Role of Stat3/Sosc3 SIgnalling in Modulating the Pathogenesis of Atherosclerosis and vascular Aneurysm – SIMPA

SOCS proteins have emerged as key physiological regulators of both innate and adaptive immunity and control the development of various immuno-inflammatory diseases. SOCS3 is expressed in atherosclerotic lesions and the current paradigm suggests an athero-protective role through inhibition of STAT3 signalling and the suppression of pro-inflammatory responses. However, its direct role in the control of inflammatory vascular disease is still unexplored. We recently observed that specific SOCS3 deletion in T cells led to a significant IL17-dependent reduction in the development of atherosclerosis and a marked dampening of lesion inflammation (Taleb S, J Exp Med 2009). Interestingly, patients with HIES have been identified as having defective STAT3 signalling with low production of IL17, and recent observational studies reported the abnormal occurrence of vascular inflammation in this setting despite the absence of classical cardiovascular risk factors. Thus, the study of SOCS3/STAT3 signalling may have important implications for the understanding of the pathophysiological mechanisms of vascular inflammation in humans and may identify novel targets for disease modulation.
Our objectives are to address in detail the role of cell type-specific STAT3/SOCS3 expression in the modulation of vascular inflammation, and more particularly, in the context of atherosclerosis and abdominal aortic aneurysm (AAA) (Wang Y, J Clin Invest 2010).

General aims of the proposal:
1. Role of T cell specific STAT3/SOCS3 expression in atherosclerosis and AAA.
2. Role of macrophage specific STAT3/SOCS3 expression on M1/M2 phenotype and its impact on atherosclerosis and AAA.
3. Role of VSMC-specific STAT3/SOCS3 expression in the regulation of cell survival, proliferation and activation, and its impact on atherosclerosis, fibrous cap formation and AAA.
4. Relevance of STAT3 pathway to cardiovascular complications in humans.

Originality:
The research programme is based on our original hypothesis that cell-specific modulation of STAT3/SOCS3 signalling controls both atherosclerosis and vascular aneurysm development. The hypothesis is supported by original and intriguing data from our laboratory (Taleb, J Exp Med 2009) and will be tested both in our experimental models (Taleb, J Exp Med 2009; Wang, J Clin Invest 2010) and in humans (Hyper-IgE syndrome and patients with acute myocardial infarction).

Novelty:
These are the first studies to address in detail and in a cell-specific mechanistic way the role of STAT3/SOCS3 pathway in the regulation of vascular inflammation. We also have the great opportunity to address the role of STAT3 both in mice and humans with defective STAT3 signalling.

Expected results:
We believe that this study will shed new light on the pathogenesis of atherosclerosis and vascular aneurysms and will identify new targets for disease modulation.
Success criteria for this programme includes : 1) increased awareness and pathophysiological understanding of the cardiovascular risk associated with defective STAT3 signalling, 2) identification of new pathophysiological targets for disease modulation, 3) publications of the results in high impact peer-reviewed journals, and 4) filing of patent application(s).