Dissecting cell autonomous roles of beta3 integrin (ITGB3VascIn)

SCHEME: CORE

CALL: 2012

DOMAIN: BM - Translational Biomedical Research

FIRST NAME: Jochen

LAST NAME: Schneider

INDUSTRY PARTNERSHIP / PPP: No

INDUSTRY / PPP PARTNER:

HOST INSTITUTION: University of Luxembourg

KEYWORDS: beta3 integrin, inflammation, atherosclerosis, cre/lox technology, transcriptional regulation,macrophages, vascular smooth muscle cells, endothelial cells.

START: 2013-08-01

END: 2016-07-31

WEBSITE: https://www.uni.lu

Submitted Abstract

Cardiovascular diseases are a common cause of death yet much of the diseases cannot be explained by common risk factors. It is known that atherosclerotic plaques result from chronic inflammation in hyperlipidemic environment. The early stages of inflammatory atherosclerosis require an intense level of communication between the extracellular matrix (ECM) and intracellular signaling pathways that is mediated by integrins. These transmembrane heterodimeric adhesion proteins not only provide a structural connection between the ECM and the intracellular cytoskeleton, but also transduce a variety of signals to intracellular pathways, thereby influencing gene expression, protein synthesis, cell survival and differentiation. This proposal focuses on the ß3 integrin that forms two heterodimers: The aIIbß3 (glycoprotein IIb/IIIa) is exclusively expressed on platelets and megakaryocytes where it plays a critical role in platelet aggregation. The antagonism of aIIbß3 is beneficial when applied short term intravenously, but not during chronic oral treatment in humans with coronary disease. The a¿ß3 is expressed in various cell including vascular and immune cells. a¿ß3 plays a role in many diseases including inflammation, atherosclerosis and cancer, yet yielded mixed results when used as target for cancer and osteoporosis. Studies using mice with a germline ß3 integrin deficiency (ß3-/-) demonstrate different results from its pharmacological inhibition. Although ß3 integrin is dispensable for embryonic blood vessel development adult ß3-/- mice display enhanced tumor growth due to increased neo-angiogenic signaling in endothelial cells; myeloid-specific ß3 integrin deletion alone is also sufficient to enhance of tumor xenografts growth. ß3 integrin-inhibition or –absence in vascular smooth muscle cells (VSMC) seems to protect from neointimal formation in hyperglycemia, but ß3-/- mice are prone to atherosclerosis, systemic inflammation, and death on a high fat diet despite a severe bleeding predisposition. We have recently demonstrated that bone marrow-derived ß3 integrin is implicated in inflammation and atherosclerosis in vivo.We hypothesize that ß3 integrin-dependent signaling is cell-autonomous in general and anti-inflammatory in macrophages and that its exact function depends on the level and locus of its expression. In this proposal, cell-specific roles of ß3 integrin will be investigated. First, we aim to determine the impact of ß3 integrin in macrophages during their differentiation and under activation by inflammatory or nutritional stimuli by carrying out an integrated –omics analysis of mRNA and microRNA expression in hyperlipidemic ß3-/- and control mice. We will also test whether conditional ß3 integrin-deficiency in VSMCs or endothelial cells is sufficient to induce inflammatory atherosclerosis in vivo and determine the transcriptional profile of VSMC-cells from hyperlipidemic ß3-/- mice with special regards to hyperglycemia, inflammation and atherosclerosis. For the successful execution of this task we will characterize atherosclerotic lesion formation in vivo using Cre/Lox technology. We will finally harvest monocytes from subjects with a constitutively active allele of ß3 integrin followed by their differentiation to macrophages and subsequent characterization with regards to activation/inflammation. Using bioinformatics analyses we will try to generate an integrated mRNA-microRNA analysis of the regulation of the tissue-specific role of ß3 integrin. Understanding of the cell-specific function of ß3 integrin has implications for clinical use of non-selective ß3 integrin antagonists in cardiology and oncology. It may also illuminate novel molecular pathways for potential novel therapeutic targets in the treatment of inflammation and atherosclerosis.

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