Toluwani Adelaja
Pronouns: She/Her
Research Mentor(s): Swati Bhattacharyya
Research Mentor School/College/Department: Internal Medicine, Rheumatology / Medicine
Program:
Authors: Toluwani Student, Swati Bhattacharyya
Session: Session 7: 4:40 pm – 5:30 pm
Poster: 9
Abstract
Systemic sclerosis (SSc), is a rare and chronic disease that causes hardening in the skin and connective tissues, and symptoms that include joint pain, exaggerated response to cold, and heartburn. The disease is heavily implicated with fibrosis, a condition which causes the build-up of scar tissue in the skin. While fibrosis is recognized as the hallmark of systemic sclerosis (SSc), the triggers and mechanisms driving myofibroblast differentiation and persistent activation seen in SSc are not well understood, and effective treatments are lacking. Previously it was found that the histone acetyltransferase (HAT) p300 is upregulated in SSc patients. Library screening of small-molecule epigenetic drugs led to the discovering the small molecule A485 as potent and specific blocker of p300 HAT activity. Here we sought to determine the impact of inhibiting HAT activity of fibrosis in vivo preclinical model of fibrosis. For this purpose, we used the bleomycin-induced mouse model of skin fibrosis. Chronic treatment of young mice with A485 was well tolerated, and resulted in significantly reduced dermal inflammation and fibrosis. Moreover, A485-treated mice showed partial preservation of the dermal adipose layer, an important marker for skin fibrosis. Altogether, our findings reveal a fundamental role of p300-mediated epigenetic remodeling in fibrosis, and indicate that selective p300 HAT inhibition using small molecules such as A485 provides a novel approach for mitigating fibrotic phenotypes in the skin, potentially representing a distinct treatment paradigm for SSc.
