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A B Niculescu

Publications and source records attributed to A B Niculescu.

11 recordsLinked to original sources
PubMed2006

Candidate genes, pathways and mechanisms for alcoholism: an expanded convergent functional genomics approach.

We describe a comprehensive translational approach for identifying candidate genes for alcoholism. The approach relies on the cross-matching of animal model brain gene expression data with human genetic linkage data, as well as human tissue data and biological roles data, an approach termed convergent functional genomics. An analysis of three animal model paradigms, based on inbred alcohol-preferring (iP) and alcohol-non-preferring (iNP) rats, and their response to treatments with alcohol, was used. A comprehensive analysis of microarray gene expression data from five key brain regions (frontal cortex, amygdala, caudate-putamen, nucleus accumbens and hippocampus) was carried out. The Bayesian-like integration of multiple independent lines of evidence, each by itself lacking sufficient discriminatory power, led to the identification of high probability candidate genes, pathways and mechanisms for alcoholism. These data reveal that alcohol has pleiotropic effects on multiple systems, which may explain the diverse neuropsychiatric and medical pathology in alcoholism. Some of the pathways identified suggest avenues for pharmacotherapy of alcoholism with existing agents, such as angiotensin-converting enzyme (ACE) inhibitors. Experiments we carried out in alcohol-preferring rats with an ACE inhibitor show a marked modulation of alcohol intake. Other pathways are new potential targets for drug development. The emergent overall picture is that physical and physiological robustness may permit alcohol-preferring individuals to withstand the aversive effects of alcohol. In conjunction with a higher reactivity to its rewarding effects, they may able to ingest enough of this nonspecific drug for a strong hedonic and addictive effect to occur.

Alcohol Drinking↗
PubMed2005

Convergent functional genomics: a Bayesian candidate gene identification approach for complex disorders.

Identifying genes involved in complex neuropsychiatric disorders through classic human genetic approaches has proven difficult. To overcome that barrier, we have developed a translational approach called Convergent Functional Genomics (CFG), which cross-matches animal model microarray gene expression data with human genetic linkage data as well as human postmortem brain data and biological role data, as a Bayesian way of cross-validating findings and reducing uncertainty. Our approach produces a short list of high probability candidate genes out of the hundreds of genes changed in microarray datasets and the hundreds of genes present in a linkage peak chromosomal area. These genes can then be prioritized, pursued, and validated in an individual fashion using: (1) human candidate gene association studies and (2) cell culture and mouse transgenic models. Further bioinformatics analysis of groups of genes identified through CFG leads to insights into pathways and mechanisms that may be involved in the pathophysiology of the illness studied. This simple but powerful approach is likely generalizable to other complex, non-neuropsychiatric disorders, for which good animal models, as well as good human genetic linkage datasets and human target tissue gene expression datasets exist.

Animals↗
PubMed2004

Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach.

Identifying genes for bipolar mood disorders through classic genetics has proven difficult. Here, we present a comprehensive convergent approach that translationally integrates brain gene expression data from a relevant pharmacogenomic mouse model (involving treatments with a stimulant--methamphetamine, and a mood stabilizer--valproate), with human data (linkage loci from human genetic studies, changes in postmortem brains from patients), as a bayesian strategy of crossvalidating findings. Topping the list of candidate genes, we have DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) located at 17q12, PENK (preproenkephalin) located at 8q12.1, and TAC1 (tachykinin 1, substance P) located at 7q21.3. These data suggest that more primitive molecular mechanisms involved in pleasure and pain may have been recruited by evolution to play a role in higher mental functions such as mood. The analysis also revealed other high-probability candidates genes (neurogenesis, neurotrophic, neurotransmitter, signal transduction, circadian, synaptic, and myelin related), pathways and mechanisms of likely importance in pathophysiology.

Animals↗
PubMed2001

Proposed endophenotypes of dysthymia: evolutionary, clinical and pharmacogenomic considerations.

Dysthymia is highly prevalent--though underdiagnosed--occurring in at least 3% of the population. We conceptualize it as the clinical extension of adaptive traits that have developed during evolution to cope with stress and failure. A classification of dysthymias into anxious and anergic subtypes--and their putative association to bipolarity--is proposed. We further posit neurochemical and neurophysiological substrates for the two subtypes. A better recognition and understanding of dysthymic subtypes and their respective place in the affective spectrum will increase the proportion of people that may benefit from targeted treatments. It would also expand the pool of subjects that may be enrolled in genetic and pharmacogenomic research studies.

Adaptation, Psychological↗
PubMed2001

Convergent functional genomics: application to bipolar disorder.

The recent development of microarray technologies has made possible the simultaneous measurement of mRNA levels for thousands of genes and a new genomic method termed gene expression profiling. The application of this approach to animal models or post-mortem tissue provides a powerful tool for the discovery of novel genes involved in psychiatric disorders. This approach has strengths that are complementary to those of another genomic method for gene discovery, positional cloning. Microarray technologies and their application to post-mortem tissue and animal models of bipolar disorder are reviewed. A novel approach termed convergent functional genomics, which integrates gene profiling and positional cloning in order to rapidly identify candidate disease genes, is also described.

Amphetamine↗
PubMed2000

Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach.

We have used methamphetamine treatment of rats as an animal model for psychotic mania. Specific brain regions were analyzed comprehensively for changes in gene expression using oligonucleotide GeneChip microarrays. The data was cross-matched against human genomic loci associated with either bipolar disorder or schizophrenia. Using this convergent approach, we have identified several novel candidate genes (e.g., signal transduction molecules, transcription factors, metabolic enzymes) that may be involved in the pathogenesis of mood disorders and psychosis. Furthermore, for one of these genes, G protein-coupled receptor kinase 3 (GRK3), we found by Western blot analysis evidence for decreased protein levels in a subset of patient lymphoblastoid cell lines that correlated with disease severity. Finally, the classification of these candidate genes into two prototypical categories, psychogenes and psychosis-suppressor genes, is described.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication.

It has been proposed that the functions of the cyclin-dependent kinase inhibitors p21(Cip1/Waf1) and p27Kip1 are limited to cell cycle control at the G1/S-phase transition and in the maintenance of cellular quiescence. To test the validity of this hypothesis, p21 was expressed in a diverse panel of cell lines, thus isolating the effects of p21 activity from the pleiotropic effects of upstream signaling pathways that normally induce p21 expression. The data show that at physiological levels of accumulation, p21, in addition to its role in negatively regulating the G1/S transition, contributes to regulation of the G2/M transition. Both G1- and G2-arrested cells were observed in all cell types, with different preponderances. Preponderant G1 arrest in response to p21 expression correlated with the presence of functional pRb. G2 arrest was more prominent in pRb-negative cells. The arrest distribution did not correlate with the p53 status, and proliferating-cell nuclear antigen (PCNA) binding activity of p21 did not appear to be involved, since p27, which lacks a PCNA binding domain, produced similar arrest distributions [corrected], DNA endoreduplication occurred in pRb-negative but not in pRb-positive cells, suggesting that functional pRb is necessary to prevent DNA replication in p21 G2-arrested cells. These results suggest that the primary target of the Cip/Kip family of inhibitors leading to efficient G1 arrest as well as to blockade of DNA replication from either G1 or G2 phase is the pRb regulatory system. Finally, the tendency of Rb-negative cells to undergo endoreduplication cycles when p21 is expressed may have negative implications in the therapy of Rb-negative cancers with genotoxic agents that activate the p53/p21 pathway.

Cyclin-Dependent Kinase Inhibitor p21↗