What was accomplished under these goals?
Disturbances of iron homeostasis can have significant clinical consequences. Iron deficiency is the world's most prominent nutritional deficiency, and anemia of chronic disease (ACD) is common in hospitalized patients. Iron overload disorders, such as hemochromatosis, are also a significant health concern. The overall aim of this study is to help us understand the genetic basis of variation in iron metabolism between people. In order to achieve our goals we have used mice as a model system for the genetic differences seen in people. We have also used three different dietary conditions to reflect iron deficiency, iron overload, and steady state iron. Objective 1 is to measure iron status in populations of inbred mice to determine phenotypic variation in iron homeostasis in mice during steady state, iron deficiency, and iron overload conditions. We continue to make progress during year three of this project. We have completed a study of iron status in six inbred mouse strains raised on three different diets; low (12ppm), high (10000ppm), and sufficient (35ppm) iron diets for six weeks. Elemental analysis (via ICP-AES) of tissues collected from these mice show significant differences in iron levels in multiple tissues. The liver is one of the key organs involved in iron metabolism, responsible for actively maintaining a consistent balance of iron levels. Significant inter-strain variation in liver iron levels (P<0.05) is seen across all strains when comparing the change in iron levels in each strain from sufficient to high iron diets. Upon analysis of other tissues known to be involved in iron metabolism, heart and spleen appear to have the most inter-strain variation. AKR/J heart iron levels are consistently higher than other strains, and A/J consistently low heart iron levels for all three diets. Splenic iron levels for C3H/HeJ are significantly higher, than all other strains for high iron, with an appearance of higher iron levels for the other two diets, and a trend for lower levels in AKR/J and C57BL/6J in the sufficient and high iron diets. The iron pancreas levels appear to mimic the pattern of iron levels in the heart for high iron diet, with significantly higher levels for AKR/J and C57BL/6J. Most variation however, is seen in the liver with the high iron diet. Together this work has validated our hypothesis of genetic variation underlying changes in iron homeostasis.
Publications
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Progress 01/01/13 to 09/30/13
Outputs
Target Audience: Our primary target audience is researchers and clinicians working on iron related disorder with a particular focus on iron deficiency and iron overload. The work has been presented at international conferences including the International Bioiron Conference and Society of Toxicology. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? Multiple undergraduates worked on the research project including Chenchen Han, Julie Luong, Ruth Hsu, Yuanchi He and Hiroko Irimagawa. Training was given in scientific techniques, including ICP sample prep, mouse care handling, basic laboratory practices, mouse genotyping (PCR), mouse dissections (multiple tissues, cardiac perfusion and cardiac stick). Student were all given the opportunity to present data findings, and journal articles of interest at weekly lab meetings, and one student (Hiroko) also had the opportunity to attend the national society of toxicology annual meeting. One post-doctoral fellow has worked on the project. She was given training in data analysis, along with the preparation of reports and proposals. Presentation of data was frequent at lab meetings, along with attendance to the following conferences for poster and/or platform presentation of data: · Kathryn E Page, David W Killilea, Simon Hui, Brian Parks, Eleazar Eskin, Aldons J Lusis, and Chris D Vulpe (2013) Genetic Variation of Iron Metabolism in Obese Mice. Gordon Research Conference – Cellular & Molecular Mechanisms of Toxicity poster session · Kathryn E Page (2013) Toxic Milk causes “Mask” phenotype hephaestin knockout mice. Gordon Research Seminar – Cellular & Molecular Mechanisms of Toxicity platform presentation · Kathryn E Page, David W Killilea, Simon Hui, Brian Parks, Eleazar Eskin, Aldons J Lusis, and Chris D Vulpe (2013) Genetic Variation of Iron Metabolism in Obese Mice. Gordon Research Conference – Cell Biology of Metals poster session · Kathryn E Page, David W Killilea, Simon Hui, Brian Parks, Eleazar Eskin, Aldons J Lusis, and Chris D Vulpe (2013) Genetic Variation of Iron Metabolism in Mice. The Northern California Society of Toxicology Spring Symposium platform presentation · Kathryn E Page, David W Killilea, Simon Hui, Brian Parks, Eleazar Eskin, Aldons J Lusis, and Chris D Vulpe (2013) Genetic Variation of Iron Metabolism in Mice. The Society of Toxicology annual meeting poster session Kathryn E Page, David W Killilea, Simon Hui, Brian Parks, Eleazar Eskin, Aldons J Lusis, and Chris D Vulpe (2013) Genetic Variation of Iron Metabolism in Obese Mice. International Bio-Iron Society annual meeting poster session How have the results been disseminated to communities of interest? Data has been communicated with the scientific community at numerous conferences, including Cell Biology of Metals Gordon Conference, and International Bio-Iron Society. Special effort has also been taken to present our data to government policy makers by presenting at the Society of Toxicology (SOT) annual meeting, Cellular & Molecular Mechanisms of Toxicity Gordon Conference and Seminar, and Northern California SOT Regional Chapter meetings. What do you plan to do during the next reporting period to accomplish the goals? We plan to proceed with the study of iron phenotypes in the inbred mouse strains originally proposed. We aim to analyze more samples from males as well as increase the study to compare the differences between the sexes. We also aim to perform gene expression analysis on the previously collected samples.
