Cardiac glycosphingolipids and their role for cardiomyocyte function

Background: The molecular mechanisms that drive the progression of heart failure are poorly understood due to the complex and multifactorial nature of the disease. Previous studies have shown that the diseased heart is associated with intracellular metabolic abnormalities, including rearrangements of cardiac lipid composition, which may play a causative role in disease progression. Emerging evidence indicates a key role for glycosphingolipids in maintenance of a healthy heart.

Aim: In this proposal, we aim to define and clarify the importance of glycosphingolipids for cardiomyocyte function.

Work plan: We will use a translational approach to elucidate the role and underlying mechanisms through which glycosphingolipids modify cardiomyocyte function. In aim 1, we will use human materials to identify clinical variables and genetic variants that modify the cardiac glycosphingolipid profile. In Aim 2, we will use cultured cardiomyocytes to define the molecular mechanisms by which glycosphingolipids affect cardiomyocyte contractility.

In Aim 3, we will use cultured human cardiomyocytes and mouse models to evaluate whether modulation of glycosphingolipid levels in cardiomyocytes is a potential therapeutic strategy.

Significance: We anticipate that modulation of glycosphingolipids may represent a promising therapeutic approach, and our long-term goal is to translate our results back to humans by developing novel treatment strategies.