Browsing by Author "Stallings, Jonathan D"
Now showing 1 - 4 of 4
Results Per Page
Sort Options
- ItemA 3-D mathematical model to identify organ-specific risks in rats during thermal stress.(2013-12-17) Rakesh, Vineet; Stallings, Jonathan D; Helwig, Bryan G; Leon, Lisa R; Jackson, David A; Reifman, JaquesEarly prediction of the adverse outcomes associated with heat stress is critical for effective management and mitigation of injury which may sometimes lead to extreme undesirable clinical conditions such as multiorgan dysfunction syndrome and death Here we developed a computational model to predict the spatiotemporal temperature distribution in a rat exposed to heat stress in an attempt to understand the correlation between heat load and differential organ dysfunction The model includes a three dimensional representation of the rat anatomy obtained from medical imaging and incorporates the key mechanisms of heat transfer during thermoregulation We formulated a novel approach to estimate blood temperature by accounting for blood mixing from the different organs and to estimate the effects of the circadian rhythm in body temperature by considering day night variations in metabolic heat generation and blood perfusion We validated the model using in vivo core temperature measurements in control and heat stressed rats and other published experimental data The model predictions were within 1 SD of the measured data The liver demonstrated the greatest susceptibility to heat stress with the maximum temperature reaching 2 C higher than the measured core temperature and 95 of its volume exceeding the targeted experimental core temperature Other organs also attained temperatures greater than the core temperature illustrating the need to monitor multiple organs during heat stress The model facilitates the identification of organ specific risks during heat stress and has the potential to aid in the development of improved clinical strategies for thermal injury prevention and management
- ItemCharacterization of chemically induced liver injuries using gene co-expression modules.(2014-09-17) Tawa, Gregory J; AbdulHameed, Mohamed Diwan M; Yu, Xueping; Kumar, Kamal; Ippolito, Danielle L; Lewis, John A; Stallings, Jonathan D; Wallqvist, AndersLiver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non invasive diagnostic tests Mapping chemical injuries to organ specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests Here we have used DrugMatrix a toxicogenomics database containing organ specific gene expression data matched to dose dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats to identify groups of co expressed genes modules specific to injury endpoints in the liver We identified 78 such gene co expression modules associated with 25 diverse injury endpoints categorized from clinical pathology organ weight changes and histopathology Using gene expression data associated with an injury condition we showed that these modules exhibited different patterns of activation characteristic of each injury We further showed that specific module genes mapped to 1 known biochemical pathways associated with liver injuries and 2 clinically used diagnostic tests for liver fibrosis As such the gene modules have characteristics of both generalized and specific toxic response pathways Using these results we proposed three gene signature sets characteristic of liver fibrosis steatosis and general liver injury based on genes from the co expression modules Out of all 92 identified genes 18 20 genes have well documented relationships with liver disease whereas the rest are novel and have not previously been associated with liver disease In conclusion identifying gene co expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects
- ItemSystems level analysis and identification of pathways and networks associated with liver fibrosis.(2014-11-08) AbdulHameed, Mohamed Diwan M; Tawa, Gregory J; Kumar, Kamal; Ippolito, Danielle L; Lewis, John A; Stallings, Jonathan D; Wallqvist, AndersToxic liver injury causes necrosis and fibrosis which may lead to cirrhosis and liver failure Despite recent progress in understanding the mechanism of liver fibrosis our knowledge of the molecular level details of this disease is still incomplete The elucidation of networks and pathways associated with liver fibrosis can provide insight into the underlying molecular mechanisms of the disease as well as identify potential diagnostic or prognostic biomarkers Towards this end we analyzed rat gene expression data from a range of chemical exposures that produced observable periportal liver fibrosis as documented in DrugMatrix a publicly available toxicogenomics database We identified genes relevant to liver fibrosis using standard differential expression and co expression analyses and then used these genes in pathway enrichment and protein protein interaction PPI network analyses We identified a PPI network module associated with liver fibrosis that includes known liver fibrosis relevant genes such as tissue inhibitor of metalloproteinase 1 galectin 3 connective tissue growth factor and lipocalin 2 We also identified several new genes such as perilipin 3 legumain and myocilin which were associated with liver fibrosis We further analyzed the expression pattern of the genes in the PPI network module across a wide range of 640 chemical exposure conditions in DrugMatrix and identified early indications of liver fibrosis for carbon tetrachloride and lipopolysaccharide exposures Although it is well known that carbon tetrachloride and lipopolysaccharide can cause liver fibrosis our network analysis was able to link these compounds to potential fibrotic damage before histopathological changes associated with liver fibrosis appeared These results demonstrated that our approach is capable of identifying early stage indicators of liver fibrosis and underscore its potential to aid in predictive toxicity biomarker identification and to generally identify disease relevant pathways
- ItemA virtual rat for simulating environmental and exertional heat stress.(2014-12-02) Rakesh, Vineet; Stallings, Jonathan D; Reifman, JaquesSevere cases of environmental or exertional heat stress can lead to varying degrees of organ dysfunction To understand heat injury progression and develop efficient management and mitigation strategies it is critical to determine the thermal response in susceptible organs under different heat stress conditions To this end we used our previously published virtual rat which is capable of computing the spatiotemporal temperature distribution in the animal and extended it to simulate various heat stress scenarios including 1 different environmental conditions 2 exertional heat stress 3 circadian rhythm effect on the thermal response and 4 whole body cooling Our predictions were consistent with published in vivo temperature measurements for all cases validating our simulations We observed a differential thermal response in the organs with the liver experiencing the highest temperatures for all environmental and exertional heat stress cases For every 3 C rise in the external temperature from 40 to 46 C core and organ temperatures increased by 0 8 C Core temperatures increased by 2 6 and 4 1 C for increases in exercise intensity from rest to 75 and 100 of maximal O2 consumption respectively We also found differences as large as 0 8 C in organ temperatures for the same heat stress induced at different times during the day Even after whole body cooling at a relatively low external temperature 1 C for 20 min average organ temperatures were still elevated by 2 3 to 2 5 C compared with normothermia These results can be used to optimize experimental protocol designs reduce the amount of animal experimentation and design and test improved heat stress prevention and management strategies