Branco Weiss Fellow Since
2023
Research Category
Structural Biology, Biophysics
Research Location
Scripps Research, La Jolla, USA
Background
Modern structural biology has given us powerful experimental and computational tools to routinely solve the static aspects of protein structures. It is now time to see their interactions and dynamics in their chaotic native environments. Specifically, Dr. Ritsch’s research is focused on proteins in flow conditions, such as found in the blood stream. As we age, the flows in our bodies begin to change, which is frequently linked with disease. Her project aims to reach a better understanding of the effects of flow conditions at the individual protein level.
Details of Research
Dr. Irina Ritsch’s study will focus on the aggregation of the human blood plasma protein transthyretin (TTR), which is associated with spontaneous and inherited amyloidosis. Preliminary experiments have revealed that TTR aggregation is weakly observed in moderately strong shear flow, and even more so in turbulent flow conditions. Excitingly, modifications of the TTR amino acid sequence found in an ortholog variants from hummingbirds are protective against aggregation under flow.
In this project Dr. Ritsch will combine in vitro biophysical methods including light scattering, fluorescence, magnetic resonance spectroscopy, and electron microscopy to investigate the detailed kinetics and aggregation intermediates of different variants of TTR under turbulent flow stress conditions. Development of a robust experimental protocol to apply controlled flows, and a better structural and dynamic understanding of early stage intermediates will allow Dr. Ritsch to evaluate how currently available small drugs designed to prevent or slow down TTR aggregation perform in the context of flow induced aggregation. In parallel, comparing the stabilized hummingbird variant to known amyloidogenic variants of human TTR may lead to novel therapeutic strategies for aggregation prevention.
Following up on the protein[nbsp] aggregation aspects of TTR, Dr. Ritsch will in a complementary approach investigate the role of flow in the protein’s native function as a thyroid hormone and retinol binding protein carrier, and screen for other protein adaptations to flow and shear stress.
