Interactions of MG53 and GsdmD for Neutrophil Pyroptosis Inhibition

St. John'S University, Queens NY

Investigators

Abstract

Project Summary/Abstract The proposed research project aims to understand how MG53, a membrane repair protein, protects heart cells after myocardial infarction (MI). When MI occurs, it causes inflammation and damage to heart cells, which can lead to further complications if not controlled. The project focuses on a process called pyroptosis, which is a type of cell death that contributes to inflammation. MG53 is known to help repair damaged cell membranes, while another protein, GsdmD, forms holes in cell membranes, leading to membrane rupture and subsequent cell death. The central hypothesis is that MG53 may prevent this harmful process by interacting with GsdmD in neutrophil cells. The long-term goal is to find a way to fine-tune the immune response to promote healing after MI without causing excessive inflammation. Preliminary data suggest that (1) Pyroptosis plays a key role in the inflammatory response shortly after MI. (2) MG53 reduces GsdmD activation and pyroptosis and improves heart damage after MI. (3) Activated GsdmD is found in neutrophils after MI. Since MG53 is naturally present in the body, targeting it for therapy should be safe and not trigger an immune reaction. The hypothesis is that MG53 prevents pyroptosis by interacting with GsdmD in neutrophils, stopping GsdmD from activating or blocking the holes activated GsdmD creates. The research will have two main Specific Aims. Aim 1: To study how MG53 and GsdmD interact before and after GsdmD activation. Research design and method: Aim 1 will investigate the binding of MG53 and GsdmD in solution and MG53’s and activated GsdmD’s colocalization on liposomes. Aim 1 will also employ an MG53 mutant that lacks membrane repair function to elucidate MG53’s role in protecting neutrophils after pyroptosis. Aim 2: To determine if neutrophil pyroptosis contributes to heart cell death. Research design and method: Aim 2 will assess the contribution of neutrophil pyroptosis to post-MI cardiomyocyte death by utilizing neutrophil- specific GsdmD knockout mice for post-MI evaluation and by evaluating if recombinant MG53 can protect cardiomyocytes from neutrophil pyroptosis. This research could lead to new therapies for treating MI by reducing damage and promoting healing.