Biomedical subjects

Bradley E Enerson

Publications and source records attributed to Bradley E Enerson.

4 recordsLinked to original sources

PubMed2006

Pathway analysis using random forests classification and regression.

MOTIVATION: Although numerous methods have been developed to better capture biological information from microarray data, commonly used single gene-based methods neglect interactions among genes and leave room for other novel approaches. For example, most classification and regression methods for microarray data are based on the whole set of genes and have not made use of pathway information. Pathway-based analysis in microarray studies may lead to more informative and relevant knowledge for biological researchers. RESULTS: In this paper, we describe a pathway-based classification and regression method using Random Forests to analyze gene expression data. The proposed methods allow researchers to rank important pathways from externally available databases, discover important genes, find pathway-based outlying cases and make full use of a continuous outcome variable in the regression setting. We also compared Random Forests with other machine learning methods using several datasets and found that Random Forests classification error rates were either the lowest or the second-lowest. By combining pathway information and novel statistical methods, this procedure represents a promising computational strategy in dissecting pathways and can provide biological insight into the study of microarray data. AVAILABILITY: Source code written in R is available from http://bioinformatics.med.yale.edu/pathway-analysis/rf.htm.

Algorithms↗

PubMed2006

Acute drug-induced vascular injury in beagle dogs: pathology and correlating genomic expression.

Acute vascular injury that leads to vascular inflammation is a common finding in the preclinical toxicity testing of drugs in rats and dogs. However, the relevance of this finding for risk to humans is unclear. Concern about the safety of these drugs is heightened by the current lack of noninvasive clinical methods to predict the onset of vascular damage in animals or humans. Determining the relevance of this poorly understood preclinical outcome for humans requires a better understanding of the molecular mechanisms of injury in addition to the development of sensitive and specific leading biomarkers for the clinical diagnosis of acute vascular damage. Most molecular research on this toxicity has been performed in rats, but recent development of canine gene expression microarrays makes transcriptomic studies now possible in the dog. In this study, we investigated the molecular mechanisms of drug-induced vascular injury in dogs using gene arrays. After treating Beagles with toxic doses of CI-947, an adenosine receptor agonist, we profiled gene expression in the coronary arteries and correlated those changes with histopathology at 16 and 24 hours after dosing. The results demonstrated that pathobiological processes such as stimulation of the innate immune response, increased extracellular matrix turnover and oxidative stress were active at times of very early injury.

Acute Disease↗

PubMed2005

The rat blood-brain barrier transcriptome.

The blood-brain barrier (BBB) is the cellular interface between the circulating blood and neural environment, and is created by apposed endothelial cells and their intercellular tight junctions. Many aspects of how the BBB functions at the molecular level remain unresolved; therefore, we report for the first time a comprehensive gene expression profile of rat brain microvessels using serial analysis of gene expression (SAGE). We assembled a full and quantitative SAGE catalog containing 101,364 tags, of which 33% of the tags matched known genes, 51% matched expressed sequence tags (ESTs) in the Unigene database, and 16% of the tags were unassigned. The transcriptome catalog contains many new and novel transcripts among known BBB genes. A large compliment of junctional proteins and an extensive assortment of facilitated carrier and ATP-dependent transporters are included. To identify microvessel-enriched transcripts, we compared the microvessel SAGE catalog to cortex and hippocampus SAGE catalogs. This resulted in identification of 864 genes, including several known for their abundant expression at the BBB, such as the transferrin receptor (TrnR). Sorting enriched genes based on function revealed groups that encode transporters (11%), receptors (5%), proteins involved in vesicle trafficking (4%), structural proteins (10%), and components of signal transduction pathways (17%). This genomic repertoire emphasizes the unique cellular phenotype existing within the brain and further implicates the BBB as a mediator between the brain and periphery. These results may provide a useful resource and reference point from which to determine the effects of different physiological, developmental, and disease processes on BBB gene expression.

Animals↗

PubMed2003

Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery.

The diffusion of monocarboxylates such as lactate and pyruvate across the plasma membrane of mammalian cells is facilitated by a family of integral membrane transport proteins, the monocarboxylate transporters (MCTs). Currently, at least eight unique members of the MCT family have been discovered and orthologs to each have been identified in a variety of species. Four MCTs (MCT1-MCT4) have been functionally characterized. Each isoform possesses unique biochemical properties such as kinetic constants and sensitivity to known MCT inhibitors. Several fold changes in the expression of MCTs may be evoked by altered physiological conditions, yet the molecular mechanisms underlying the regulation of MCTs are poorly understood. Post-translational regulation of MCT1 and MCT4 occurs, in part, by interaction with CD147, an accessory protein that is necessary for trafficking, localization, and functional expression of these transporters. Because of the physiological importance of monocarboxylates to the overall maintenance of metabolic homeostasis, the function of MCTs is significant to several pathologies that occur with disease, such as ischemic stroke and cancer. Finally, the expression of MCT1 in the epithelium of the small intestine and colon and in the blood-brain barrier may provide routes for the intestinal and blood to brain transfer of carboxylated pharmaceutical agents and other exogenous monocarboxylates.

Animals↗