The UAB C-PAM Disease Modeling Unit (DMU) includes expertise across a number of models (mouse, rat, zebrafish, C. elegans, cell lines, and Xenopus) allowing us to select the best model for the disorder. When producing a model, the ideal species can depend on a number of variables including the organ system being studied, ease of studying (e.g. brain size and infrastructure required for housing), cost of housing/propagation, or the amount of a drug needed for testing. The DMU takes all of these under consideration when determining a model.

As part of C-PAM the DMU is responsible for:

  • Production of in vivo models of gene variants identified in human patients.  ​
  • Establishment of baseline phenotypes of new patient variant-derived models.​
  • Development and implementation of new technologies to enhance capacity in production, phenotyping, and development of novel drug therapeutic approaches.

Models

Mouse and Rat

As mammals, mice and rats share many anatomical, genetic, and physiological features in common with humans. Their genomes are very similar to ours. On average, the protein-coding regions of mouse genes are 85% identical to human genes. Gene editing technologies have made it easy to manipulate the mouse genome to model a specific disorder and/or patient variant.

Mouse and rat genomes can be altered to reflect the underlying genetic causes found in patients with rare genetic disorders. The process depicted above shows the steps involved in generating transgenic rodent models. Figure made with BioRender.

Zebrafish

Zebrafish and humans share about 70% of the same genes. Zebrafish lay hundreds of eggs and fertilize externally, and their embryos are nearly transparent. Since they are small, zebrafish are also perfect for medium-throughput drug screens. Zebrafish and humans also share many of the same major organs and tissues, including muscles, kidneys, and eyes.

Zebrafish’s rapid developmental process makes it ideal for screening variants that impact development. Their large number of offspring and low cost for propagation make them ideal for target drug screens. Figure made with BioRender.

C. elegans

C. elegans are simple organisms that are perfect for high-throughput drug screening. Like zebrafish, C. elegans produce many offspring and develop very quickly. Their development is well-characterized, down to each individual cell, making it easy to study the development process under a microscope. They are transparent throughout their life, and their simplicity makes them easy to propagate.

C. elegans make ideal model organisms due to their low cost in propagation, large number of offspring, and the many levels at which phenotypes can be studied.

Xenopus

The Xenopus model has many advantages, including low cost of housing, the ability to monitor development due to large oocyte and embryo size, high fecundity, and rapid external development. The DMU employs a power developmental screen to detect variants with a dominant impact by overexpressing the wild-type (WT) and patient-variant allele in the oocytes.

Differences in development between oocytes expressing the patient variant versus the wildtype (WT) transcript indicate a dominant impact of the variant.

DMU Team

Bob Kesterson, PhD

DMU Core Lead

Brad Yoder, PhD

DMU Core Co-Lead

Chenbei Chang, PhD

John Parant, PhD

Matthew Alexander, PhD

Laura Lambert, PhD

CJ Haycraft, PhD

Craig Powell, MD, PhD

Deeann Wallis, PhD

Jeremy Foote, PhD, DVM