Molecular Drivers of Atherosclerosis in Diabetes

PROJECT SUMMARY The mortality rate among individuals with type 1 diabetes (T1D) remains significantly elevated due to cardiovascular complications, highlighting a critical need for innovative research focused on understanding and mitigating cardiovascular disease (CVD) in this population. Unlike type 2 diabetes (T2D), T1D presents a unique trajectory of CVD progression, with persistently elevated risk factors that are not fully explained by conventional cardiovascular risk assessments. Emerging evidence suggests that T1D's autoimmune nature may contribute to CVD through inflammatory pathways, yet this area remains underexplored. This grant proposal aims to elucidate the molecular and cellular mechanisms underlying the increased CVD risk in T1D compared to T2D and non-diabetic individuals. Leveraging an interdisciplinary team with a strong track record of collaboration and expertise in T1D, CVD genetics, single-cell technologies, and disease modeling, we propose a comprehensive study that builds on preliminary findings indicating distinct genetic and molecular drivers of atherosclerosis in diabetic patients. In aim 1 of this proposal, we will delineate the differential immune profiles in T1D, T2D, and non-diabetic individuals by analyzing serum proteins and immune cell characteristics. In aim 2, we will identify cellular and molecular differences in atherosclerotic plaques across these groups, focusing on variations in plaque composition, cell-cell communication, and regulatory networks. And in aim 3, we will validate the key regulators of atherosclerosis-relevant phenotypic changes in diabetic states through functional experiments. The outcomes of this study are expected to provide unprecedented insights into the immune-mediated mechanisms of CVD in T1D, leading to the identification of novel molecular targets for therapeutic intervention. To maximize the impact of our findings, we will create a user-friendly website to share our comprehensive -omics datasets with the broader research community, fostering further discovery and collaboration.