Robert Kesterson, Ph.D. – Director
Contact: (205) 934-7206
Genetic animal models play a critical role in our evolving understanding of human diseases and treatment thereof, as well as addressing fundamental questions relating to basic in vivo biological processes. However, due to the pleotropic nature of many cancers that can develop in over 100 distinct mammalian cell types, we are still lacking adequate animal models for studies of pathogenesis or treatment for most. Pharmacologic, dietary and gene therapy regimens all require disease models for full development. To date, genetically modified mice have been the species of choice as a mammalian research model due to significant advantages over other species including: well-defined genetic characteristics and mapping data, short generation time, large litter size, definable and measurable environmental influences, maintenance of pathogen free status, and relatively inexpensive husbandry.
Historically, a primary advantage afforded mice was the ability to create specific mutations in the mouse germline via embryonic stem (ES) cell technology; however, recent advances in nuclease-based gene targeting have allowed the rapid emergence of other species as alternative genetic model systems.
Animal models of cancer have contributed greatly to our understanding of the pathological processes involved to address fundamental questions such as: why do cancers arise, what are early markers of cancer formation, what influences the metastasis of primary tumors, how effective are various methods of preventive interventions and treatments, what are effective treatments for the inhibition of growth or spread of tumors? However, there are many obstacles that prevent laboratories from fully utilizing in vivo models due to limitations associated with the time, effort, cost, and expertise needed to generate, maintain, and analyze specialized genetic animal models. As these limitations slow the pace of research into the causes and potential treatments of cancer, the Transgenic Animal Shared Facility will assist clinical and basic scientists in overcoming these obstacles and facilitate better utilization of a wide range of highly informative genetic models through the following three aims:
Aim 1. Provide efficient, cost-effective production of transgenic and genetically-engineered animal models for Comprehensive Cancer Center investigators. To enhance cancer research the core will continue its productive history of developing novel mouse models by microinjection of gene constructs into fertilized mouse eggs or ES cells into blastocysts, and additionally now offers services to create both rat and zebrafish genetic models.
Aim 2. Provide additional essential services in animal model development and support. Development and management of animal models will include: TALEN and CRISPR synthesis and gene targeting, cryopreservation of embryos and sperm, embryo re-derivation to produce pathogen-free animals, assisted reproduction techniques (e.g., in vitro fertilization [IVF], superovulation, and embryo transfer).
Aim 3. Provide expert consultation services to help investigators design the most effective transgene and gene targeting constructs, strategies for molecular identification, and breeding strategies required for generating genetically modified experimental animals and appropriate control animals.
Overall, these approaches will accelerate genetic, biochemical, and cellular analyses of pathogenic mechanisms of cancer, as well as provide in vivo models for the assessment of human disease alleles and genetic avatars for personalized cancer therapy and future testing of therapeutic strategies by the user base. Importantly, the services provided are not available through any other mechanism except external commercial or academic alternatives that do not supply the complete set of services provided by this facility, or are prohibitively costly in terms of both expense and/or time impediments.
Services offered by the Shared Facility:
- Animal model development (mice, rats, zebrafish)
- Microinjection of nucleic acids (pronuclear)
- CRISPR synthesis and gene targeting
- ES cell gene targeting (with & without screening)
- ES cell microinjection (blastocysts)
- In vitro fertilization (IVF)
- Embryo and sperm cryopreservation
- Assisted reproduction / re-derivations
- Consulting and training
Director: Bob Kesterson, Ph.D.
Phone: (205) 934-7206
Manager: Larry W. Johnson
Phone: (205) 934-2999