TRAF6 Nanoimmunotherapy to Resolve Plaque Inflammation

Aim 1: To apply TRAF6i-HDL to prevent myocardial infarction-induced plaque aggravation in atherosclerotic mice. Our preliminary data show that TRAF6i-HDL nanobiologic immunotherapy dampens plaque inflammation by inhibiting monocyte migration. As plaque aggravation after myocardial infarction is driven by increased monocytosis, we hypothesize that TRAF6i-HDL will prevent the detrimental accumulation of inflammatory monocytes in the vessel wall. In myocardial infarction-induced atherosclerosis aggravation we will: 1A Study TRAF6i-HDL’s behavior by combined in vivo imaging and ex vivo immunological assays. 1B Investigate the underlying mechanisms by which TRAF6i-HDL prevents monocyte recruitment to plaque. 1CExecute a longitudinal and imaging-guided therapeutic study. Aim 2: To induce plaque regression in a nonhuman primate atherosclerosis model by TRAF6i-HDL. Our preliminary data show that TRAF6i-HDL displays a favorable biodistribution and safety profile in nonhuman primates. These observations, in conjunction with the mouse efficacy data, support this new immunotherapy’s further translation. In atherosclerotic nonhuman primates, we will: 2A Establish atherosclerotic plaque targeting by in vivo by positron emission tomography with magnetic resonance imaging (PET/MRI). 2B Investigate (atherosclerotic plaque) cellular specificity and immunomodulation by a combination of ex vivo techniques, including cell and RNA profiling. 2C Execute a full-blown regression study, using a combination of in vivo PET/MRI and ex vivo assays to evaluate efficacy.