Cardiovascular disease (CVD) continues to be the leading cause of death in the developed world and is a considerable economic burden. A principle causes of CVD is atherosclerosis, an immunologically complex inflammatory condition within the intima of arterial vessel walls. Current clinical treatments for atherosclerosis focus on lowering serum levels of low density lipoprotein (LDL) using therapeutics such as statins, administration of antithrombotic drugs, and surgical intervention. For patients that experience a major adverse cardiovascular event (MACE), the probability of experiencing a second MACE is 70-80%. While acknowledging the seminal and ongoing work of previous investigators in the field, we also accept that with diseases as complex as CVD, a single curative strategy is unlikely to be found. A key weaknesses within current therapeutic strategies is cell-mediated inflammation, and we intend to modulate specific dendritic cell (DC) and monocyte subsets that function as systemic and local sources of inflammation during the progression of atherosclerosis. Such immunotherapies that reduce vascular inflammation by targeting specific immune cell populations may show enhanced therapeutic efficacy when used in combination with strategies that decrease blood LDL levels. We hypothesize that rationally designed pathogen-mimicking nanomaterials that target specific cellular inflammatory components of atherosclerosis can synergize with statin-and vaccination-based therapies for improved therapeutic treatment of CVD. Our objective is therefore to develop adjuvanting immunotherapies that may enhance current CVD therapies by eliciting both a systemic and local atheroprotective anti-inflammatory immunoregulatory profile. Focus will be placed on developing two separate nanomaterial formulations: 1) an adjuvant formulation to elicit a systemic cytokine profile from splenic DCs that supports the generation of atheroprotective regulatory T cells and 2) a formulation to promote the local efflux of atherogenic monocytes that accumulate within atherosclerotic lesions. Our nanomaterials consist of custom block copolymers engineered to self-assemble into virus-like nanostructures for morphology-based targeting of specific inflammatory cell populations. These materials will be tagged with a near infrared fluorescence (NIRF) imaging agent for in vivo real time imaging of targeted cells. If successful, my project will initiate a new, diverse area of therapeutic intervention for the treatment of atherosclerosis that focuses on the strategic elicitation of atheroprotective immunoregulatory profiles to enhance combination therapy. Three key innovations will be presented: 1) the rational design of targeted immunomodulatory nanomaterial formulations that address the inflammatory component of atherosclerosis both locally and systemically, 2) the testing and validation of adjuvanting immunotherapies to enhance current statin-based treatments of CVD and 3) NIRF tracking of critical inflammatory cell populations during the progression of atherosclerosis.
|Effective start/end date||9/30/15 → 6/30/20|
- National Heart, Lung, and Blood Institute (1DP2HL132390-01)
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