Role of miRNA-503 in diabetes-induced impairment of post-ischaemic neovascularisation in limb muscles
Lead Research Organisation:
University of Bristol
Department Name: Bristol Heart Institute
Abstract
A high number of diabetic patients develop critical restriction in the blood supply to the legs as a result of a major artery becoming blocked, resulting in the skeletal muscles being starved of oxygen. The condition is characterized by pain at rest and/or established sores that endanger the integrity and function of the legs. No effective drug is available to treat the condition, and reopening the blocked artery by surgery is often unfeasible or is unsuccessful. This means that the outcome for patients remains very poor, and the condition frequently leads to foot amputation. Even this course of action is associated with a high death rate, with 5 to 20% of patients dying early after surgery, and of those who survive, only 60% survive beyond 2 years. A second amputation is required in 30% of cases. A diabetic patient is more susceptible to progression of this condition because the growth and development of new blood vessels around and below a blocked artery is impaired. The research we propose aims to help the development of new blood vessels, which could delay progression of the condition and help save the patient?s life. This therapeutic strategy is now a possibility following the discovery of vascular growth factors that stimulate the growth of blood vessels. Scientists have also recently discovered that in diabetes the production of these vascular growth factors can be inhibited. We propose that this inhibition occurs due to a wrong signal from a newly discovered class of molecules called microRNAs, which regulate expression of our genes and thus control protein production. Each microRNA influences the production of several proteins, so a single microRNA could suffice to create major health problems. We know that diabetes can lead to the overproduction of microRNA-503, and that an excess of this leads to poor development of blood vessels. We propose to show that by inhibiting the action of microRNA-503 in vascular cells exposed to high glucose, mimicking the diabetic condition, the status of blood vessels is improved. This research could lead to the development of new therapeutic treatments for use in diabetes.
Technical Summary
When an ischaemic event occurs as a consequence of blockage of an artery by clots, the organism reacts by mounting a neovascularization response aiming at restoring blood perfusion. This reparative response is remarkably compromised by diabetes mellitus, due to the concomitant impairment of collateral remodelling and microvascular angiogenesis, which accounts for the poor clinical outcome of diabetic patients with ischaemic complications. Remedies to prevent and treat diabetic macro/microvascular complications are urgently needed.
MicroRNAs (miRNAs) are small noncoding RNAs, which mediate either translational arrest or degradation of targeted mRNA transcripts through imperfect base pairing with their 3?-UTR (untranslated regions). miRNAs are emerging as important regulators of gene expression. The pathogenic role of miRNAs has been described in cancer and cardiovascular diseases and miRNAs are currently at the forefront of biomedical research.
We hypothesize that dysregulation of miRNA expression in microvascular endothelial cells (ECs) is responsible for diabetes-induced defective angiogenesis. In particular, this project will focus on microRNA-503 (miR-503), which is over-expressed in diabetic ECs. Bioinformatics analyses predict that genes controlling cell cycle and angiogenesis are potential targets for miR-503. Moreover, pilot data showed that miR-503 over-expression impairs EC proliferation and in vitro angiogenesis, while miR-503 inhibition normalizes ECs proliferation in culture conditions which mimic diabetes.
This proposal aims to demonstrate that miR-503 is a key player in and a potential therapeutic target for diabetes-induced impairment of post-ischaemic reparative neovascularization. Specifically, we propose to employ and compare two strategies, e.g. systemic administration of single-stranded RNA oligonucleotides complementary to miR-503 ?antagomir- and a novel gene therapy approach based on the adenovirus-mediated local delivery of a 3?UTR decoy miR-503, to down-regulate miR-503 in diabetic and ischaemic murine muscles.
We additionally propose to validate the target genes that mediate the deleterious effects of miR-503 on ECs.
The ultimate goal of our research is to improve the understanding of the molecular changes underpinning the damaging action of hyperglycaemia on ECs and exploit the new knowledge to cure diabetes-induced ischaemic complications. To the best of our knowledge, this innovative project is the first to elucidate the importance of a miRNA in the context of diabetic endotheliopathy, thus posing the cornerstone for the exploitation of miRNAs as drugable targets for the treatment of vascular complications of diabetes.
MicroRNAs (miRNAs) are small noncoding RNAs, which mediate either translational arrest or degradation of targeted mRNA transcripts through imperfect base pairing with their 3?-UTR (untranslated regions). miRNAs are emerging as important regulators of gene expression. The pathogenic role of miRNAs has been described in cancer and cardiovascular diseases and miRNAs are currently at the forefront of biomedical research.
We hypothesize that dysregulation of miRNA expression in microvascular endothelial cells (ECs) is responsible for diabetes-induced defective angiogenesis. In particular, this project will focus on microRNA-503 (miR-503), which is over-expressed in diabetic ECs. Bioinformatics analyses predict that genes controlling cell cycle and angiogenesis are potential targets for miR-503. Moreover, pilot data showed that miR-503 over-expression impairs EC proliferation and in vitro angiogenesis, while miR-503 inhibition normalizes ECs proliferation in culture conditions which mimic diabetes.
This proposal aims to demonstrate that miR-503 is a key player in and a potential therapeutic target for diabetes-induced impairment of post-ischaemic reparative neovascularization. Specifically, we propose to employ and compare two strategies, e.g. systemic administration of single-stranded RNA oligonucleotides complementary to miR-503 ?antagomir- and a novel gene therapy approach based on the adenovirus-mediated local delivery of a 3?UTR decoy miR-503, to down-regulate miR-503 in diabetic and ischaemic murine muscles.
We additionally propose to validate the target genes that mediate the deleterious effects of miR-503 on ECs.
The ultimate goal of our research is to improve the understanding of the molecular changes underpinning the damaging action of hyperglycaemia on ECs and exploit the new knowledge to cure diabetes-induced ischaemic complications. To the best of our knowledge, this innovative project is the first to elucidate the importance of a miRNA in the context of diabetic endotheliopathy, thus posing the cornerstone for the exploitation of miRNAs as drugable targets for the treatment of vascular complications of diabetes.
