OSU BME Seminar Series: Dr. Scott Johnstone, Fralin Biomedical Research Institute at Virginia Tech Carillion

In-person 2000 Fontana Labs
https://osu.zoom.us/j/97585376045?pwd=c1BESDR1V1NZZVpYMndKTnlMU3UxUT09
Password: 495324
United States

Scott Johnstone, PhD
Assistant Professor
Cardiovascular Research 
Fralin Biomedical Research Institute at Virginia Tech Carillion

Abstract:

"Cell Signaling in human vascular disease: The many ways connexins control proliferation."

Connexin proteins form gap junctions allowing for communication between cells. Alterations in gap junctions have been associated with pathological proliferation in disease since their discovery in the 1950s. Yet the mechanisms of control have been the topic of debate for almost as long, and are further complicated by the notion that connexin proteins themselves may play a role. We have worked to define specific cellular pathways controlled by connexins and gap junctions, with the aim of defining new therapeutic targets. I will present data highlighting the role of connexin proteins in the setting of vascular disease, looking at how connexin 43 (Cx43) regulates pathological smooth muscle cell (SMC) proliferation, which can thicken the blood vessel walls limiting blood flow. Our studies suggest that Cx43 can control proliferation independent of gap junctions. In vascular disease, post-translational modification of Cx43 promotes its binding of cell cycle proteins such as cyclin E. Using peptide arrays, we have identified cyclin E binding sites on Cx43, defined critical protein phosphorylation residues, and generated a novel connexin mimetic peptide named CycliCx. I will present data showing that the CycliCx peptide disrupts Cx43/cyclin E interactions and reduces cell proliferation and migration in models of vascular disease including in ex vivo human saphenous vein preparations. Finally, I will present data suggesting that the process may be more complicated in large blood vessels, with gap junction signaling occurring between recruited inflammatory cells and smooth muscle cells, potentially leading to a change in their phenotypic state. Taken together our data suggest that there is a complex interplay between gap junction signaling involving multiple cell types and direct control of cell cycle proteins that regulate SMC proliferation.

Bio:

Restoring blood flow to the heart by surgery can be complicated by cells in the blood vessel wall dividing continuously after surgery, eventually blocking blood flow again. We know that many therapeutics used to stop cells from dividing also affect surrounding cells, leading to reductions in vascular health. We are interested in understanding the basic cellular mechanisms, signaling, and functions in vascular physiology and pathology. Our research centers around cell communication through membrane channels such as the pannexins and connexin gap junction channels. We aim to understand how protein modifications such as phosphorylation can impact channel signaling and protein-protein interactions. We have identified disease-specific changes in connexins that can initiate binding and control of cell cycle protein functions, and identified novel pannexin channel-mediated control of pro-inflammatory cytokine release. Our research themes involve i) understanding the process of vascular cell differentiation ii) Pathways involved in the recruitment of inflammatory cells in the vasculature, iii) vascular wound repair and iv) identification of targets for therapeutic intervention. We employ a wide range of approaches to help understand these disease processes from the biochemical level in cells to animal models including multiple transgenic lines targeting smooth muscle cells, endothelial cells, and macrophages. Translational science is at the core of our research, and we use human vascular tissues to model disease and test newly designed therapeutics from the lab. In defining these processes, we aim to provide more specific targets that could be used to promote vascular health and improve patients' lives.