Email

rhu@bcm.edu

Positions

PhD candidate

Pathology
Baylor College of Medicine
Houston, TX US

Education

BS from National Sun Yat-sen University

06/2014 - Kaohsiung, Taiwan

MS from National Taiwan University

08/2016 - Taipei, Taiwan

Professional Statement

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disease with a mutation prevalence of 1:2100 that affects skeletal muscle, heart, central nervous system, and gastrointestinal tissues. Over 50% of DM1-affected individuals have cardiac symptoms, predominantly conduction abnormalities and life-threatening arrhythmias, accounting for 25% mortality and the second leading cause of death following respiratory failure.

DM1 is caused by an expanded CTG repeat in the 3' UTR of the DMPK gene. The mutant allele ranges from 50 to >4000 repeats compared to 5-35 repeats in those unaffected. DM1 is caused by an expanded CTG repeat in the 3' UTR of the DMPK gene. The mutant allele ranges from 50 to >4000 repeats compared to 5-35 repeats in those unaffected. RNA containing expanded CUG repeats (CUGexp) transcribed from the mutant DMPK allele accumulates in nuclear RNA foci and causes DM1 pathogenesis by disrupting functions of two conserved families of RNA binding proteins that regulate alternative splicing transitions during postnatal heart development. CUGexp RNA binds and sequesters muscleblind-like (MBNL) proteins, causing their loss of function, and induces upregulation of CUGBP and Elav-like family member 1 (CELF1). Widespread alternative splicing misregulation leads to the expression of fetal protein isoforms that are incompatible with adult heart function causing disease features.

While the molecular effects of CUGexp RNA have been well-studied in skeletal muscles, the molecular mechanisms of DM1 heart pathogenesis remain unclear. Our lab previously generated a bitransgenic mouse model (CUG960) for heart-specific and doxycycline (dox)-inducible expression of RNA containing 960 interrupted CUG repeats in the context of the human DMPK 3'UTR. Induced CUG960 (CUG960 +dox) mice consistently display DM1-like abnormalities including conduction abnormalities, arrhythmias, nuclear RNA foci with MBNL colocalization, and splicing defects as observed in DM1 heart tissue. Importantly, the phenotypic and molecular effects are reversed after the reduction of CUGexp RNA levels by halting dox administration to turn off the transgene.

In my project, I will use the CUG960 mice to determine: (i) the dominant mechanisms of DM1 cardiac pathogenesis using phenotypic rescue by restoring MBNL and CELF1 functions, (ii) the therapeutic potential of using CRISPR to reduce the toxic CUGexp RNA in vivo, and (iii) the impact of long-term CUGexp RNA expression on DM1 cardiac pathogenesis and rescue.

Funding

Mechanisms of DM1 Cardiac Pathogenesis and Potential Therapeutics

(01/01/2021 - 12/31/2022) Grant funding from Myotonic Dystrophy Fundation (MDF)

Reversal of Cardiac Phenotypes in Myotonic Dystrophy Type I by CRISPR-Based Approaches - #23PRE1020500

(01/01/2023 - 01/31/2023) Grant funding from American Heart Association