Research in the lab at DU is clustered into two areas:
1) ongoing investigation of Xrn1-mediated RNA decay processes
2) new investigations into the phase-separation behavior of RNA-binding proteins, specifically the ALS-linked protein TDP-43
Xrn1-mediated RNA Decay
Decay by the 5'->3' exoribonuclease Xrn1 is the end of the road for most messenger RNAs. Xrn1 is both an RNA hydrolase and helicase, responsible for processive decay of a wide array of structured RNA substrates. The lab is currently examining the thermodynamic basis for the decay of structured RNAs using a combination of fluorescent RNA decay assays and isothermal calorimetry experiments. We hope to experimentally test and develop thermodynamic models that account for the energy involved in the decay of folded RNA substrates.
Pathological Aggregation of TDP-43
The RNA binding protein TDP-43 is a major constituent of proteinaceous granules observed in brain tissue of patients suffering from a diverse spectrum of neurological diseases including ALS, AD and CTE. RNA is known to influence the mechanisms by which TDP-43 and other similarly dynamic, intrinsically disordered, proteins undergo liquid-liquid phase separation and pathological aggregation. The lab is interested in understanding the biophysical basis for TDP-43 aggregation and details regarding how RNA influences in vitro and in vivo phase-separation and corresponding pathogenicity. Our ultimate goal is to provide proof-of-concept data for new types of RNA medicines to combat these currently untreatable diseases.
Investigations in the Chapman lab have been funded by an R00 award from the National Institute of General Medical Sciences and startup funding provided by the University of Denver.
We are currently in the hunt for additional funding from a variety of sources including federal agencies and research foundations.