The primary research goal of my laboratory is to investigate RNA regulatory mechanisms that govern cell proliferation and cell death and to understand how RNA misregulation contributes to various incurable human diseases. Our ultimate goal is to develop RNA-based methodologies to correct aberrant RNA processing, providing effective and targeted therapeutic strategies for these conditions.

Nonsense-mediated mRNA decay (NMD) is a crucial cellular RNA surveillance mechanism that selectively degrades mutated transcripts containing premature termination codons (PTCs). These PTCs are responsible for approximately one-third of inherited human diseases. NMD is essential for cell homeostasis and survival as it represses the expression of potentially toxic truncated proteins, which potentially lead to dominant-negative effects. Beyond mutated transcripts, NMD also degrades viral RNAs, protecting host cells from viral infections.

Over the past decade, our research team has demonstrated that NMD also plays a significant role in normal cell proliferation and differentiation, particularly in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). At the molecular level, NMD ensures RNA quality and maintains proper gene expression by degrading various coding and noncoding RNAs. Disruption of NMD is implicated in several neurodevelopmental and neurodegenerative diseases, as well as cancers such as breast and colorectal cancer. However, the underlying molecular mechanisms in these diseases remain largely unknown. Thus, understanding and controlling NMD activity is an attractive approach for developing novel therapeutics for many genetic disorders and infectious diseases.

In my lab, we aim to elucidate the physiological roles of NMD across various cell types. To achieve this, we will employ a comprehensive series of assays, including quantitative biochemistry, transcriptome/proteome-wide analyses, CRISPR-Cas9 for genome editing, and techniques to culture and differentiate human cell lines, ESCs, iPSCs, and primary neurons. These systematic approaches will facilitate a thorough understanding of the molecular mechanisms of NMD and eventually lead to the development of novel RNA-based therapeutic strategies.

As a second research direction, we will focus on RNA misregulation in the neurodegenerative disease spinocerebellar ataxia type 10 (SCA10). SCA10 is a dominantly inherited disease characterized by progressive cerebellar dysfunction, limb and gait ataxia, epilepsy, cognitive impairment, and peripheral neuropathy. It is caused by the expansion of the ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene. While normal individuals have 9-32 ATTCT repeats, SCA10 patients can have up to 4,500, leading to abnormal RNA accumulation in patient cells. Our short-term research focus is to understand the abnormal RNA processing in SCA10 using a range of biochemical techniques and various cell models, including lymphoblastoid cells, fibroblasts, iPSCs, and iPSC-derived neurons. Based on these molecular studies, our long-term goal is to develop strategies to normalize aberrant noncoding RNA processing using SCA10 cell and mouse models.

-------We are currently seeking postdocs, laboratory technicians, and students. Please contact us if you are interested in joining our exciting research group!!-------