Characterization of immune determinants of aggravated atherosclerosis in patients with T2DM, obesity, and optimal LDL-C reduction

• Applicant: Hauke Horstmann
• Subject Area: Cardiology, Angiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537103624

I have outlined four scientific aims to describe the pathophysiology of atherosclerosis in patients with Type-2 Diabetes Mellitus (T2DM). In this grant proposal, I hypothesize that cardiometabolic disorders such as obesity and T2DM drive plaque-specific immune dysregulation that contributes to aggravated atherosclerosis and increased rates of adverse CV outcomes among patients with T2DM. In addition, I will assess how sexual dimorphism of these alterations impairs plaque regression and stabilization in women. The following experimental aims will identify the immune determinants of aggravated atherosclerosis in patients with T2D, obesity and optimal LDL-C reduction: 1. To build a comprehensive scRNAseq atlas of human atherosclerotic plaques. 2. To dissect the single-cell immune variations and key genes associated with pathological features of impaired vascular repair in T2DM. 3. To identify regulatory gene networks (GRNs) causally implicated in impaired vascular repair in male and female patients with T2D. 4. To build associations between the leukocyte repertoire and clinical signs of complicated and generalized atherosclerosis. Taken together, the proposed project will contribute to a better understanding of atherosclerosis in patients with T2DM. Additionally, this study will, for the first time, shed light on the differences in the pathology of atherosclerosis between men and women, and will extrapolate why women are more susceptible to severe CVD complications. These insights will pave the way for new anti-inflammatory therapies within the framework of personalized precision medicine, particularly benefiting women who are inadequately treated by conventional approaches.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Chiara Giannarelli