Alcohol and Monocyte Signaling Administrative Supplement

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT of the supplement This administrative supplement is in response to NOSI for Research Supplements to Promote Re-entry, Re- integration and Re-training in Health-Related Research Careers (NOT-OD-23-170). Specifically, the purpose of this re-training supplement is to support Marcelle de Carvalho Ribeiro, PhD to return to and advance her research career after a gap due to family reasons. This is a critical phase in Dr. Ribeiro’s career to gain new research skills, techniques and concepts that will be instrumental for her future plans to become an independent research investigator. Experiments proposed in this administrative supplement are fully complementary to those described in the parent grant without creating any overlap. In this proposal, we will dissect the role of NLRP3 in alcohol- induced trained immunity. To our knowledge, this a novel research question that is fully aligned with the scope of the parent RO1. NLRP3, as the mechanistic focus of this supplement, is also highly relevant to the previous experiences of Dr. Ribeiro on NLRP3 activation and biology. The specific aims of this supplement are: Aim#1: To evaluate the role of NLRP3 in trained immunity in chronic inflammation and immunosuppression in alcoholic hepatitis by a) assessing NLRP3 inflammasome activation in trained immunity induced by alcohol; b) Determining whether NLRP3 is required for alcohol-induced trained immunity in mice, using genetic knockout models and pharmacological approaches. Aim#2: To target immunometabolic pathways in alcohol trained macrophages to determine their role in NLRP3 activation by a) elucidating the effects of itaconate on NLRP3 activation and the phenotypic signature associated with trained immunity in alcohol-exposed macrophages and in mouse model of alcohol induced trained immunity; b) investigating the impact of glutamine metabolism on NLRP3 activation and the phenotypic characteristics of trained immunity in alcohol-exposed macrophages and a mouse model of alcohol-induced trained immunity. In Aim 1, the candidate will learn to study trained immunity in a mouse-model induced by alcohol and new techniques of phospho- and acetyl-proteomics and related bioinformatic assessment. In Aim 2, Dr. Ribiero will acquire new knowledge about immunometabolism in alcohol induced trained immunity and learn liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. These will be complemented by a rigorous mentoring plan. The scientific scope of this administrative supplement is fully in line with the scientific goals of the parent grant and promises to gain new knowledge on the role of NLRP3 inflammasome in alcohol-induced trained immunity and immunometabolic reprogramming.