The Lu Chen laboratory studies molecular secrets underlying all things RNA biology – how RNAs are chemically modified, how their exact molecular forms are precisely defined, and how they cooperate with proteins to carry out molecular functions at specific cellular locations. We are translating our basic science discoveries into therapeutic options to combat cancer immortality, stem cell exhaustion, and degenerative diseases. We use diverse approaches, including protein-RNA reconstitution, Next-gen RNA structural profiling, CRISPR-engineering of human primary stem cell and mouse models, and single-molecule RNA imaging.
Target recurrent cancer driver mutations
Almighty cancers can get complacent when they become addicted to dominant-acting mutations. We seek to elucidate specific onco-driver mechanisms underlying "oncogene-addiction", while building relevant pre-clinical models to test nucleic acid and small molecule therapeutics. Our long-term goal is to precisely target cancer's Achilles heel with novel cancer drugs for phase I clinical trials.
RNA and RNP biology
Misregulated RNA biogenesis can lead to human conditions, including cancers and degenerative diseases.
We study the structure of function of noncoding RNAs - how they are chemically modified, how their exact molecular forms are precisely defined, how they are instructed by proteins to perform molecular functions at specific cellular locations. Here are 4 ongoing pursues in the lab:
RNA 5' cap modification: identify RNA cap-modifying enzymes, and define their targeting specificity to RNA clients.
RNA 3' processing: how RNA 3' end processing is defined, and how it can be coupled with its 5' cap modification?
RNP assembly: identify assembly factors that are necessary for RNA catalysis.
RNA trafficking: why RNA preferentially localize to certain phase-separated bodies? What controls their in and out?
Telomere-elongating approaches to combat stem cell exhaustion
Stem cell exhaustion can curb tissue engineering, stem cell therapy, including immunotherapy, and can precipitate aging and degeneration. Lab mouse strains, common model for human diseases, does not subject to replicative senescence - a hallmark driver for human carcinogenesis; ex vivo expansion of adult human stem cells are too often limited by various "culture shocks" and show wide-ranging clonal variations that can lead to challenges in bulk analyses.
To overcome these bottlenecks, we aim to
1) introduce human-like replicative senescence into lab mice. Specifically, we have successfully engineered a humanized mouse strain that recapitulate key features of telomerase expression.
2) we seek to develop telomerase and telomere measurement on a single cell level - both are excellent biomarkers that reflects cell proliferative potential or records cellular aging, respectively.
Our efforts will elucidate the cell-of-origin for cancers and stem cell diseases.