Calvier Lab

The prevalence of chronic inflammatory diseases greatly increases during aging. They can affect every organ, from the brain (causing dementia) to the joints (arthritis) or the gut (e.g. inflammatory bowel disease), causing a loss of economic productivity and invalidity. One of the most common inflammatory neurodegenerative diseases, Alzheimer’s disease (AD), affects 6.7 million Americans alone with a new diagnosis occurring every minute. In 2023, the total economic burden associated with AD was estimated at $345 billion. The number of diagnosed cases is projected to double by 2050 with a projected increase in cost to nearly $1 trillion. Despite extensive research on AD, current strategies targeting amyloid-β (Aβ) and tau aggregates continue to face significant challenges in clinical trials, , thus prompting a shift toward other aspects of the disease, notably its inflammatory component. Overcoming these challenges requires a deep understanding of the pathophysiological processes, the vascular barrier, and the immune system to identify novel and effective treatment modalities. An effective approach our team has uncovered involves a circulating endothelial signaling factor named Reelin. It functions as a master regulator of endothelial adhesion proteins by activating the ApoE receptor 2 and NF-κB pathway, thus promoting the endothelial inflammatory response. This mechanism facilitates the infiltration of circulating inflammatory cells into the affected tissue, a process common to most chronic inflammatory diseases. Our published and preliminary data validate Reelin-depletion to reduce inflammation and disease severity in various preclinical models including AD, rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We propose to use antibody-mediated depletion of circulating Reelin in age-related inflammatory diseases to restore the endothelial barrier function and mitigate excessive leukocyte infiltration in chronic inflammatory diseases.