TargEting TREM-1 Receptor in Abdominal Aortic Aneurym – TETRAAA

Non-syndromic abdominal aortic aneurysm (AAA) is one of the leading causes of cardiovascular death particularly in men and women aged over 60 years and its incidence will increase during the next 30 years. The pathophysiology of AAA is complex, including elastin degradation, collagen remodeling, smooth muscle cell apoptosis and accumulation of inflammatory cells. There is a large body of human and experimental evidence showing that myeloid cells are involved in the formation of AAA and its life-threatening complications such as abdominal aortic rupture. Unfortunately, there is currently no specific treatment targeting the immuno-inflammatory response in human AAA, and no anti-inflammatory medical therapy shown to prevent excessive inflammatory remodelling of the abdominal aortic wall in patients with AAA.
We hypothesized that targeting a specific pathway involved in innate immunity, TREM-1, could be a promising therapeutic approach in the setting of AAA. TREM proteins, for Triggering Receptors Expressed on Myeloid cells, belong to a family of cell surface receptors expressed broadly on myeloid cells. TREM-1 acts as a major modulator of the innate immune response in septic and sterile inflammatory processes, regulating cytokine and chemokine production, cell trafficking and oxidative burst. To date, no study has addressed the role of TREM-1 in AAA. Recently, we have generated important data (unpublished) implicating the TREM-1 pathway in the pathophysiology of AAA. We aim to decipher the role of TREM-1 in the immuno-inflammatory response associated with AAA development and its life-threatening complications, and to test a new anti-inflammatory treatment based on TREM-1 inhibition, using the patented peptide inhibitor LR-12. We propose to address the role of TREM-1 expression/activity in the context of AAA, in vitro and in vivo, using both peptide inhibitor and genetically deleted cells/animals. We will also investigate the expression of TREM-1 in human tissue samples (Aortic tissues, blood leukocytes, plasma) and determine the relationship between TREM-1 expression and disease severity in patients with newly discovered AAA