Leading AAV capsid engineering efforts to discover novel capsids that can target the different organs and cell types through different routes of administration.Identified novel AAV capsids targeting cardiomyocytes following systemic delivery.Investigating the impact of various regulatory elements on the strength and specificity of AAV transgene expression.

Established Tenaya in-house AAV capsid engineering platform and successfully screened over 30 diverse, proprietary AAV libraries (peptide insertion, variable region, chimeric, rational design, scanning, etc.) representing more than one billion of unique capsids in multiple in vivo and in vitro models to discover novel AAV capsids that can target the different types of cells in the heart through different routes of administration.Developed and optimized methodologies for high-complexity library construction, in vivo and in vitro screening, animal tissue processing, NGS data analysis, novel AAV capsid candidate identification and validation, etc.Currently focusing on targeting cardiomyocytes following systemic delivery and have identified novel AAV capsids with superior properties (data presented at ASGCT 2022 and ESGCT 2022).

Project 1: Performed RNA-seq, ribosome profiling, and mass spectrometry to systematically probe mRNA, translation, and protein changes in a panel of ribosomal protein mutants with various global protein synthesis rates in Saccharomyces cerevisiae, discovered gene expression signatures that were either unlinked from or linked to cellular growth rate, and tested three current hypotheses explaining how human ribosome deficiencies cause tissue-specific ribosomopathies.Project 2: Performed simultaneous genome-wide measurements of mRNA, translation and protein levels through meiotic differentiation in budding yeast, identified several hundred cases where the mRNA levels and the protein product levels were anti-correlated, and showed that at least 380 of them were regulated by switching between production of a canonical, translatable transcript and a 5’ extended untranslatable isoform.Project 3: Measured translation efficiency and total abundance of ribosome biogenesis (RiBi) gene transcripts with or without global translation inhibition, and showed that cycloheximide (CHX) and other translation inhibitors were able to increase RiBi mRNA abundance and thus, cause apparent translational repression of these genes in translation efficiency assays.

Achieved reliable conditional gene knockout in C. elegans for the first time by expressing transcription activator–like effector nucleases (TALENs) in somatic cells, demonstrated that somatic TALENs were able to edit the genome and elicit mutant phenotypes in both spatially and temporally specific manners, and applied this method to determine the role of an embryonically essential gene in neuronal development.