The Chandler lab focuses on the regulation of pre-mRNA splicing and its disruption leading to pediatric cancer and spinal muscular atrophy. We utilize cell culture models and mouse models to better understand the role of the alternative spliced forms as a manifestation of a disease.
The Chandler Lab was established in 2005 and is housed on 5th floor of Research Tower II of Nationwide Children’s Hospital.
The research in Dr. Chandler’s lab is centered on understanding the regulation of alternative pre-mRNA splicing and how disruption of this highly regulated process leads to diseases such as cancer and spinal muscular atrophy. The research focus is to define the mechanisms by which disruption of regulated splicing of pre-mRNA leads to altered cell function. Dr. Chandler’s lab is developing in vitro and animal model systems that can be used to develop novel therapies targeting these disrupted pathways.
This research represents a novel perspective in pediatric research that highlights the role of perturbation of pre-mRNA processing in disease phenotypes. The increased awareness of regulated RNA processing and recent identification of several disease-causing mutations that affect splicing give rise to a new generation of potential therapeutic targets. Point mutations and the resultant splice variants may both be successfully targeted for therapeutic benefits in the future.
Cancer and Splicing
Current work in our lab elucidates alternative splicing as a novel mechanism by which cellular injury can control the activity of p53 and how changes in the regulation of splicing can lead to tumorigenesis. The transcription factor p53 is known to induce G1 arrest of the cell cycle and/or apoptosis. MDM2 is one of the most critical regulators of p53. Using in vitro biochemical assays and genetically engineered mouse models we are currently investigating differential RNA splicing of both the MDM2 and p53 pre-mRNAs and investigating the roles of each in normal cell function as well as disease.
SMA and Splicing
Proximal Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality in humans, is in part due to a mutation that affects splicing of a duplicated gene that controls neuronal growth (SMN2). We are interested in generating viable mouse models for human SMA with the long-term goal of testing candidate therapies that target the human SMN2 gene. To do this, we are generating mouse lines that will be utilized to answer many questions pertaining the therapeutic possibilities of SMN replacement, splicing correction by drug or antisense treatment, and the correct timing of such therapies.