Stephen Malin

Background: Atherosclerosis is a chronic inflammatory disease and the leading cause of cardiovascular morbidity and mortality worldwide. While lowering plasma apoB-containing lipoproteins has significantly reduced cardiovascular risk, many patients continue to experience adverse events despite optimal lipid-lowering therapy. A critical knowledge gap in our understanding is the earliest cellular and molecular events that initiate plaque development. Traditional mouse models like Apoe-/- and Ldlr-/- have provided essential insights but are limited in their ability to capture disease onset, as they are born dyslipidemic. Recent discoveries by PhD student Xueming Zhang suggests that the way cholesterol is elevated not just the level itself critically shapes the early immune response, vascular integrity, and plaque trajectory. Aim: This project aims to define the initiating immune and vascular events that lead to atherosclerosis. Specifically, we seek to (1) identify the earliest immune cells that respond to atherogenic lipoproteins, (2) determine how different genetic drivers of hypercholesterolemia shape immune activation and endothelial dysfunction, and (3) investigate whether early immune responses converge toward a common inflammatory profile across models. Work Plan: We use two novel mouse models that allow precise induction of dyslipidemia: an inducible ApoE knockout (cKO) and a PCSK9 D374Y knock-in, both crossed with mCherry-ApoB reporter mice. These models allow real-time visualization and tracking of APOB-lipoprotein uptake in vascular and immune tissues. Using single-cell RNA sequencing, spatial transcriptomics (Xenium), and histological analysis, Xueming will map early cellular and transcriptional changes in the aorta. She will investigate endothelial integrity via permeability assays and single-cell profiling of CD45+CD31+ endothelial cells. Immune modulation studies, including B and T cell depletion and CSF1R blockade, will assess causal roles of specific cell types in early lesion formation. Significance: Understanding the earliest events in atherosclerosis initiation could transform how we approach cardiovascular prevention. By identifying the first immune cells and pathways that respond to dyslipidemia, Xueming aims to uncover novel targets for early intervention before irreversible vascular damage occurs.

Background. It would be of considerable benefit if we could understand how atherosclerotic plaques are initially formed. This would allow us to target the sub-clinical disease rather than acting after an event such as heart attack or stroke has occurred. Over the last decades, the pathology of atherosclerosis has begun to be understood as a systemic disorder that involves an inflammatory response to retained lipoproteins in susceptible sites of the vasculature and incorporates other risk factors such as clonal haematopoiesis and liver dysfunction. Discovering mechanisms underpinning these disparate organ pathologies and discerning which are critical and targetable in atherosclerotic cardiovascular disease is the motivation behind our research. Aims. We hypothesize that If atherosclerosis stems from the immune response to APOB-lipoprotein retention, then characterizing and targeting inflammation could prevent disease. We aim is to discover how plaques are formed, to develop and test a new therapy that targets plaque inflammation, and to determine to what extent the pathology of atherosclerosis can be reversed. The contribution of clonal haematopoiesis and fatty liver to early plaque growth will also be determined. Workplan. We have created unique mouse strains that allow for 1) the acute induction of atherogenic dyslipidemia, 2) the tracking of disease-causing lipoproteins in vivo, and 3) a reversal of high blood cholesterol levels. We combine this with human samples. Through this approach, we are creating a multi-organ map of tissue responses following induction of atherosclerosis. Following our initial discoveries, we are creating a new inhibitor of plaque-specific inflammation within the Swedish Drug Discovery and development platform maintained at SciLifeLab. Significance. We aim for a complete description of how the first atherosclerosis plaques grow, so that we can create therapies that aim at preventing plaque formation. We provide evidence that multiple pathways exist at the earliest stages of atherosclerosis, but common inflammatory mechanisms are present as plaque grow. Our therapeutic under development will target this inflammation. We will integrate how clonal haematopoiesis and fatty liver can affect the formation and composition of new plaques. Together we aim for a comprehensive understanding of atherosclerosis with the goal of preventing future clinical events.

