Published May 22, 2019
Alexander is principal investigator on a three-year, $717,000 grant titled “Mechanisms of Complement Dependent Immune Complex-Mediated Glomerulonephritis,” funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
“Our project attempts to understand the mechanism or mechanisms that cause complement activation, alter macrophages (defense cells) and lead to inflammation,” Alexander says. “This study may lead to important findings with therapeutic implications for kidney disease.”
In renal diseases, complement (C) activation and macrophage (MØ) infiltration are two crucial events that occur. Both facets can be beneficial or detrimental, and behave differently at different locations, depending on the microenvironment.
Complement signaling directs MØ to sites of inflammation and participates in local MØ amplification, which can negatively impact renal function.
“Although MØ and C are intertwined, we are only beginning to understand how these two facets of inflammation interact,” Alexander says.
The goal of the project is to understand glomerular inflammation using factor H (FH)-dependent immune complex mediated glomerulonephritis (ICGN) model. FH is an important complement inhibitor of the alternative complement pathway.
Preliminary studies have shown a significant increase in recruitment of MØ and T lymphocytes across the glomerular filtration barrier, resulting in chronic inflammation that leads to fibrosis and functional renal failure in FH-dependent ICGN.
“Based on our results, our hypothesis is that signaling through complement receptors leads to recruitment of MØ precursors to the kidney and alteration of MØ in the kidney, where they aggravate disease pathology,” Alexander says.
To test their hypothesis, researchers will determine:
“Our model of FH-dependent ICGN and GEB in culture are unique, with experimental features that are unrivaled,” Alexander says. “Our studies using these models can provide considerable insights into mechanisms of disease that are relevant to humans.”
Lee D. Chaves, PhD, research assistant professor of medicine, is co-investigator on the study.
Collaborators from the Jacobs School of Medicine and Biomedical Sciences are:
Sharon S. Evans, research professor of oncology and immunology in the Department of Immunology at Roswell Park Comprehensive Cancer Center, is another collaborator.