Decoding the role of adipocyte-derived extracellular vesicle cargo in modulating distal inflammation - PROJECT SUMMARY/ABSTRACT Obesity is on the rise, with over half the United States population predicted to be obese within the next decade. Cardiovascular disease (CVD), the leading cause of death worldwide, is influenced by obesity and is an independent risk factor for CVD. While obesity leads to metabolic complications, such as metabolic syndrome that affects CVD, patients with obesity who are metabolically healthy are still at risk of developing CVD. Adipose tissue (AT) inflammation occurs in obesity, with evidence suggesting its role in CVD; however, the mechanism by which adipocytes influence vascular inflammation remains unclear. Therefore, this multidisciplinary proposal integrates advanced mouse models, bioengineering, and artificial intelligence (AI) to investigate how inflamed AT modulates vascular inflammation through adipocyte-derived extracellular vesicles (AdEVs). Preliminary data demonstrate that AdEVs constitute a significant interorgan signaling mechanism that accelerates atherosclerosis in recipient mice, particularly when harvested from obese but not lean donors. The central hypothesis is that AT inflammation alters the bioactive cargo of AdEVs delivered to the arterial wall, promoting vascular inflammation in tissue-resident cells while serving as a biomolecular predictor of CVD. To address this hypothesis, the proposal is divided into three aims. Aim 1 will compare the role of AdEVs harvested from inflamed and non-inflamed AT on inflammation and the progression of atherosclerosis. Aim 2 will utilize an integrated AI model to identify bioactive cargo in AdEVs from inflamed AT, engineer AdEVs to overexpress candidate cargo, and evaluate their effects on inflammation and atherosclerosis. Lastly, in Aim 3, disease-inducing cargo in AdEVs, in conjunction with machine learning (ML), will be utilized as a prognostic assay for CVD. The proposal will be conducted under the primary mentorship of Dr. Willa A. Hsueh, a leading physician-scientist in the field of immunometabolism. During the K99 mentored phase, the candidate will receive formal training in metabolic phenotyping, flow cytometry, vascular biology, immunology, AdEV bioengineering, AI/ML, and clinical translation for obesity and CVD. To achieve these goals, the candidate assembled a multidisciplinary mentorship team comprising experts in extracellular vesicle (EV) cargo loading, AI/ML, CVD clinical translation, and EV characterization. The multidisciplinary mentorship team and comprehensive training plan, along with the collaborative research environment and cutting-edge resources provided by The Ohio State University, position the candidate for a successful transition to an independent career during the R00 phase, with the long-term goal of establishing a research program on adipocyte interorgan signaling at the interface of bioengineering and medicine. This proposal has the potential to advance mechanistic understanding of CVD, enabling AdEV- based early-detection prognostic assays in the short term and informing novel therapeutics in the long term.
