Title of project

Glycerol-3-Phosphate Phosphatase: A Novel Regulator in Metabolic Health and its Potential to Mitigate Cardiovascular Disease Progression

Abstract

Cardiovascular disease (CVD) remains the leading cause of death worldwide, especially in obese and type 2 diabetes (T2D) patients, where conditions that impair insulin sensitivity argument CVDs. Despite treatment T2D still suffers from CVD events like stroke or myocardial infarction, indicating a need for new strategies to address the metabolic-vascular link driving these diseases. This PhD project focuses on glycerol-3-phosphate phosphatase (G3PP), a newly identified metabolic regulator of glucose and lipid metabolism that thereby influencing insulin sensitivity, oxidative stress, and lipid handling. Yet its role in diabetic cardiometabolic disease mechanisms including skeletal muscle insulin sensitivity and the interplay with vascular endothelial dysfunction that promote CVDs remain unknown.

We hypothesise that elevated G3PP activity in skeletal muscles and/or vascular endothelium protects against nutrient excess induced insulin resistance and endothelial dysfunction and thereby mitigate T2D accelerated CVDs.

To test the hypothesis we will use different approaches: (i) in vitro studies of in endothelial and muscle cells to identify how G3PP is regulated by simulated T2D conditions and how modulation of G3PP influences cell metabolism, mitochondrial function, generation of reactive oxygen species (ROS) and inflammation under the aerobic nutrient stress, (ii) functional studies in mice, where the effect of muscle- and endothelium-specific G3PP knockout on disease progression of T2D and CVD, (iii) testing an innovative therapeutic nanoparticle delivery of G3PP mRNA to selectively boost G3PP in activated endothelial cells, and (iv) translational profiling of G3PP in human muscle biopsies and arterial tissue from Odense Artery Biobank and population-based cohorts (VIVA, DANCAVAS), linking clinical phenotype such as insulin sensitivity and cardiorespiratory fitness, and disease progression to G3PP tissue levels. Feasibility is ensured by preliminary data including AAV-mediated G3PP overexpression lowering body weight independent of calorie intake and elevated G3PP expression in human AAA tissues. Models, biobank access, and technical platforms are established, and ethical approvals are in place. By integrating basic, therapeutic, and translational approaches, this project will clarify G3PP’s role in metabolic-cardiovascular diseases and evaluate its potential as a novel therapeutic target.