Endothelial Autonomous Mechanisms of Exacerbated Outcomes in Mice with Autoimmune Demyelinating Disease and SARS-CoV-2
Abstract
The COVID-19 pandemic has already deeply touched multiple sclerosis (MS) communities. In addition to the numerous ways that pandemic life compromises routine MS care (hesitancy to visit the doctor, concerns about safety of immunosuppressive therapy, stress of social isolation), there is the striking possibility that COVID-19 directly exacerbates the underlying biology of MS disease. That is, COVID-19 could make MS worse, and MS could make COVID-19 even more lethal than it already is in the general population. In this proposal, we will develop a new system to study what happens to the body when MS and COVID-19 are combined. We induce in small animals autoimmune demyelinating disease like MS, and we utilize cutting-edge gene manipulation approaches to target COVID-19 infection to the brain blood vessels. We then can ask two key questions: (1) How does the combination of MS and COVID-19 damage the brain blood vessels and (2) what main biologic pathways are likely to become effective medical targets to stop disease? We and others have shown that MS profoundly damages the blood vessels of the brain. Emerging evidence suggests that COVID-19 also damages brain blood vessels. In both diseases, this happens, in part, through inflammation and loss of oxygen. In this proposal, we determine when and how blood vessel inflammation takes place. We will study brain blood vessel leakiness due to tight junction disruption, accelerated cellular transport, and immune cell entry to the brain. We will correlate these features with VEGF, a known mediator of blood vessel damage in response to inflammation and oxygen loss that has previously been clinically targeted in other disease states. We will explore and develop the hypothesis that VEGF signaling causes brain blood vessel damage in MS and COVID-19. We have assembled a team of three highly regarded specialists to accomplish these goals. Our team consists of (1) a neuroimmunologist specializing in the ways that MS damages the brain and its blood vessels in mice; (2) a virologist specializing in creating new animal models of highly pathogenic viruses; and (3) a seasoned DOD researcher with decades of experience developing new therapeutic candidates targeting blood vessel cells.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110893
Entities
People
- Sarah E Lutz
Organizations
- United States Army
- University of Illinois at Chicago