Since my childhood, I knew that my career would involve helping people. When I began learning about biology and chemistry in school, I found out that the human body's biology is closely linked to the chemistry between molecules of human cells. I gained a passion for it and believed that my future would be related to the study of molecular medicine. As such, I chose to study biochemistry in college and then pursued studying genetic diseases in my PhD program.
My primary research interest is determining the function of unstable RNA repeats in the pathology of neuro-muscular conditions. In my laboratory, we are working on uncovering the molecular mechanisms and development of therapies for two intricate genetic conditions known as Myotonic Dystrophy type 1 and Myotonic Dystrophy type 2.
One of the most innovative discoveries I have contributed toward is the identification of the RNA mechanism for Myotonic Dystrophy type 1 (DM1) in 1996. DM1 is a complicated disorder that has a mutation in the 3’ UTR of the DMPK gene. At that time, the major doctrine stated that the expanded DNA CTG repeats within the 3’ UTR of the DMPK gene causes a disorder by reducing the DMPK protein or by decreasing the transcription of genes located up-stream and down-stream of the DMPK gene.
My colleagues and I were the first to state that the expanded DNA CTG repeats cause DM1 through accumulation of RNA CUG repeats. We also suggested that the DM1 pathogenesis could be mediated by RNA-binding proteins that interact with the mutant RNA CUG repeats.
Our team discovered an RNA-binding protein known as CUGBP1/CELF1, a protein impacted by CUG repeats in DM1. These new findings transformed the sector of Myotonic Dystrophy and developed a setting for analyzing the RNA-based pathogenesis of DM1, DM2 and other diseases, associated with expansions of noncoding repeats.
The findings of the RNA mechanism for DM1 moved the field to a completely new level. This led to the present developments of treatments for DM1.
Our research further led us and other laboratories to identify other members of the family called CUGBP1 ELAV-like proteins, CELF. Many researchers have found this family of proteins regulates RNA metabolism at the stages of the management of RNA stability, translation and splicing. The family members here function in various tissues, such as skeletal muscle, brain, heart and liver, and control cell development and many cellular functions.
We also uncovered that treatment for DM1 should be based on the degradation of the mutant CUG RNA or the modification of RNA-binding proteins impacted by the mutant CUG repeats. In addition, we discovered that the GSK3-cyclin D3 signaling pathway manages the CUGBP1 activity and that this pathway is changed in the DM1 muscle. Furthermore, fixing the GSK3-CUGBP1 pathway in DM1 mice greatly lowers the pathology of DM1 muscle.
This research led us into a new direction for designing a DMI therapy based on GSK3 inhibitors. Using our findings, AMO Pharma has been developing a clinical trial to treat juvenile and congenital Myotonic Dystrophy type 1 using GSK3 inhibitors. The pediatric congenital DM1 clinical trial is moving through Phase 2 and Phase 3.
My team is also working with the molecular processes that raise the steadiness of the mutant RNAs in DM1 and DM2. We discovered that RNA helicase p68 is decreased in patients with DM1 and DM2. Then we observed that p68 is essential for degradation of the mutant RNAs due to unwinding the dsCUG/CCUG duplexes. Our research implies that the mutant RNAs in DM1 and DM2 may be degraded by the correction of RNA helicase activities.
Throughout my career, I have received numerous recognitions, including:
- Continuous funding awards from the National Institutes of Health (NIH) funding from 1997 to 2020
- Dr. Michael DeBakey’s award from Baylor College of Medicine for discovering the RNA-based molecular pathogenesis of DM1
- Invitations to participate in multiple international and national review panels, including review of the research, business and training projects and research centers proposals
- My research has been published in numerous journals, including Science, PNAS (USA), Journal of Clinical Investigation, Cell Reports and others
I have more than 35 years of experience in the fields of molecular biology and molecular genetics and first started working at Cincinnati Children’s Hospital Medical Center in 2014.
I am sincerely happy with my work as a research scientist. I find it fulfilling to see my lab’s published findings and have our proposals lead to further research among other groups worldwide. The best part of my career is speaking with patients and families impacted by DM1 and DM2 about potential treatment developments. Along with science, I truly enjoy spending time with my family.
Congenital myotonic dystrophy; adult myotonic dystrophy type 1; myotonic dystrophy type 2; FXTAS
Molecular pathobiology and development of therapies for adult and congenital forms of neuro-muscular disease myotonic dystrophy type 1 and myotonic dystrophy type 2; the role of toxic RNAs containing long repeats in regulation of gene expression; skeletal muscle
Professor, UC Department of Pediatrics