Translational rheumatology and immunology is the focus of the newest lab in the Department of Cellular and Molecular Medicine in Cleveland Clinic’s Lerner Research Institute. Specifically, the lab is homing in on the molecular basis of immune-mediated diseases, particularly psoriatic conditions like psoriasis and psoriatic arthritis.
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The Husni research lab is an interdisciplinary team combining the clinical expertise of M. Elaine Husni, MD, MPH, Director of the Arthritis and Musculoskeletal Center in the Department of Rheumatic and Immunologic Diseases, with the biochemical and molecular biology expertise of the Lerner Research Institute’s Unnikrishnan Chandrasekharan, PhD. The team (shown in the new lab in the photo above) will conduct clinical and basic science investigations with the aim of advancing discoveries in psoriatic diseases.
“We believe combining our clinical and basic science backgrounds can provide an immense advantage in translating basic discoveries into novel clinical applications,” explains Dr. Husni. “We are thrilled and look forward to this exciting scientific partnership, which was made possible by the vision and mentorship of Drs. Paul DiCorleto and Stanley Hazen of the Lerner Research Institute.”
“This collaboration enables our team to ask the basic questions pertinent to the underlying pathogenesis of chronic inflammatory diseases,” says Dr. Chandrasekharan. “We hope it will lead to discovery of new signaling pathways and molecules critically involved in inflammatory diseases and immune disorders that we can then apply therapeutically.”
Marrying molecular biology with a biorepository
The new laboratory melds state-of-the-art biochemical and molecular biology approaches with clinically based discovery and access to high-quality human specimens from a longitudinal psoriatic disease biorepository that Dr. Husni has developed over a number of years. This includes the collection of plasma, serum, urine and genetic analyses that are carefully annotated with yearly clinical, demographic, pharmacologic and disease activity assessments. The biorepository is made possible by research funding support from Cleveland Clinic’s R.J. Fasenmyer Center for Clinical Immunology.
“The framework for designing and evaluating a translational research program is evolving, especially with the interdisciplinary approach needed to support more personalized medicine,” Dr. Husni notes. “It’s more important than ever to move scientific research in the direction of multidisciplinary or collaborative teams.”
Early focus: Selective TNF-α receptor inhibition
A particular focus of the lab will be to further understanding of how the inflammation, dysregulated immune responses and accelerated atherosclerosis that occur in psoriatic diseases can be halted and/or ameliorated. Another focus will be defining novel disease-specific signaling pathways to allow more precise targeting of effector molecules involved in psoriatic diseases than is possible with current disease-modifying agents such as anti-tumor necrosis factor (TNF) inhibitors.
To that end, the lab is focusing on the cell signaling of cytokine TNF-α, as its dysregulation plays a significant role in the skin and joint pathology of psoriatic diseases. Most anti-TNF medications act by binding TNF-α in the circulation before it binds to its immune cell surface receptors. In contrast, Drs. Husni and Chandrasekharan are investigating selective inhibition of one of the two distinct TNF-α immune cell receptors, TNFR1 and TNFR2.
A new study in mice initiated by Dr. Chandrasekharan has begun to uncover clues about the relative roles of these two receptors in psoriatic diseases. Mice genetically engineered to selectively eliminate TNFR1 or TNFR2 receptors responded differentially to a chemically induced psoriasis animal model. The new findings suggest that blockade of specific TNF receptors, rather than TNF, may produce sufficient reduction in inflammation to lessen the harmful effects of psoriatic diseases while maintaining normal immune response to infection and cancer.
Dr. Chandrasekharan is investigating the knockout of specific target molecules required for the cell regulatory effects of either TNFR1 or TNFR2 activation by circulating TNF-α. The hope is that this receptor-specific approach will ultimately ameliorate symptoms of psoriatic diseases while preserving protective aspects of the immune system.