Biomedical subjects

Amar V Singh

Publications and source records attributed to Amar V Singh.

4 recordsLinked to original sources

PubMed2007

Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome.

Fetal Alcohol Spectrum Disorders (FASD) are birth defects that result from maternal alcohol use. We used a non a priori approach to prioritize candidate pathways during alcohol-induced teratogenicity in early mouse embryos. Two C57BL/6 substrains (B6J, B6N) served as the basis for study. Dosing pregnant dams with alcohol (2x 2.9 g/kg ethanol spaced 4 hr on day 8) induced FASD in B6J at a higher incidence than B6N embryos. Counter-exposure to PK11195 (4 mg/kg) significantly protected B6J embryos but slightly promoted FASD in B6N embryos. Microarray transcript profiling was performed on the embryonic headfold 3 hr after the first maternal alcohol injection (GEO data series accession GSE1074). This analysis revealed metabolic and cellular reprogramming that was substrain-specific and/or PK11195-dependent. Mapping ethanol-responsive KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways revealed down-regulation of ribosomal proteins and proteasome, and up-regulation of glycolysis and pentose phosphate pathway in B6N embryos; and significant up-regulation of tight junction, focal adhesion, adherens junction, and regulation of the actin cytoskeleton (and near-significant up-regulation of Wnt signaling and apoptosis) pathways in both substrains. Expression networks constructed computationally from these altered genes identified entry points for EtOH at several hubs (MAPK1, ALDH3A2, CD14, PFKM, TNFRSF1A, RPS6, IGF1, EGFR, PTEN) and for PK11195 at AKT1. Our findings are consistent with the growing view that developmental exposure to alcohol alters common signaling pathways linking receptor activation to cytoskeletal reorganization. The programmatic shift in cell motility and metabolic capacity further implies cell signals and responses that are integrated by the mitochondrial recognition site for PK11195.

Analysis of Variance↗

PubMed2005

Searching for biomarkers of developmental toxicity with microarrays: normal eye morphogenesis in rodent embryos.

Gene expression arrays reveal the potential linkage of altered gene expression with specific adverse effects leading to disease phenotypes. But how closely do microarray data reflect early physiological or pharmacological measures that predict toxic event(s)? To explore this issue, we have undertaken experiments in early mouse embryos exposed to various teratogens during neurulation stages with the aim of correlating large-scale changes in gene expression across the critical period during exposure. This study reports some of the large-scale changes in gene expression that can be detected in the optic rudiment of the developing mouse and rat embryo across the window of development during which the eye is exceedingly sensitive to teratogen-induced micro-/anophthalmia. Microarray analysis was performed on RNA from the headfold or ocular region at the optic vesicle and optic cup stages when the ocular primordium is enriched for Pax-6, a master control gene for eye morphogenesis. Statistical selection of differentially regulated genes and various clustering techniques identified groups of genes in upward or downward trajectories in the normal optic primordium during early eye development in mouse and rat species. We identified 165 genes with significant differential expression during eye development, and a smaller subset of 58 genes that showed a tight correlation between mouse-rat development. Significantly over-represented functional categories included fatty acid metabolism (up-regulated) and glycolysis (down-regulated). From studies such as these that benchmark large-scale gene expression during normal embryonic development, we may be able to identify the panel of biomarkers that best correlate with species differences and the risks for developmental toxicity.

Animals↗

PubMedDate not supplied

Computational systems analysis of developmental toxicity: design, development and implementation of a Birth Defects Systems Manager (BDSM).

Birth defects and developmental disabilities remain an important public health issue worldwide. With the availability of genomic sequences from a growing number of human and model organisms and the rapid expansion of the public repositories holding large-scale gene expression datasets, a computational systems analysis of developmental toxicology can incorporate this vast digital information toward the realization of predictive models for complex disease. Here we describe the initial design, development and implementation of a Birth Defects Systems Manager (BDSM). The project was motivated by the need for a computational-bioinformatics infrastructure to manage vast digital information from functional genomics and for a new knowledge environment specifically engineered for the analysis of developmental processes and toxicities. Proof-of-concept tested BDSM using meta-analysis of gene expression data collected from different laboratories, technology platforms, and study models. The composite dataset incorporated 232 microarray comparisons of RNA samples by single or dual microarray platforms, cDNA or oligonucleotide based probes, and human or mouse sequence information. Preliminary results identified system-level features in the embryonic transcriptome as it reacted to various developmental-teratological stimuli. BDSM is open access through the worldwide web (http://systemsanalysis.louisville.edu/) and can be integrated with other bioinformatics tools and resources to advance the pace of discovery in birth defects research.

Animals↗

PubMedDate not supplied

Data input module for Birth Defects Systems Manager.

The need for a computational bioinformatics infrastructure to manage the vast digital information from functional genomics and proteomics motivated us to develop Birth Defects Systems Manager (BDSM) as an open resource to facilitate analysis and discovery in developmental biology and developmental toxicity. This report describes the design, development and implementation of the data loading module of BDSM, referred to as LoadBDSM. It includes a shared data directory resource that can be granted various levels of security for different research groups or investigators to manage experimental datasets individually or in groups. LoadBDSM allows the upload of data and experiment details using controlled semantics for developmental exposure (toxicant, dosing scenario, intervention), biological sample (species, tissue, stage) and disease outcome (time, risk, phenotype). It adheres to existing controlled vocabulary plus rules of inference (ontologies) for experiment, data and metadata annotations. LoadBDSM extends the capabilities of BDSM to support the emergence of "embryo-formatics" defined here as the data, information and knowledge from genomic sciences applied to, or derived from, an embryological context. This includes, but is not limited to, delineating pathways and biological regulatory networks for specific chemicals or classes of developmental toxicants, developing novel biomarkers indicative of exposure and/or predictive of adverse effects, and integrating modern computing and information technology with data from molecular biology.

Abnormalities, Drug-Induced↗