Research Projects
IRF7 as the pathological link between interferon pathway activation and fibrosis in systemic sclerosis:
Interferon regulatory factor 7 (IRF7) is the top predicted transcription factor for the systemic sclerosis signature in peripheral blood and skin. We have shown IRF7 interacts with SMAD3 and potentiates TGFβ induced fibrosis signaling in fibroblasts. Moreover, global Irf7 knockdown attenuates dermal fibrosis in two murine dermal fibrosis models. We are further elucidating the role of IRF7 in skin and lung fibrosis using cell-type specific knock-out and overexpression murine models of fibrosis, as well as single-cell transcriptomic/spatial studies. Moreover, in-vitro studies aimed at elucidating the interaction between IRF7 and TGF-β pathway are being carried out. This project is co-led by Drs. Assassi and Wu and is funded by the NIH.
NUDT21 mediated alternative polyadenylation as a key regulator of skin and lung fibrosis in systemic sclerosis:
NUDT21 is a master regulator of alternative polyadenylation. In an NIH-funded project, we have shown that NUTD21 levels are decreased in systemic sclerosis skin and fibroblasts. Moreover, mice with CFIm25 deletion in fibroblasts show exaggerated skin fibrosis upon bleomycin treatment, and CFIm25 restoration attenuates bleomycin-induced skin fibrosis. Building on these results, our lab, in close collaboration with Mills lab, is currently elucidating the role of NUDT21-mediated polyadenylation in other important cell types and cell-specific overexpression murine models.
Pathogenic effects of the DNASE1L3 R206C variant in systemic sclerosis:
Our Division has a longstanding interest in genetic susceptibility to systemic sclerosis. One of the susceptibility variants, we identified causes an amino acid substitution in DNASE1L3 (R206C), an endonuclease with a critical role in protection against autoimmunity. We have demonstrated that systemic sclerosis patients harboring this variant have impaired digestion of circulating self-DNA derived from apoptotic cells. Using in-vitro enzymatic assays, murine models, and profiling of immune cells from systemic sclerosis patients, our ongoing work is designed to determine the impact of DNASE1L3 on clearance of circulating DNA and the immunologic consequences of DNASE1L3 loss-of-function. Dr. Skaug leads this project funded by the NIH (K08 – PI: Skaug) and the Rheumatology Research Foundation.
Molecular predictors of interstitial lung disease course and response to treatment in systemic sclerosis:
Assassi Lab serves as the Biorepository Coordinating Center for several multicenter longitudinal cohorts, including GENISOS and CONQUER studies. Our lab is performing multilevel molecular profiling (at the transcriptomic and proteomic levels) and combining them with clinical data in observational cohorts and clinical trial samples, using sophisticated longitudinal models, as well as machine learning approaches. The goal of these projects is to enable personalized medicine for the treatment of systemic sclerosis-related interstitial lung disease. This project is funded by a CDMRP award.
Molecular predictors of spinal disease progression in ankylosing spondylitis:
Ankylosing spondylitis (AS) is a chronic inflammatory arthritis with a predilection for the spine and sacroiliac joints, affecting 0.5-0.6% of the US population. Our lab is performing multilevel molecular profiling (at the transcriptomic and proteomic levels) in valuable biospecimens collected in the longitudinal PSOAS observational cohort. These data are combined with the clinical variables using sophisticated longitudinal models, as well as machine learning approaches with the ultimate goal of developing prediction tools for spinal disease progression in ankylosing spondylitis. Dr. Hwang leads this NIH-funded project (NIN/NIAMS K23 – PI: Hwang).
Optical coherence tomography/elastography/angiography for assessing systemic sclerosis skin involvement:
Skin is a prominently affected endorgan in systemic sclerosis. However, there are no established methods to measure systemic sclerosis-related skin involvement in an objective and quantitative manner. In an NIH-funded project, our lab, in close collaboration with Larin lab at the University of Houston, has shown that a custom-made optical coherence device is able to assess skin and provide information on tissue stiffness and vascularity. Our lab is currently collecting longitudinal optical coherence data in comparison to histological and clinical assessment for developing accurate outcome measures to assess skin fibrosis and vasculopathy in systemic sclerosis.
AD-PluReceptor-NK cells for the treatment of systemic sclerosis:
Cell therapy can lead to long-term benefits in patients with autoimmune diseases. UTHealth Houston Scleroderma Program is conducting a phase I/II clinical trial, sponsored by MD Anderson Cancer Center, to examine the efficacy of AD-PluReceptor NK cells Plus Tafasitamab for the treatment of systemic sclerosis and systemic lupus erythematosus. Assassi lab, in close collaboration with Rezvani Lab at MD Anderson, will be performing multi-level longitudinal molecular profiling in biospecimens collected in this investigator-initiated clinical trial. The ultimate goal of this project is to elucidate the molecular changes ensuing from AD-PluReceptor NK treatment and to correlate them with clinical outcomes.