Qingde Wang, MD, PhD

Ribonucleic Acid (RNA) along with deoxyribonucleic acid (DNA) and protein compose the major materials that are essential for all known forms of life. Life's message, written by more than 3 billion nucleotides in specific sequences that are stored in cell nuclear, needs variant RNA molecules to carry the information from the nucleus to the cytosol by messenger RNA (mRNA) and assemble machinery to convert the sequence messages to proteins by tRNA and rRNA. In a typical human cell, there is about 10-50pg RNAs, 1.5 to 5 fold more that DNA contents, that are mainly distributed in the cytoplasm. Some other types of RNAs, such as translation inhibiting small RNAs (eg. microRNAs and siRNAs) also play crucial roles in the regulations of gene activities. Aberrant RNA metabolism or abnormal function will most certainly lead to malfunction of cells and therefore link to pathologic conditions.

RNA is also encoded by DNA in the nucleus. Most RNAs exert their function in the cytoplasm therefore the nascent RNA synthesized in the nucleus needs to be transported to the cytoplasm. Sophisticated processes take place in RNA molecules during RNA maturation from nascent RNA, include 5’ capping, splicing and 3’ tailing, as well as RNA editing. The Wang Lab has been working on the function and molecular mechanisms of RNA processes, particularly the RNA editing process. Adenosine deaminase acting on RNA 1 (ADAR1)  is an RNA editing enzyme that binds to and changes the sequence information of RNA molecules. We have demonstrated that ADAR1 is an essential enzyme for animal survival and embryonic development. In ADAR1 knockout mice, embryo die around day 11-12. Employing conditional and inducible knockout models, we also found that adult cells, including adult stem cells, require ADAR1 for their differentiation and normal functions. ADAR1 is dispensable for the homeostasis of organs including the liver, pancreas,  and intestines, as well as that of T and B lymphocytes and the skin. For example, in a liver-specific knockout animal model, deletion of ADAR1 caused profound hepatocyte death and persistent liver regeneration that led to severe liver function damage.

There is evidence that ADAR1 is involved in interferon (IFN) signaling pathways. In ADAR1 knockout animals, IFN levels and its regulated genes are upregulated. IFNs play critical roles in pathogen infections and also in inflammation responses. It conceivable that cells change their RNA content biologically or by invading pathogens that need ADAR1 to copy with. Inappropriate RNA processes owill activate the IFN pathway cascade that could lead to severe tissue damage. We currently focus our interests in the function of ADAR1 in the surgical pathological context. Hopefully, our research will contribute to a better understanding of the molecular mechanisms of inflammation development in surgical infection and trauma.