Closing In On The Culprits.
Case Western Reserve scientists have taken a huge leap toward identifying root causes of psoriasis, an inflammatory skin condition affecting 125 million people around the world. Of the roughly 50,000 proteins in the human body, researchers have zeroed in on four that appear most likely to contribute to this chronic disease. The findings, published this month in Molecular & Cellular Proteomics, dramatically advance efforts to understand how psoriasis develops and, in turn, how to stop it.
“Psoriasis affects 2 to 3 percent of the population worldwide,” said senior author Nicole L. Ward, PhD, associate professor of dermatology and neurosciences, Case Western Reserve University School of Medicine. “The underlying cause of psoriasis remains unknown, and the specific signals that trigger disease onset are still being investigated. There currently is no cure.”
Ward’s lab is focused on studying the pathogenesis of the disease and its co-morbidities, including heart attack and stroke. Her group is actively working to identify new molecules key to the disease process that could become potential drug targets. Ward has a personal interest in this research; her father suffers from psoriasis.
Psoriasis is an autoimmune skin disease characterized by well-demarcated areas of red, raised and scaly skin next to areas of normal-appearing skin. Autoimmune diseases are those where the body launches an abnormal immune response against its own tissues. Another complication of psoriasis is joint involvement, a condition termed psoriatic arthritis.
Ward and her team first narrowed their pool of potential culprits to about 1,280 proteins that are differentially regulated in the condition. From there, they focused on five that stood out either because of their high prevalence in human psoriasis or their prominence in other studies relating to human psoriasis tissue. Ward’s lab team took skin tissue samples from her well-established psoriasis transgenic mouse model, called the KC-Tie2 mouse, and compared it to skin tissue samples of normal mice. Her lab collaborated with Mark R. Chance, PhD, director of the Center for Proteomics and Bioinformatics, CWRU School of Medicine, and his team at the center to identify new proteins that were differentially regulated in the skin tissue of psoriasis mice compared to the skin tissue of healthy mice.
To ensure that the proteins identified in the mouse were important to human psoriasis, her team then examined human psoriasis skin cells, known as keratinocytes, and human psoriasis skin tissue samples to confirm the increased presence of these proteins in human disease. In the skin of the psoriasis mice, investigators first identified increases in stefin A1 (342.4-fold increased; called cystatin A in humans); slc25a5 (46.2-fold increased); serpinb3b (35.6-fold increased; called serpinB1 in humans) and KLK6 (4.7-fold increased). The team found no increases of the Rab18 protein in skin tissue of the mice, and so ruled it out as a psoriasis-generating culprit. Investigators then confirmed the increased presence of the Serpinb3b, KLK6, Stefin A1 and Slc25a5 proteins in human lesional psoriasis skin tissue, and human lesional psoriasis skin cells compared to healthy control skin tissue and skin cells.
“We were interested in looking for the increased presence of these proteins, not just in the psoriasis-like skin inflammation of the mouse, but more importantly, we needed to know how the increased presence of these proteins translated to human psoriasis,” Ward said. “So we took the information we discovered in the mouse model and went back to the patients and confirmed the increase in these proteins in their lesional psoriasis skin tissue. We are really focused on, and enthusiastic about, our ability to perform successfully translational bench-to bedside-and-back-again psoriasis research here at CWRU School of Medicine Department of Dermatology and the Murdough Family Center for Psoriasis at University Hospitals Case Medical Center. It’s what we excel at and what we love to do.”
The next step in pursuing this line of research for Ward’s team will be uncovering the role and significance of each of these proteins in the progression of psoriasis. Determining the individual contributions of each protein will help provide strategic therapeutic targets to change the course of a patient’s psoriasis or, at the very least, provide a better understanding of how a change in the regulation of these proteins contributes to skin inflammation and psoriatic disease.
“We are always looking for novel targets or new insight into disease progression, remission or susceptibility,” Ward said. “It’s all about the patients. Even though what we are doing at the bench seems focused on mouse, the ultimate goal is to improve patient care and quality of life for patients.”