Abdominal aorta aneurysm (AAA) is a common and lethal disease of adult Americans. Progressive AAA enlargement, over the course of months to years, leads to ever-increasing risk of sudden death from catastrophic rupture. Currently, rupture can only be prevented by timely surgical repair, which carries considerable morbidity and/or requirements for ongoing surveillance and periodic re-intervention. Prior attempts to identify specific mediator or pathway targets for medical intervention have not translated to effective clinical therapies. As the final common effector cell for aneurysmal degeneration, the activated infiltrative macrophage represents a novel and potentially highly effective target for suppression therapy. Surface expression of the folate receptor 2 (FR2) identifies a subset of activated macrophages found to promote various inflammatory conditions including atherosclerosis, arthritis and lupus. Although we have recently confirmed that FR2-positive macrophages are present in significant numbers in experimental aneurysms, the role these cells may play in AAA pathogenesis remains unknown. Based on available supporting information, it is our fundamental hypothesis that FR2-expressing macrophages modulate AAA initiation and progression. To pursue this hypothesis, we propose the following Specific Aims: 1. Quantify the location, timing, and functional correlates of FR2-expressing mural macrophages during AAA disease progression. 2. Define the functional consequences of FR2-expressing macrophage depletion in experimental AAA. Using established and complementary murine models of experimental AAA disease, we will employ immunohistochemical techniques to analyze the kinetics and functional status of FR2-positive macrophages during aneurysm development. We will analyze the functional significance of this subset of activated macrophages by pan- and selected macrophage depletion studies prior to and following initiation of experimental aneurysms. Confirming the pathogenetic significance of activated macrophages in AAA disease will facilitate the rapid translation of emerging anti-FR2 therapeutic strategies to effective non-surgical methods of aneurysm suppression.
Abdominal aortic aneurysm (AAA) is a common, morbid and frequently lethal disease. In the course of investigating how activated macrophages (as defined by folate receptor expression status) influence aneurysm progression, we hope to discover novel treatment strategies to limit progression of early AAA disease and, in the process, improve the health and well-being of millions of Americans.
|Xuan, Haojun; Xu, Baohui; Wang, Wei et al. (2017) Inhibition or deletion of angiotensin II type 1 receptor suppresses elastase-induced experimental abdominal aortic aneurysms. J Vasc Surg :|
|Fujimura, Naoki; Xiong, Jiang; Kettler, Ellen B et al. (2016) Metformin treatment status and abdominal aortic aneurysm disease progression. J Vasc Surg 64:46-54.e8|
|Fujimura, Naoki; Xu, Baohui; Dalman, Jackson et al. (2015) CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow. Sci Rep 5:11664|
|Rouer, M; Xu, B H; Xuan, H J et al. (2014) Rapamycin limits the growth of established experimental abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 47:493-500|
|Iida, Yasunori; Xu, Baohui; Xuan, Haojun et al. (2013) Peptide inhibitor of CXCL4-CCL5 heterodimer formation, MKEY, inhibits experimental aortic aneurysm initiation and progression. Arterioscler Thromb Vasc Biol 33:718-26|
|Iida, Yasunori; Xu, Baohui; Schultz, Geoffrey M et al. (2012) Efficacy and mechanism of angiotensin II receptor blocker treatment in experimental abdominal aortic aneurysms. PLoS One 7:e49642|