Matthew Strang
Research Mentor(s): Swati Bhattacharyya
Department or Program: Internal Medicine
Authors: Matt Strang 1 , Priyanka Verma PhD 2 , Matija Bajželj PhD 2 , Swati Bhattacharyya PhD 2 1 Washtenaw Community College, and 2 Division of Rheumatology, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, United States
Session: Session 1: 12:00pm-12:50pm
Poster: 49
Abstract
UROP ABSTRACT 2024 – Matt Strang Selective Inhibition of p300/CBP by A485 Suppresses TGF-β-Induced Pro-Fibrotic Response. Matt Strang 1 , Priyanka Verma PhD 2 , Matija Bajželj PhD 2 , Swati Bhattacharyya PhD 2 1 Washtenaw Community College, and 2 Division of Rheumatology, Department of Internal Medicine, School of Medicine, University of Michigan, Ann Arbor, United States Systemic sclerosis (SSc) is a chronic autoimmune disease marked by fibrosis, leading to excessive extracellular matrix deposition, tissue hardening, and organ dysfunction. Transforming growth factor-β (TGF-β) is a pro-fibrotic cytokine that stimulates collagen synthesis and is implicated in fibrotic diseases. Previous studies identified p300-catalyzed histone hyperacetylation as key in TGF-β-driven collagen production. The small molecule A485 was discovered as a potent inhibitor of p300 HAT activity. This study employs three-dimensional (3D) organotypic skin raft cultures (ORCs) verifying inhibition of HAT activity on fibrosis. Objective: To investigate the novel anti-fibrotic role of A485, a highly selective p300 HAT inhibitor, in TGF-β-induced 3D organotypic cultures (ORCs) to mimic responses in fibrotic diseases. Methods: 3D organotypic skin rafts were created using collagen gel and fibroblasts, which were subsequently treated with TGF-β and A485. RNA was extracted and converted to cDNA, followed by qPCR to measure the expression of ACTA2, COL8, and COL1A1 genes. Results: Our results demonstrate that inhibiting p300 HAT activity with A485 significantly reduced TGF-β1-stimulated collagen synthesis and myofibroblast differentiation in 3D skin rafts. This was evidenced by decreased expression levels of fibrosis-related genes (ACTA2, COL8, and COL1A1) in real-time PCR. Conclusions: Our findings indicate that inhibiting HAT activity with A485 effectively suppresses p300/CBP HAT activity and blocks TGF-β-induced pro-fibrotic responses. These results warrant further investigation into A485’s potential as an anti-fibrotic therapy in murine fibrosis models.
