Genetic Dissection of Defensin Signaling in the Pathogenesis of Psoriasis
Principal Investigator: Xintong Dong, Ph.D.
Institution: The University of Texas at Dallas
Grant Mechanism: Discovery Grant
Funding Amount: $75,000
Project Start Date: August 1, 2023
Project End Date: July 31, 2024
Keywords: Psoriasis, Disease Models, Genetics, Immunology, Inflammation, Neuroimmunology, Basic Science
Defensins are biomarkers for psoriasis. In healthy skin, these peptides serve as a defense mechanism to prevent infections. In psoriasis, however, the levels of defensins are abnormally high without any infections. Despite their abundance, the exact role of defensins in psoriasis remains a mystery largely due to the lack of animal models to study them. There are >50 defensin genes in mice, and deleting any single gene does not produce much effect. To solve this problem, we made a cluster knockout mouse line, removing all defensins from the skin. We found that defensins are important pro-inflammatory factors in the development of psoriasis and cause psoriatic itch. The objective for this proposal is to 1) figure out the roles of defensins in psoriasis, 2) identify defensin receptors on immune cells and 3) understand how defensins cause psoriatic itch. Our work builds key knowledge about a highly abundant peptide family in psoriasis, and can potentially reveal new therapeutic targets.
How will your project help improve the lives of the 125 million affected by psoriatic disease?
Defensins are some of the highest expressed genes in psoriasis but not much is known about what they do in this disease. Our research will fill this major knowledge gap and reveal the mechanisms by which defensins promote inflammation in psoriasis. The main goal is to understand which cell types (including immune cells and sensory neurons) are influenced by defensins, and to identify the cell surface receptors for these peptides. Antagonistic drugs can then be developed for these receptors to reduce inflammation and itch in psoriasis. The potential advantage of this approach over the currently available anti-TNF or anti-lL-17 therapies is reduced systemic side effect and improved symptom relief.
Why is psoriatic disease research important to you, personally? What role will this award play in your research efforts or career development?
The first human beta defensin peptide was isolated from psoriatic lesions (Harder et al, 1998). In the next 20 years, the fields of antimicrobial peptide and psoriasis research both saw revolutionary advances, but exactly what these peptides do in psoriasis is still a mystery. Since the day I began studying defensins as a postdoctoral fellow, psoriasis has always been a top priority. After years of efforts, we finally have the animal model to thoroughly tackle this question. The Discovery Grant is my first grant award as an independent investigator and will provide crucial supports for the comprehensive genetic, immunological and neurobiological analyses necessary for this project. We sincerely thank the foundation for believing in our vision and wish that our research will one day translate into new and better treatments for the millions of psoriasis patients.
Dr. Xintong Dong is an Assistant Professor at the University of Texas - Dallas. She received her bachelor's degree from the University of Wisconsin - Madison and Ph.D. from Stanford University. She conducted her postdoctoral research at the Johns Hopkins University School of Medicine under the guidance of Dr. Xinzhong Dong who is a world expert on itch physiology and neuro-immune crosstalk. Dr. Xintong Dong's current research focuses on antimicrobial peptides and their receptors in skin diseases and microbe-host interactions.