Ph.D. National Yang-Ming University
Our research focuses on two main projects in understanding (1) the regulatory mechanism involved in the transition from compensation to decompensation and heart failure, and, (2) the neural pathogenesis of congenital myotonic dystrophy.
Re-induction of fetal gene program is associated with pathological cardiacremodeling. How the fetal gene program is activated and whether reinduction of fetal gene program in adult heart contributes to adverse cardiac phenotypes remains largely unclear. Whether induction of fetal gene program is differentially regulated in the transition from adaptive or compensatory stage to decompensation and heart failure also remains elusive. CELF1 (CUGBP Elav-like family member 1) is an RNA-binding protein that regulates alternative splicing and mRNA degradation. CELF1 is highly expressed in embryonic heart and down-regulated in adult heart. We have recently shown that elevated CELF1 expression in dilated cardiomyopathy (DCM), the most common cause of heart failure, causes degradation of connexin 43 and vascular endothelial growth factor (Vegf) mRNAs leading to conduction defect and vascular rarefaction. While the results suggest a pathogenic role for CELF1 during heart failure and CELF1 might be a potential therapeutic target in heart failure, it is still unclear the functional role of CELF1 during heart development. It remains elusive whether CELF1-regulated fetal gene programs during embryonic development and pathological condition are similar or distinct. Therefore, our goals are to understand the functional role of CELF1 during heart development and determine whether CELF1 could be a potential therapeutic target in heart failure.
Cognitive deficits are found in a high percentage of individuals with myotonic dystrophy type 1 (DM1). The cognitive impairments include mental retardation, anxiety, autism spectrum disorder (ASD), depression and attention deficit hyperactivity disorders (ADHD). The genetic basis of DM1 is caused by an expansion of CTG repeats in the 3’ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. DMPK mRNA containing expanded CUG repeats accumulates in nuclear foci and affect nuclear and cytoplasmic activities of RNA binding protein such as muscleblind like (MBNL). We previously generated a mouse model for postnatal expression of expanded CUG RNA in the brain that recapitulates several features of adult-onset DM1 including learning disability, neurodegeneration and misregulated RNA processing. How expanded CUG RNA affects early stage of neurodevelopment remains largely unknown. To understand this, we have generated a mouse model of congenital DM1 and investigated how expanded CUG RNA affects RNA processing during neurogenesis.
Loss of MBNL1-mediated retrograde BDNF signaling in the myotonic dystrophy brainActa Neuropathologica Communications, Mar 15, 2023
Calpain-2 Mediates MBNL2 Degradation and a Developmental RNA Processing Program in NeurodegenerationJournal of Neuroscience, May 23, 2022