Erythrocyte-derived non-coding RNAs and vascular complications in diabetes

Bakgrund:

Type 2 diabetes (T2D) constitutes an important risk factor for cardiovascular disease. Endothelial dysfunction is a key factor behind macro- and micro-vascular complications in diabetes. We recently demonstrated a new function of red blood cells (RBCs) that RBCs act as novel disease mediator for the development of endothelial dysfunction in T2D.

Circulating ncRNAs levels are associated with vascular dysfunction in T2D. RBCs, constituting ~45% of the blood volume, contain diverse and abundant ncRNA, of which the expression and function are unknown in T2D. We hypothesize that altered expression and function of RBC-derived ncRNAs dysregulate key vascular signaling pathways resulting in endothelial dysfunction in diabetes.

Målsättning: 1) To identify ncRNAs in RBCs and their target genes in vasculature. 2) To characterize the functional role of ncRNAs in RBCs. 3) To elucidate how RBC-derived ncRNAs dysregulate vascular target genes. 4) To explore efficacy of RBC ncRNA modulation for the treatment. Arbetsplan:

RBCs are isolated from patients, rats and mice with T2D as well as corresponding healthy controls. ncRNAs are identified via RNA deep sequencing and qPCR. Key ncRNAs are also validated in extracellular vesicles released from RBCs. Vascular target genes dysregulated by RBC ncRNAs are profiled by NanoString and functional analysis.

The functional role of RBC-derived ncRNAs in endothelial dysfunction is examined with ex vivo RBC-healthy vessel segment/endothelial cell co-incubation and in vivo rodent RBC transfusion models. The dysregulation of RBC ncRNAs and key signaling transmitted between RBC and vasculature are determined using pharmacological and genetic tools targeting RBC ncRNAs and vascular genes.

Finally, modulation of RBC ncRNAs levels in vitro followed by RBC transfusion back to the same diabetic animals provides therapeutic potential for the treatment of endothelial dysfunction in T2D. Betydelse:

This project will identify new disease mechanism and treatment targets of vascular complications in T2D, and may thereby provide new therapeutic strategies for patients with diabetes.