Regulatory T cell Uhrf1 and DNA methylation in repair of acute lung injury

Project: Research project

Project Details


Statement of the Problem: Despite extensive research into the initial injury and inflammation that drive ARDS, no targeted therapies accelerate its resolution. Experimental studies established that committed regula-tory T cells (Tregs)—immune system cells that limit inflammation and orchestrate repair of damaged tissues—resolve inflammation in mouse models of lung injury. However, the mechanisms that cause Tregs to execute their pro-repair program following lung injury remain unknown. Our preliminary data identify DNA methylation, which involves a DNA methyltransferase adapter protein known as Uhrf1, as a critical phenomenon limiting expression of the main protein that directs Treg pro-repair function: Foxp3. Thus, we hypothesize that Uhrf1 deficiency in committed Tregs will lead to Foxp3 locus hypomethylation, increased Foxp3 expression, and en-hanced Treg pro-repair function that facilitates resolution of acute lung injury. To test this hypothesis we propose the following Specific Aims: 1) define the role of Uhrf1 in promoting DNA methylation at the Foxp3 locus in committed Tregs following lung injury, and 2) define the role of Uhrf1 on committed Treg pro-repair function and immunoregulatory phenotype. Experimental Approach: To specifically test our hypothesis we are breeding novel mice that have Uhrf1 deficiency only within Tregs. We have also designed an RNA interference strategy to acutely knock down Uhrf1 in cultured Tregs. Major methods for this proposal include an established mouse model of acute lung injury (intratracheal lipopolysaccharide administration), DNA methylation sequencing tech-niques, and multicolor flow cytometry. Significance of the Results: Accomplishment of these aims will provide a rigorous training program for Dr. Singer and uncover mechanisms controlling Treg function during resolution of acute lung injury that could be translated for therapeutic benefit in ARDS.
Effective start/end date7/1/156/30/18


  • Francis Family Foundation (Award Letter 10/6/15)


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