Linkage Analysis of Familial Psoriasis
Principle Investigator: James Elder, M.D., Ph.D.
Institution: University of Michigan
Grant Mechanism: R01 Bridge Grant
Funding Amount: $100,000
Project Start Date: February 1, 2023
Project End Date: January 31, 2024
Keywords: Psoriasis, Psoriatic Arthritis, Basic Science, Clinical Research, Gene Expression, Genetics, Immunology, Inflammation, Multi-omics
Why do only some people get psoriasis? How does it start? How is it maintained? Many have turned to immunology for answers; we add genetics. To better understand psoriasis genetic signals, most of which are regulatory, we purified white blood cell (WBC) subsets from 153 people with or without T-cell activation. We found that monocytes are critical for Th17 expansion, via a process requiring contact with activated T-cells that results in monocyte death. Notably, FASLG encoding FasL, a key cell death mediator, maps to a psoriasis susceptibility region.
Monocytes migrate into tissue and cluster with T-cells at inflammation sites where they promote Th17 polarization, suggesting an ongoing cycle of monocyte tissue entry and death. To test this model, while bringing our genetic studies to fruition, we propose three aims:
- To complete and publish our most recent psoriasis genome-wide association studies (GWAS).
- To pinpoint psoriasis causal variants by integrating our GWAS data with ATAC-seq, RNA-seq, and chromatin looping data from our WBC experiments.
- To better understand monocyte-dependent Th17 expansion, by T-cell-monocyte mixing experiments, staining for doublets in WBC cultures and skin, and FasL blockade.
Dr. James T. Elder, M.D, Ph.D. is the Kirk D. Wuepper Professor of Molecular Genetic Dermatology and professor of dermatology at the University of Michigan Medical School. Dr. Elder received his M.D. and a Ph.D. in Molecular Biophysics and Biochemistry, from Yale University Medical School and completed an internal medicine Internship, dermatology residency, and research fellowship at the University of Washington. Following his residency, Dr. Elder completed a Senior Research Fellowship at the University of Michigan.
The Elder laboratory utilizes tools of molecular biology and genetics to better understand several human skin diseases. Dr. Elder's lab is a world leader in the use of genetic linkage and association techniques to learn more about how the immune system activates the epidermal wound healing mechanism in psoriasis and triggers joint destruction in psoriatic arthritis. In 2006, his laboratory identified HLA-Cw6 as the disease allele at PSORS1, the major psoriasis susceptibility locus in the major histocompatibility complex (MHC). His current efforts in this area are focused on identification of psoriasis susceptibility genes outside the MHC, with nine loci confirmed thus far. His laboratory also has a long-standing interest in the role of the EGF receptor (also known as ErbB1) as an activation signal for epidermal wound healing and carcinogenesis. Active projects in this area are exploring the roles of autocrine EGF-like growth factors in psoriasis, wound healing, and cancer. Finally, Dr. Elder's laboratory has also identified somatic mutations in melanocytic nevi and melanomas of varying degrees of progression.