A key event in atherothrombotic vascular disease is the conversion of subclinical lesions to disrupted plaques that trigger acute lumenal thrombosis. The PI's laboratory is focused on cellular and molecular processes involved in a critical feature of dangerous plaques, the necrotic core, which contributes to inflammation, plaque disruption, and thrombosis. Necrotic cores arise from the apoptosis of advanced lesional macrophages coupled with defective phagocytic clearance, or """"""""efferocytosis,"""""""" of the apoptotic macrophages. The objective of this proposal is to elucidate mechanisms and consequences of defective efferocytosis in the two major populations of monocyte-derived cells in advanced atherosclerosis, macrophages and dendritic-like cells (DCs).
Aim 1 will explore the hypothesis that ADAM17-mediated cleavage of the efferocytosis receptor MerTK in advanced lesional macrophages contributes to defective efferocytosis and plaque necrosis.
Sub aim 1 A will explore in vitro and in vivo a new mechanism that leads to MerTK cleavage involving athero-relevant activators of a CD36/Toll-like receptor 2/NADPH oxidase/PKC4 pathway. One such activator is apolipoprotein(a), which associates with apoB to form lipoprotein(a) [Lp(a)] and is genetically associated with human CAD.
Sub aim 1 B will first investigate the temporal and quantitative relationships between lesional sol-Mer and plaque stage in murine and human atheromata and then will test causation by using a mouse with non-cleavable MerTK, which we predict will be protected from defective efferocytosis and plaque necrosis during lesion progression.
Aim 2 will explore the hypothesis that enrichment of atheromata with mature DCs (mDCs), which lose efferocytic capacity, contributes to defective efferocytosis and plaque necrosis. We have shown that areas of advanced plaques enriched in mDCs, like those enriched in macrophages, are located near areas of plaque necrosis and have even worse efferocytosis than macrophage-rich regions.
Sub aim 2 A will test the hypothesis that MerTK cleavage in DCs leads to defective efferocytosis by promoting DC maturation through inflammatory signaling.
Sub aim 2 B will first study the relationships among lesional DCs, efferocytosis, and plaque necrosis in human carotid atheromata and in plaques of fat-fed Ldlr-/- and Apoe-/- mice and will then test causation by assessing the effect of two genetic manipulations that suppress DC development or maturation-GM-CSF deficiency and DC MyD88 deficiency. Achieving the stated objective will provide critical information for understanding how necrotic cores form and may help in the design of new therapeutic strategies to prevent the clinical progression of atherosclerotic lesions.
Heart attacks, strokes, and sudden death due to heart disease-the leading cause of death in our society-are triggered by a sudden cutting off of the blood supply feeding these organs by platelet plugs, which form because the vessel in that area has a disease process called """"""""atherosclerosis"""""""" (""""""""hardening of the arteries""""""""). In view of the fact that only certain types of atherosclerotic lesions trigger platelet plugs, the overall objective of this proposal is to understand what processes influence the formation of these dangerous atherosclerotic lesions. In this context, we will study a fundamental protective process carried out by certain types of white blood cells, called """"""""efferocytosis,"""""""" which becomes defective in lesions destined to become dangerous and thus may offer new clues to prevent dangerous atherosclerotic lesions from forming.
|Kamaly, Nazila; Fredman, Gabrielle; Fojas, Jhalique Jane R et al. (2016) Targeted Interleukin-10 Nanotherapeutics Developed with a Microfluidic Chip Enhance Resolution of Inflammation in Advanced Atherosclerosis. ACS Nano 10:5280-92|
|Tabas, Ira (2016) Heart disease: Death-defying plaque cells. Nature 536:32-3|
|Tabas, Ira; Bornfeldt, Karin E (2016) Macrophage Phenotype and Function in Different Stages of Atherosclerosis. Circ Res 118:653-67|
|Cai, Bishuang; Thorp, Edward B; Doran, Amanda C et al. (2016) MerTK cleavage limits proresolving mediator biosynthesis and exacerbates tissue inflammation. Proc Natl Acad Sci U S A 113:6526-31|
|Subramanian, Manikandan; Thorp, Edward; Tabas, Ira (2015) Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling. Circ Res 116:e13-24|
|Hansson, G K; Libby, P; Tabas, I (2015) Inflammation and plaque vulnerability. J Intern Med 278:483-93|
|Tabas, Ira; GarcÃa-CardeÃ±a, Guillermo; Owens, Gary K (2015) Recent insights into the cellular biology of atherosclerosis. J Cell Biol 209:13-22|
|Williams, Kevin Jon; Tabas, Ira; Fisher, Edward A (2015) How an artery heals. Circ Res 117:909-13|
|Wang, Ying; Tabas, Ira (2014) Emerging roles of mitochondria ROS in atherosclerotic lesions: causation or association? J Atheroscler Thromb 21:381-90|
|Fredman, Gabrielle; Ozcan, Lale; Tabas, Ira (2014) Common therapeutic targets in cardiometabolic disease. Sci Transl Med 6:239ps5|
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