HHU StartMedizinische FakultätIRTG 1902PeoplePrincipal InvestigatorsProject 12 - Grandoch: Inhibitor of differentiation (Id)-3 Regulation of Hyaluronic Acid expression in Adipose Tissue

Project 12

Inhibitor of differentiation 3 (ID 3) regulation of hyaluronic acid synthesis in adipose tissue

Principal Investigator HHU

Prof. Dr. med. Maria Grandoch

Dept. of Pharmacology and Clinical Pharmacology

Background:

Obesity is a well-known risk factor for cardiovascular diseases and thereby represents a potential target for the prevention of atherosclerosis and myocardial infarction.

Inhibitor of differentiation (Id)-3 is a broadly expressed protein acting as a dominant-negative inhibitor of basic helix-loop-helix (bHLH) protein function via binding to E-proteins. In turn, the bHLH-family of transcription factors is known to be crucially involved in cell growth and differentiation.

Previous work:

The Grandoch group has investigated intensively inflammatory mechanisms in the arterial wall with a specific focus on the interrelation between immune cell functions and extracellular matrix such as hyaluronan (hyaluronic acid, HA) and proteoglycans. HA, an unbranched polysaccharide consisting of alternating units of N-acetylglucosamine and glucuronic acid, has also been reported to be an important modulator of metabolic dysfunction in obesity and Type 2 diabetes mellitus (T2DM) (Kang, Lantier et al. 2013). Furthermore, the importance of HA in AT inflammation was shown.

Aims:

The working hypothesis assumes an important role of Id3 in the transcriptional regulation of HA synthase isoenzymes and functionally associated matrix components (such as HA-binding proteins and HA-degrading hyaluronidases) as well as matrix receptors (such as CD44) in adipose tissue (AT), which in turn regulate AT inflammation and atherosclerosis.

Since perivascular fat (PVAT) has been reported to directly affect vascular wall inflammation and subsequently atherosclerotic lesion development (reviewed in Brown, Zhou et al. 2014), peri-organ AT such as PVAT and pericardial fat will also be analyzed.

Specifically, the following aims will be addressed in this project: (i) to elucidate the role of Id3 in the regulation of HAS expression in AT. (ii) to analyze functional effects of HA accumulation on different immune cell composition and immunomodulatory functions in AT depots. (iii)  to unravel the role of Id3 in regulating the perivascular HA expression and function during atherosclerosis in ApoE/Id3-deficient mice. (iv) to analyze human plasma samples of a large patient cohort phenotyped for obesity endpoints, metabolic syndrome and CVD.

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