This pilot project was funded in 2021 and its success led the way to Dr. Skopelja-Gardner becoming a full member of the CQB in 2022.
Principal Investigator: Sladjana Skopelja-Gardner, PhD
Dr. Skopelja-Gardner is an Assistant Professor in the Department of Medicine, the division of Rheumatology. Her expertise is innate immunity in both humans and mice, with the focus on mechanisms of disease pathogenesis in SLE. She has extensively studied immune responses to ultraviolet light in vivo, in both skin and kidney tissues, with the goal to understand photosensitivity in SLE.
Project Description
Although sensitivity to ultraviolet (UV) sunlight rays affects most systemic lupus erythematosus (SLE) patients (~80%), the cellular and molecular mechanisms responsible for UV light-triggered kidney disease flares in SLE are unknown. The long-term goal is to identify targetable pathways by which photosensitivity triggers systemic disease in SLE. The overall objectives of this project are
- to define the effects of SLE autoantibodies on immune cell migration to the kidney and renal inflammatory pathways triggered by UV light
- to identify which tubular and/or glomerular kidney cell subsets are injured as a result of UV exposure.
The central hypothesis is that skin exposure to UV light triggers recruitment of myeloid cells (monocytes and neutrophils) to the kidney, where they mediate inflammation and damage tubules and podocytes. In the presence of autoantibodies, this damage leads to persistent proteinuria and kidney pathology.
The central hypothesis will be tested by pursuing two specific aims:
- Identify the myeloid cell populations and inflammatory pathways in the kidney after skin exposure to UV light in normal and SLE conditions; and
- Define the structural renal cells damaged by UV light in the presence of SLE autoantibodies.
Under the first aim, enriched renal immune cells and immune pathways will be analyzed by single-cell transcriptomics (scRNA-Seq) following skin exposure to UV light in three conditions: i) normal mice, ii) in the presence of kidney-specific SLE-like IgG, and iii) in the presence of systemic SLE-like IgG. Tissue, urine, and serum proteomics will be integrated.
For the second aim, scRNA-Seq of enriched glomerular and tubular cells will define differential expression of tissue injury pathways in two models of SLE IgG (kidney vs. systemic) combined with urine proteomics and tissue pathology studies. Analysis of ligand-receptor interactions will reveal which immune cells directly mediate renal injury.
This research is innovative, as it focuses on the novel paradigm of a skin-kidney axes of pathogenesis in SLE, which is mediated by innate immune cells and affects renal integrity. The research is significant because it is expected to identify specific molecular and cellular targets that link local skin and distal renal injury in SLE. Ultimately, such knowledge has the potential of offering new opportunities for the development of innovative therapies to prevent photosensitive reactions in SLE patients.