Impacts
What was accomplished under these goals?
Disturbances of iron homeostasis can have significant clinical consequences. Iron deficiency is the world's most prominent nutritional deficiency, and anemia of chronic disease (ACD) is common in hospitalized patients. Iron overload disorders, such as hemochromatosis, are also a significant health concern. The overall aim of this study is to help us understand the genetic basis of variation in iron metabolism between people. In order to achieve our goals we have used mice as a model system for the genetic differences seen in people. We have also used three different dietary conditions to reflect iron deficiency, iron overload, and steady state iron. We have gathered data supporting our contention that genetic variation contributes to iron metabolism in mammalian system through the use of the mouse as a model system. This data will inform our understanding of iron metabolism in people and livestock. Objective 1 was to measure iron status in populations of inbred mice to determine phenotypic variation in iron homeostasis in mice during steady state, iron deficiency, and iron overload conditions. Significant progress has been made into achieving this goal during year two. We have collected multiple tissue samples from six inbred mouse strains, exposed to three different dietary conditions; a low iron diet representing “iron deficiency, a high iron diet representing “iron overload”, and a control defined iron diet representing “steady state” iron. Elemental analysis (via ICP-AES) of livers collected from these mice show significant differences in liver iron levels for mice fed the high iron diet. The mice fed the high iron diet also showed a decrease in body fat levels when compared to the two other diets. Hepcidin levels were also measured for these mice, but showed no significant change between strains for each diet, although differences were seen between the three diets. Objective 2 and 3 are dependent on completion of Objective 1.
Publications
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Progress 01/01/12 to 12/31/12
Outputs
OUTPUTS: The overall aim of this study is to help us understand the genetic basis of variation in iron metabolism between people. Our approach is to use mice as model system to identify genetic variants that underlie differences in iron metabolism. Our first goal is to measure iron status in a set of genetically defined mice, inbred and recombinant inbred, called the Hybrid Diversity Mapping Panel. We have made significant progress towards this goal in year one. We have collected samples from multiple inbred mouse strains from mice on two different diets, 1) high fat diets and 2) defined iron diets. Preliminary data suggests that although there is an indication of inter-strain variation among the HMDP mice given a high fat diet, the fatty condition of their livers produces much variation; when compared to past data collected on a defined diet in which the intra-strain variation was much less. As a result, we are modifying our procedures to allow for normalization as result in different lipid levels in the liver. The analysis of these samples have increased the efficiency of the collection, preparation and analysis of the mouse tissues, as well as help identify key tissues on which to concentrate our future work. PARTICIPANTS: Chris Vulpe (PI) supervised the project and contributed to planning and implementation of the work. He also contributed to data analysis, trouble shooting, and subsequent problem solving. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Recent studies have shown a link between iron deficiency and obesity. Among the Hybrid Diversity Mapping Panel mice there is a subset that are widely used to study genetic diversity of obesity and related phenotypes (e.g. body weight). This subset involves the two inbred strains LG/J (large) and SM/J (small), as well as crosses of the two strains. We have taken liver, spleen and kidney samples from LG/J, SM/J and crosses of these strains (AIL) in order to determine iron content. Preliminary results show liver iron levels are higher in the SM/J mice than the LG/J mice supporting a correlation between iron status and weight. Interestingly preliminary data from analysis of the LG/J, SM/J and AIL mice also show significant correlation to weight for calcium (Ca), manganese (Mn), and zinc (Zn), as well as iron. These results suggest a potential relationship between metal micronutrients and body weight.
Publications
- No publications reported this period
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