Michael Konadu
Research Mentor: Eliza Tsou
Mentor Department: Internal Medicine, Medicine
Author(s): Michael Konadu, Sunny Kataria , Eliza PS Tsou
Session: Session 3 (11:00 AM – 11:50 AM)
Presentation Type: Poster 94
Abstract
Systemic sclerosis is a common name for a group of rare autoimmune diseases characterized by tightening and hardening of the skin. Additionally, it is also known to adversely affect blood vessels and internal organs, leading to other complications. One key characteristic of systemic sclerosis is fibrosis: uncontrolled pathological accumulation of excess collagen, often with fatal consequences. We have identified two signaling pathways that drive fibrosis, and we are exploring whether inhibiting these pathways can reverse it. First is a cascade of reactions involving an intramolecular protein known as CaM, which, when bound to calcium ions, triggers the activation of another intramolecular protein known as CaMKIIa, which, when phosphorylated, ultimately leads to a fibrotic response in the fibroblasts as measured by the production of collagen. Using the inhibitor for this pathway, KN93, we have observed the prevention of fibrotic response when the inhibitor is applied. Consequently, the second pathway of interest involves mitochondrial reactive oxygen species (mitoROS), which can oxidize multiple proteins, leading to a fibrotic response by the fibroblasts. We have observed that when a mitoROS quencher, Mitoquinol, is applied, it reverses fibrotic responses as well. Oxidization has been reportedly shown to activate CAMKIIa independent of phosphorylation and CaM activity. On the other hand, activated CAMKIIa might cause an increase in mitoROS levels as well. We thus aim to explore if both the calcium signaling pathway and the mitoROS pathway, which lead to fibrosis, converge at CAMKIIa. We probed phospho- and Oxi-CAMKIIa levels upon treatment with specific inhibitors and observed how KN93 alters Oxi-CAMKIIa while mitoQ alters phospho-CAMKIIa in dermal fibroblasts from patients by Western blotting. We found that these inhibitors decrease Oxi-CAMKIIa and phospho-CAMKIIa, which suggest that the anti-fibrotic effect of these two inhibitors in systemic sclerosis could be explained in part by affecting the CAMKIIa activities.
