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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Macrophage heterogeneity in human and murine atherosclerosis: a therapeutic opportunity?

Awarded: NOK 2.4 mill.

Atherosclerosis is a slowly progressing inflammatory disease of the large arteries. During its chronic phase it is largely symptomless, but its acute clinical manifestation after atherosclerotic plaque rupture is responsible for severe cardiovascular events like stroke and myocardial infarction (MI), the most common causes of death in the Western society. Most alarmingly, CVD incidence is expected to increase over the next decade, mainly due to an aging population and the increasing prevalence of obesity. Current gold standard treatments, including lipid-lowering therapy such as statins, have been proven effective in preventing primary or recurrent CVD events in around 30% of all patients, but fail in the remaining 70% of cases. This prompts the design of more effective and supplementary therapies to enable improved individualized treatment, based on the newest insights into the critical mechanisms that drive atherosclerosis and plaque rupture. Macrophages is a cell type of the immune system that is central to the development of atherosclerosis and its complications. However, this is not a uniform cell type and there are different types of macrophages where some actually inhibit atherosclerosis. There is also uncertainty about whether the macrophages in the atherosclerotic lesions come from the bloodstream or whether they develop within the plaque. Before one can develop new therapies targeting these cells, these are crucial questions that need to be answered. In the present study our overall aim is to develop new treatment modalities in atherosclerotic disorders. So far we have obtained: (i) characterization of the role of NLRP3 inflammasome in the regulation of macrophage phenotype among others through its interaction with cholesterol crystals. (ii) Examine the role of genome stability and DNA glycosylase in the regulation macrophage function. (iii) We have in a recent placebo-controlled randomized trial showed the inhibition of the inflammatory cytokine improve the potential for myocardial recovery in patients with acute myocardial infarction and we are now studying if this effect involve modulation of macrophage function and phenotype. (iv) We have shown that serum from patients with myocardial infarction induce reprogramming of macrophages in vitro, illustrating a link between an inflammatory environment and macrophage phenotype in these patients. (iv) We ae planning studies that will characterize macrophage phenotype at the single cell level within the atherosclerotic lesion. Overall the project has obtained novel knowledge on the regulation of macrophage function in atherosclerosis and importantly, these studies have paved the way for further studies that will give additional and novel insight on the function of intraplaque macrophages, the most crucial and prominent cell in plaque progression. If successful our results could have several important implementations in relation to patient care. Our findings could have major impact not only on the treatment of patients with atherosclerosis, but also on other inflammatory disorders where macrophages are involved such infectious and autoimmune disorders and cancer.

Det henvises tiltidligere innsendt og godkjent prosjektrapport

Atherosclerosis-related cardiovascular diseases are the most important causes of death worldwide. As the most abundant immune cell type in the plaque, macrophages play crucial roles in the pathogenesis throughout the disease course. Due to their versatile and plastic phenotype in response to locally-produced factors, and depending on differences in their ontogeny (monocyte-derived vs. tissue-resident), macrophages are very heterogeneous and can exert pro- as well as anti-atherogenic activity. As context and origin, and hence macrophage heterogeneity, are disease stage-dependent, this considerably complicates the design of effective macrophage-targeting therapies. Here, a complimentary team of experts in plaque pathophysiology (EB), macrophage systems biology (JS), macrophage differentiation (MS) and cardiovascular medicine (PA) joins forces to tackle this major challenge. We will provide a detailed transcriptional, ontogenic, contextual and functional macrophage map for several disease stages. These unprecedented new insights into atherosclerotic macrophage heterogeneity in human and mouse will allow identification of gene programs and regulatory cues driving critical functions of plaque macrophages. Finally, through a network-guided systems medicine approach we will identify effective compounds based on known interactions between existing FDA approved drugs and our identified molecular networks, validate them in in vitro high throughput screenings, in vivo mouse models, ex vivo human plaques and provide proof-of-concept for clinical applications

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering