Finding brings scientists closer to developing treatments that target causes of painful, inflammatory skin condition
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 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."
Joining Ward in the psoriasis investigation were lead author Kathleen C. Lundberg, and contributing authors Daniela Schlatzer, Giridharan Gokulrangan and Mark Chance, all of the Center for Proteomics and Bioinformatics, CWRU School of Medicine; Yi Fritz and Thomas S. McCormick, the Department of Dermatology, CWRU School of Medicine; and Andrew Johnston, Alexander M. Foster, Jaymie Baliwag and Johann E. Gudjonsson, the Department of Dermatology, University of Michigan, Ann Arbor.
This work was supported by the National Psoriasis Foundation, The Lozick Discovery Grant, National Psoriasis Foundation, Babcock Foundation Endowment, National Institutes of Health (P30 AR39750, P50 AR05508, RO1 AR063437, RO1 AR062546, R21 AR063852, K01 AR064765, K08 AR060802, UL1 TR000439), the Murdough Family Center for Psoriasis, A. Alfred Taubman Medical Research Institute Frances and Kenneth Eisenberg Emerging Scholar Award.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu
About University Hospitals
University Hospitals, the second largest employer in Northeast Ohio with 25,000 employees, serves the needs of patients through an integrated network of 15 hospitals, 28 outpatient health centers and primary care physician offices in 15 counties. At the core of our $3.5 billion health system is University Hospitals Case Medical Center, ranked among America's 50 best hospitals by U.S. News & World Report in all 12 methodology-ranked specialties. The primary affiliate of Case Western Reserve University School of Medicine, UH Case Medical Center is home to some of the most prestigious clinical and research centers of excellence in the nation, including cancer, pediatrics, women's health, orthopaedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and genetics. Its main campus includes UH Rainbow Babies & Children's Hospital, ranked among the top children's hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center at Case Western Reserve University. For more information, go to http://www.uhhospitals.org
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