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Warren Ladiges

Publications and source records attributed to Warren Ladiges.

6 recordsLinked to original sources
PubMed2006

Comparative Mouse Genomics Centers Consortium: the Mouse Genotype Database.

The Comparative Mouse Genomics Centers Consortium (CMGCC) is a branch of the Environmental Genome Project sponsored by the National Institute of Environmental Health Sciences (NIEHS) focusing upon the identification of human single nucleotide polymorphisms (SNPs) that may confer disease susceptibility within the human population. The goal of the CMGCC (http://www.niehs.nih.gov/cmgcc/) is to make genetic mouse models for human SNPs within cell cycle control, DNA replication and DNA repair genes that may be associated with human pathologies. In order to facilitate information sharing and analysis within the consortium a set of informatics resources have been generated to support the mouse model development efforts. The primary entry point for information about the mouse models developed by the consortium is through the CMGCC Genotype Database (http://mrages.niehs.nih.gov/genotype/), which maintains both a consortium specific and public access display of the available and developing mouse models.

Animals↗
PubMed2005

Extension of murine life span by overexpression of catalase targeted to mitochondria.

To determine the role of reactive oxygen species in mammalian longevity, we generated transgenic mice that overexpress human catalase localized to the peroxisome, the nucleus, or mitochondria (MCAT). Median and maximum life spans were maximally increased (averages of 5 months and 5.5 months, respectively) in MCAT animals. Cardiac pathology and cataract development were delayed, oxidative damage was reduced, H2O2 production and H2O2-induced aconitase inactivation were attenuated, and the development of mitochondrial deletions was reduced. These results support the free radical theory of aging and reinforce the importance of mitochondria as a source of these radicals.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Polymorphisms in the DNA repair gene XRCC1 and age-related disease.

The recent hypothesis that common variants (single nucleotide polymorphisms or SNPs) in the population may contribute significantly to genetic risk for common diseases permits a conceptually straightforward approach to identifying age-related disease-causing mutations. Functional variants of DNA replication and repair genes might be expected to be highly significant to cancer and aging since replication must proceed with high fidelity in a cellular environment where an estimated 10000 nucleotides are damaged daily. Single-strand breaks (SSB) are one of the results of DNA damage either by methylation, oxidation, reduction or fragmentation of bases by ionizing radiation, and arise in cells directly by disintegration of damaged sugars or indirectly as intermediates of base excision repair. Studies have demonstrated a role for XRCC1 both in vitro and in vivo during the repair of SSB. A number of SNPs have been identified for the XRCC1 gene, and several have been associated with age-related diseases, especially cancer. This report provides resequencing data confirming the existence of commonly occurring SNPs, including Arg194Trp and Arg399Gln, and briefly summarizes epidemiological and functional relevance to cancer and other age-related diseases. XRCC1 SNPs will be useful probes for investigating age-associated pathobiology in epidemiological and mechanistic studies.

Aging↗
PubMed2002

Expression of human PKR protein kinase in transgenic mice.

There is a large amount of evidence describing the expression, interaction, and mode of activation of the human interferon (IFN)-mediated double-stranded RNA-activated protein kinase (PKR) gene. Studies from Pkr-null mice have defined the kinase as a transducer of dsRNA signals that converge on transcription, translation, and apoptotic programs involved in the innate resistance to viral infection. In vitro studies also suggest that PKR may possess important cell growth regulatory and tumor suppressor properties. However, the study of Pkr-null mice has not fully elucidated the role that the kinase plays in these processes, in part because of apparent redundancies in PKR-dependent and PKR-independent regulatory pathways. To overcome such limitations and to begin to examine the role of PKR in a complex biologic system, we have generated transgenic mice overexpressing wild-type human (Hu) PKR. HuPKR was expressed and active in various tissues and associated with a small body phenotype. Spleen cells from transgenic mice were resistant to apoptosis when treated with the genotoxic agent actinomycin D and showed a decrease in proliferation in response to concanavalin A (ConA) compared with spleen cells from wild-type control mice. The initial characterization of this transgenic mouse line suggests it may be useful as a model for investigating biology and diseases relative to a number of scientific disciplines.

Animals↗
PubMed2002

Hepatocyte-specific inhibition of NF-kappaB leads to apoptosis after TNF treatment, but not after partial hepatectomy.

One of the earliest TNF-dependent events to occur during liver regeneration is the activation of the transcription factor NF-kappaB through TNF receptor type 1. NF-kappaB activation in the liver can have both antiapoptotic and proliferative effects, but it is unclear which liver cell types, hepatocytes or nonparenchymal cells (NPCs), contribute to these effects. To specifically evaluate the role of hepatocyte NF-kappaB, we created GLVP/DeltaN-IkappaB(alpha) transgenic mice, in which expression of a deletion mutant of IkappaB(alpha) (DeltaN-IkappaB(alpha)) was induced in hepatocytes after injection of mifepristone. In control mice, injection of 25 microg/kg TNF caused NF-kappaB nuclear translocation in virtually all hepatocytes by 30 minutes and no detectable apoptosis, while in mice expressing DeltaN-IkappaB(alpha), NF-kappaB nuclear translocation was blocked in 45% of hepatocytes, leading to apoptosis 4 hours after TNF injection. In contrast, expression of DeltaN-IkappaBalpha in hepatocytes during the first several hours after partial hepatectomy did not lead to apoptosis or decreased proliferation. As NF-kappaB activation was not inhibited in liver NPCs, it is likely that these cells are responsible for mediating the proliferative and antiapoptotic effects of NF-kappaB during liver regeneration.

Active Transport, Cell Nucleus↗