Issues of critical importance
- The importance of the lipid research initiative and its impact to public health: Developing new targeted therapies for lipid-elicited illnesses—major complications of type 2 diabetes and metabolic syndrome—has a global impact to human health, as the prevalence of both conditions are on a sharp rise in many parts of the world. To achieve our goal, we address the critical issues below, based on our evidence-based assumption that L5 and V5 are the atherogenic lipoproteins.
- Chemical composition and structural orientation of LDL and VLDL subfractions: The cytotoxic L5 and V5 result from altered receptor affinity (secondary to abnormal protein assembly) and contact of its toxic components (mostly lipids) with the cells. Lipids orchestrate physiological responses by acting as signaling molecules or as membrane components that modulate protein function. Therefore, we shall focus on analyzing the lipid constituents and examining their interactions with cell membrane apparatus and intracellular compartments. The information will be provided to other core labs and organ system research teams to assist their studies.
- Impact on cardiovascular health: As cardiovascular complication are the major cause of morbidity and mortality of diabetes, and L5 is significnatly increased in STEMI. In additon to the clinical study using MD-CT imaging described above, we will address the following important issues. L5 and epigenetics: L5 from STEMI patients has the ability to disrupt FGF2-Akt signaling by inducing methylation of the FGF2 promoter. On this basis, we will examine whether L5 epigenetically modulate endothelial function through methylation of multiple genes. L5 and arrhythmias: Ventricular arrhythmias are the primary etiology of sudden cardiac death associated with acute MI. On the basis our preliminary ion-channel studies, we will delineate the mechanisms underlying L5-mediated arrhythmias. L5 and L1, as well as their active lipid components to be defined by the Chemistry Core Lab, will be used for patch clamp analysis in cultivated CMs. To examine L5’s effects on spatial and temporal heterogeneities and cell-to-cell coupling throughout the organ, an optical mapping technique will be used with the employment of voltage sensitive dyes and calcium indicators for recording action potentials and calcium transients. L5 and cardiorenal syndrome: CKD, even at early stages, is an important etiology of cardiac dysfunction. In our CKD cohorts, both L5 and H5 are increased in their plasma. We have established animal models to examine the mechanisms and statistical models to analyze the correlation between plasma L5/H5 levels and clinical manifestations of systolic and diastolic cardiac dysfunction through kidney-heart interactions.