DESCRIPTION (provided by applicant): 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 o lowering serum levels of low density lipoprotein (LDL) using therapeutics such as statins, administration of antithrombotic drugs, and surgical intervention. For patients who 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 a single curative strategy is unlikely to be found for diseases as complex as CVD. A critical weakness of current therapeutic strategies is cell- mediated inflammation. We intend to address this weakness by modulating specific dendritic cell (DC) and monocyte subsets that function as systemic and local sources of inflammation during the progression of atherosclerosis. Such immunotherapies, which 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, targeting 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 will enhance current CVD therapies by eliciting a systemic and local atheroprotective anti-inflammatory immunoregulatory profile. We will focus on developing two separate nanomaterial formulations: 1) an adjuvant formulation to elicit a systemic cytokine profile from splenic DCs to support 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 wil initiate a new 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 statin-based treatments of CVD and 3) NIRF tracking of monocyte and DC subsets during the progression of atherosclerosis.

PUBLIC HEALTH RELEVANCE: Atherosclerosis is an immunologically complex inflammatory condition within the intima of arterial vessels and a primary cause of cardiovascular disease (CVD). The goal of this proposal is to develop combination immunotherapies that address both the local and systemic sources of atherosclerotic inflammation. We will achieve this by targeting, imaging and modulating specific atheroprotective and atherogenic immune cell subsets with separate rationally designed pathogen-mimicking nanocarriers.