Cardiovascular disease (CVD) is recognized as a leading cause of death worldwide, resulting in 20 million deaths each year . At the core of most CVDs is atherosclerosis, a chronic vascular inflammatory driven by both the innate and adaptive immunity processes. Low-density lipoproteins (LDLs), transporters of cholesterol, initiate the inflammation. Oxidized LDLs (oxLDLs) activate endothelial cells to promote secretion of chemokines. These draw the immune cells, including innate immunity peripheral monocytes, dendritic cells (DCs) and adaptive immunity T cells, into the intima. There they react with ApoB100 to initiate inflammation. Currently, antigen-specific immunotherapy to establish immune system tolerance is showing promising results [2-4]. Nevertheless, there are still challenging problems to be addressed: 1) Inflammatory immune cells within lesions must be targeted more specifically and effectively. 2) Host immunity cannot be compromised and deleterious side effects must be minimized for long- term host survival. The solution: The development of a nanostructure-enhanced targeting system that efficiently targets DCs in atherosclerotic lesions, regulating inflammatory immune cells specifically to minimize systemic side effects. AIM 1: Construct a DC-targeting peptide-based polymersome system to specifically and efficiently target plaque-resident DC populations. I have shown PEG-bl-PPS polymersomes’ superior specificity to DCs in atherosclerotic lesions. Additional modifications to link a DC-targeting peptide with non-activating fashion, P-D2, to polymersomes will offer better specificity and efficiency. AIM 2: Effectively modulate DCs by utilizing antigen ApoB-100 peptide P210 and 1,25(OH)2D3 to induce Treg cells and inhibit T effector responses to ApoB-100. To induce antigen specific tolerance to attenuate inflammation, polymersomes will deliver ApoB-100 and vitamin D3 agonist to DCs, which will induce ApoB-100 specific Tregs.
|Effective start/end date||7/1/17 → 6/30/19|
- American Heart Association (17POST33670713)
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