Dawn S. Chandler, PhD

• Hematology/Oncology & BMT
  Principal Investigator
• Dawn Chandler Lab
  Principal Investigator
• Center for Childhood Cancer
  Principal Investigator
• Primary Department
  Center for Childhood Cancer

Our lab is interested in the regulation of pre-mRNA splicing and how disruption of this regulation can lead to pediatric diseases such as cancer. 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. Another pediatric disease 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.Our 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.

Publications

Center for Childhood Cancer