Thursday, November 21, 2024
11/21/2024
Project Summary Sepsis is a leading cause of death in critical care units. Our long-term research goal is to understand the mechanisms of sepsis-induced multi-organ failure and to identify potential new therapeutic opportunities for this devastating clinical condition. Studies proposed in this application are designed to elucidate novel pathological functions of an immunometabolism regulator, growth hormone secretagogue receptor (GHS-R), in sepsis-induced cardiomyopathy using preclinical models. Recent studies revealed that macrophages localized in the heart are originated from different sources. With diversified functions ranging from reparative to inflammatory, the dynamics of changing these macrophage subsets forms a diagram of cardiac macrophage plasticity. Our ongoing investigation have obtained exciting preliminary evidence showing that GHS-R is a critical cellular switch that reprograms macrophage polarization to an inflammatory state. Furthermore, in a newly generated genetic mouse model, our data showed that ablation of myeloid linage macrophage-specific GHS-R attenuated systemic inflammation and improved heart function in response to endotoxemia challenge, which benefits were well associated with responses in metabolism, mitochondria, and autophagy in the heart. In this exploratory project, we will use in vitro and in vivo approaches to test the hypothesis that macrophage GHS-R reprograms cardiac macrophage plasticity and stimulates inflammation during sepsis (aim 1). We will further address whether macrophage GHS-R stimulates mitochondrial deficiencies, metabolic perturbations, and maladaptive autophagy in the heart during sepsis (aim 2). Together, this investigation is expected not only to advance the fundamental understanding of sepsis pathology but also to evaluate whether targeting GHS-R signal improves cardiac outcomes in sepsis, laying a scientific foundation for future development of novel therapies.
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