Dr. Bhama Ramkhelawon nourishes 2 career goals during this award. An immediate goal to gain knowledge into the expression of the neuronal guidance cue, Netrin-1 in macrophage-elicited inflammation in Abdominal Aortic Aneurysms (AAAs) and a long-term career goal to become an independent investigator capable of leading research and ascribe a possible role Netrin-1 as a novel target for development of therapies to curb the burden of AAA. AAA is characterized by a focal dilation of the aortic diameter >30 mm located in the infrarenal section of the aorta. Roughly 25,000 AAA repairs are performed each year, and despite progress in primary preventive measures, AAA still accounts for > 13,000 deaths annually in the United States. Previous histological studies have revealed that transmural inflammation is manifested by the presence of monocytes/macrophages. This inflammation is associated with the proteolytic destruction of the aortic wall through the degradation of elastin and collagen by matrix metalloproteinases (MMPs). Numerous studies have profoundly explored the mechanisms related to the proteolitic disruption of the blood vessel. To better appreciate preventive therapeutic strategies, it is crucial to understand the broad spectrum of the physiopathology. Since M have important roles in both the induction and resolution of inflammation, I hypothesize that in addition to signals directing their recruitment to the focal site of aortic dilation, other cues are expressed to orient the advanced avenues related to the laminal destructive capacity of these cells. We have recently demonstrated a critical role for the neuronal guidance cue, Netrin-1 in promoting atherosclerosis by blocking their chemotaxis to exit signals such as CCL-19. Interestingly, my preliminary data show that the signals (IL-6 and TNfa) that direct M recruitment can also induce the expression of retention cues such as Netrin-1 in both mice and clinical human AAA specimens. We propose another innovative role for Netrin-1 in orchestrating AAA-induced inflammation in a non-lipidemic environment. In this grant, we will use novel mouse models of tissue-specific or conditional deletion of Netrin-1 to determine how this guidance cue alters the dynamic regulation of M into AAA sites, and direct their polarization. During the mentored research phase (K99), I will complete my ongoing research projects under Dr. Moore?s supervision at New York University Langone Medical Center. I will gain expertise in important aspects of M elicited inflammation in AAA in her laboratory. I will take the opportunity of all the facilities available at the research center to perform key experiments required to study AAA and hence specialize myself in this field. Dr. Moore will serve as Primary Mentor and oversee all aspects of my transition to become an Independent Researcher. Together we have elaborated a career development plan, which encompasses guidance in project progress, manuscript and grant writing, animal breeding, congress attendance and to perform training in the responsible conduct of research. In addition, a team of four Co-Mentors will provide me with complementary research guidance and help which will greatly enhance and diversify my research skill set. Together, the team of Mentors has pledged to guide me to extend my research interests and approaches, and to ensure a successful transition to an independent researcher. During the independent phase (R00) of this award, I will test the therapeutic avenues of silencing Netrin-1 by using nanoparticles encapsulating siRNA in the AAA mouse model. We expect to successfully dampen M inflammation associated with vessel wall destruction by targeting Netrin-1 in vivo. These experiments will provide key insights into promising surgery alternatives and will head toward translationally applied future drug development to treat AAA.
Abdominal aortic aneurysm (AAA), characterized by the enlargement of the aorta, affects approximately 5% of elderly men and there are currently no drug treatments for this deadly disease. AAA development is associated with inflammation caused by macrophages and other immune cells, which can promote thinning of the aorta wall and life-threatening rupture. Our proposal addresses the urgent need to better understand the mechanisms by which macrophages accumulate in AAA and contribute to disease progression.
|Dann, Rebecca; Hadi, Tarik; Montenont, Emilie et al. (2018) Platelet-Derived MRP-14 Induces Monocyte Activation in Patients With Symptomatic Peripheral Artery Disease. J Am Coll Cardiol 71:53-65|
|Hadi, Tarik; Boytard, Ludovic; Silvestro, Michele et al. (2018) Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells. Nat Commun 9:5022|
|Ouimet, Mireille; Ediriweera, Hasini; Afonso, Milessa Silva et al. (2017) microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis. Arterioscler Thromb Vasc Biol 37:1058-1067|
|Feinstein, Jordyn; Ramkhelawon, Bhama (2017) Netrins & Semaphorins: Novel regulators of the immune response. Biochim Biophys Acta Mol Basis Dis 1863:3183-3189|
|Herbin, Olivier; Regelmann, Adam G; Ramkhelawon, Bhama et al. (2016) Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1. Arterioscler Thromb Vasc Biol 36:1791-801|