Background. It would be of considerable benefit if we could understand how atherosclerotic plaques are initially formed. This would allow us to target the sub-clinical disease rather than acting after an event such as heart attack or stroke has occurred. Over the last decades, the pathology of atherosclerosis has begun to be understood as a systemic disorder that involves an inflammatory response to retained lipoproteins in susceptible sites of the vasculature and incorporates other risk factors such as clonal haematopoiesis and liver dysfunction. Discovering mechanisms underpinning these disparate organ pathologies and discerning which are critical and targetable in atherosclerotic cardiovascular disease is the motivation behind our research. Aims. We hypothesize that If atherosclerosis stems from the immune response to APOB-lipoprotein retention, then characterizing and targeting inflammation could prevent disease. We aim is to discover how plaques are formed, to develop and test a new therapy that targets plaque inflammation, and to determine to what extent the pathology of atherosclerosis can be reversed. The contribution of clonal haematopoiesis and fatty liver to early plaque growth will also be determined. Workplan. We have created unique mouse strains that allow for 1) the acute induction of atherogenic dyslipidemia, 2) the tracking of disease-causing lipoproteins in vivo, and 3) a reversal of high blood cholesterol levels. We combine this with human samples. Through this approach, we are creating a multi-organ map of tissue responses following induction of atherosclerosis. Following our initial discoveries, we are creating a new inhibitor of plaque-specific inflammation within the Swedish Drug Discovery and development platform maintained at SciLifeLab. Significance. We aim for a complete description of how the first atherosclerosis plaques grow, so that we can create therapies that aim at preventing plaque formation. We provide evidence that multiple pathways exist at the earliest stages of atherosclerosis, but common inflammatory mechanisms are present as plaque grow. Our therapeutic under development will target this inflammation. We will integrate how clonal haematopoiesis and fatty liver can affect the formation and composition of new plaques. Together we aim for a comprehensive understanding of atherosclerosis with the goal of preventing future clinical events.

An excess of lipoproteins can result in their storage in inappropriate organs. This provokes the immune system and results in tissue damage and diseases, such as atherosclerosis and fatty liver. We want to discover how these diseases are initiated and how germinal centre formation can influence plaque formation in the aorta. We will look across multiple tissues to see how tissue identity imprints macrophage responses to dyslipidemia and how this can lead to inflammatory cross-talk between tissues. A special case will be the bone marrow, where lipoproteins are thought to interact with clonal haematopoiesis, perhaps through modifying niche macrophages. We outline how signalling through the Interleukin 7 receptor permits bone marrow B cells to take up lipoproteins to actually aid their growth, including in leukemia.To achieve this, we have created the first experimental system that allows a window into lipoprotein uptake and for monitoring the ‘Dyslipidemic insult’. We provide extensive preliminary results and outline our novel mouse models. Our approach uses multiple next-generation sequencing approaches together with classical pathology and immunology techniques.Our approach aims at disease prevention rather than cure, with an emphasis on atherosclerosis and fatty liver disease. We harness the power of immunotherapy to see if modifying immune responses can alleviate disease.

Heart attacks and strokes are the most common consequences of atherosclerosis, a chronic inflammatory disease affecting arteries. Atherosclerosis develops when cholesterol accumulates as plaque in the vessel wall, where it  triggers an inflammatory response. Recent clinical studies have shown that, in addition to lowering blood cholesterol levels, certain drugs that block inflammation can also help prevent atherosclerosis. However, these drugs have broad anti-inflammatory effects and are also associated with increased susceptibility to infections. Therefore, there is a great need to identify more specific drug targets that lack these side effects. B lymphocytes, a subset of white blood cells that are important to the immune response and the production of antibodies, are highly promising in this regard. The B cells in cardiovascular disease consortium (BCVD) will characterize these cells and their functions in human atherosclerosis and test the mechanisms by which they  can help to hinder disease in preclinical models. Based on these insights, the BCVD will develop novel innovative interventions that can ultimately be used as more precise anti-inflammatory therapies for the prevention of atherosclerotic cardiovascular disease.