Annual Meeting Program - Society of Toxicology

Society of Toxicology 2008
Continuing Education (Continued)
assessment using a variety of modeling techniques and addressing key
considerations of current interest.
• Introduction to Identifying Critical Effects for Quantitative
Risk Assessment, Andrew Maier, Toxicology Excellence for Risk
Assessment, Cincinnati, OH
• Dose-Response Modeling Techniques, Qiyu (Jay) Zhoa, U.S. EPA,
Risk Assessment, Cincinnati, OH
• Dose-Response Estimation and Critical Effect Selection:
Application for Occupational and Environmental Health Settings,
David G. Dolan, Amgen Inc., Thousand Oaks, CA
• Dose-Response Estimation and Critical Effect Selection—Special
Issues, Robert Sussman, SafeBridge Inc., New York, NY
Sunday, March 16
8:15 AM–12:00 NOON
Level 6 (See signage at CE Booth for room locations)
The Use of Transgenic Animal Technology in
Toxicological Research
AM05
BASIC
Chairperson(s): Daniel K. Ness, Elan Pharmaceuticals, Inc., South San
Francisco, CA and Roy Forster, CIT, Evreux, France
Endorsed by:
Comparative and Veterinary Specialty Section*
Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
The ability to direct genetic changes at the molecular level in vivo has
resulted in a revolution in biology. Nowhere has this been more apparent
than in the production of transgenic animals. A host of techniques has
been used to effect change in gene expression and develop new toxicological
testing paradigms. Genetically modified animals are commonly
produced and often yield important information relevant to safety/toxicological
assessment. This session will help guide the toxicologist in the
use and interpretation of data derived from transgenic models. The first
speaker will introduce this topic and set the stage for subsequent speakers.
The second speaker will review the history of genetic engineering technologies
leading to the development of loss-of-function, gain-of-function
modeling technologies across mammalian platforms. Transgenic animals
have provided us with powerful tools to explore cellular and physiological
processes in vivo. Current technologies allow us to modify cell-, tissue-or
organ-specific gene expression in controlled temporal and spatial fashion.
Accordingly, experimental considerations including strain-specific variability
impacting experimental outcomes will be explored. The third
speaker will cover current practice and previous experience gained in the
regulatory use of transgenic animals in testing new products. In the area
of safety evaluation, transgenic models have been used in the testing of
biotechnology products (homologous models), in carcinogenicity testing,
and in early toxicology screening. The presentation will cover the use of
transgenics from the point of view of theory, the concrete practical aspects
of putting such studies in place and new developments in this area. From
gene-targeting, gene-trapping, and conditional expression modeling, gene
knockout technology in mice is employed as an integrated platform to
study physiological and behavioral functions and pharmaceutical utility
of targeted genes. The fourth speaker will present recent data comparing
pharmacological inhibition of selected targets, with a focus on differentiating
between mechanism and nonmechanism-based toxicity and in
determining on-target versus off-target toxicity for drug candidates. The
final speaker will discuss how the lack of practical methods for the study
of mutagenesis using endogenous genes stimulated the development of
alternative mutation assays. These mutation analytical systems, developed
first in rodents, and subsequently in fish share a similar general approach.
Transgenic mutation models provide opportunities for comparative studies
of complex processes of mutagenesis simply not possible otherwise. The
introduction of a mutation model based on a transgenic fish, here the
transgenic medaka, builds upon the knowledge and experience gained
from the rodent models, and expands opportunities for increasing the
understanding of fundamental mechanisms of mutagenesis.
• Introduction, Daniel K. Ness, Elan Pharmaceuticals, Inc., South San
Francisco, CA
• Overview of Transgenic Animal Technology, Carl A. Pinkert, Auburn
University, Auburn, AL
• Current Use of Transgenics in Screening and Regulatory
Toxicology, Roy Forster, CIT, Evreux, France
• Using Mouse Knockouts to Predict Mechanism-Based Toxicity,
Brian P. Zambrowicz, Lexicon Pharmaceuticals, The Woodlands, TX
• From Transgenic Rodent to Fish Modeling: Enhancing Insights
into Shared Mechanisms of Mutagenesis, Richard N. Winn,
University of Georgia, Athens, GA
Sunday, March 16
8:15 AM–12:00 NOON
Level 6 (See signage at CE Booth for room locations)
Process-Based Approaches to Modulating Gene and
Protein Expression In Vivo and In Vitro
AM06
BASIC
Chairperson(s): Richard S. Pollenz, University of South Florida, Tampa,
FL and Robert Tanguay, Oregon State University, Corvallis, OR
Endorsed by:
Mechanisms Specialty Section
Molecular Biology Specialty Section*
The mechanistic analysis of cellular responses to xenobiotics
requires the ability to modulate important genes involved in specific
pathways. Such genes include those that encode receptors that
associate with xenobiotics as well as the enzymes involved in xenobiotic
metabolism. The ability to modulate these genes and proteins
in vitro and in vivo has become accessible to more laboratories with the
refinement of techniques such RNA interference (RNAi), viral gene
delivery, morpholino-mediated gene knock down and targeted gene
disruption. However, the ability to utilize these techniques and generate
reproducible results requires a detailed understanding of the advantages
and applications of each procedure. Thus, the goal of this course is to
provide the investigator with an overview of experimental design and the
use of proper controls for four cutting-edge techniques. The first talk will
focus on experimental design and analysis of RNAi to reduce endogenous
target proteins in culture cells with emphasis on controls and endpoint
analysis. The second presentation will move to the zebrafish model system
and discuss the use of morpholino-mediated gene knock down to reduce
the expression of specific proteins in embryos. The third presentation
will discuss gene delivery utilizing the adenovirus system for reduction
of gene expression in mice. The fourth presentation will detail the use
or transgenic approaches in mouse models to modulate the expression of
specific target genes or knock-in genes from other species. This course
should be of broad interest to laboratories considering a mechanistic
approach to understanding signal transduction pathways, gene expression
and protein-protein interactions as well as those currently investigating
these endpoints.
• Use of siRNA Technology to Modulate Gene Expression in Culture
Cells, Richard S. Pollenz, University of South Florida, Tampa, FL
• Use of Morpholinos to Modulate Gene Expression in Zebrafish,
Robert Tanguay, Oregon State University, Corvallis, OR
CE
up-to-date information at www.toxicology.org 73