Macrophages and endothelial cells are essential components of the immune system, playing crucial roles in both innate and adaptive immune responses. These cells work in concert to maintain tissue homeostasis and respond to various inflammatory stimuli.
Macrophages are highly versatile immune cells that can adopt diverse phenotypes depending on the environmental cues. They are capable of phagocytosis, a process by which they engulf and degrade foreign particles and cellular debris. Macrophages also secrete a wide range of cytokines and chemokines, which can either promote or suppress inflammation.
Endothelial cells form a single layer lining the blood vessels. They are not merely passive conduits for blood flow but actively regulate vascular permeability, leukocyte recruitment, and coagulation. In response to inflammatory stimuli, endothelial cells undergo activation, leading to the expression of adhesion molecules and the release of chemokines. These changes facilitate the recruitment of immune cells, including macrophages, to the site of inflammation. Our project aims to elucidate the intricate interplay between metabolism, inflammation, and vascular function, with a particular focus on the role of ACLY. We will investigate the impact of ACLY on key metabolic pathways, including the electron transport chain (ETC), aspartate (Asp) synthesis, and nitric oxide (NO) production.
We will explore the relationship between ETC function, Asp synthesis, and NO production in macrophages and endothelial cells. By investigating the impact of ETC inhibition and Asp supplementation on NO levels and cellular function, we aim to uncover the underlying mechanisms linking these metabolic processes.
Furthermore, we will delve into the role of ACLY in cellular metabolism, focusing on its impact on Asp synthesis, lipid metabolism, and the regulation of inflammatory pathways. Utilizing genetic and pharmacological approaches to modulate ACLY activity, we will assess the consequences of these interventions on cellular phenotype and function.
To gain a deeper understanding of the regulatory mechanisms governing ACLY activity, we will identify and characterize the specific sites of post-translational modifications, such as itaconation and mesaconation, on the ACLY protein. By investigating the functional consequences of these modifications, we aim to elucidate how they impact ACLY's enzymatic activity and contribute to metabolic reprogramming and inflammatory responses.
Through a combination of cellular, biochemical, and animal model studies, we aim to gain a comprehensive understanding of the molecular mechanisms underlying ACLY-mediated metabolic regulation and its impact on inflammatory diseases. This knowledge may lead to the identification of novel therapeutic targets for the treatment of metabolic and inflammatory disorders.