VascmiR (Vascular remodelling and miRNA therapeutics)

VascmiR (Vascular remodelling and miRNA therapeutics)

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The central hypothesis of VascmiR is that microRNAs (miRs) fundamentally control pathological remodelling of the vasculature. The complexity of vascular bed heterogeneity and subsequent response to injury, the potential importance of miRNA in vascular pathology and the paucity in knowledge relating to many facets of miRNA function in the vessel wall including target pathways, mechanistic features of miRNA-mediated cell:cell communication mediated by miRNA export and uptake etc. provides an excellent opportunity for groundbreaking basic and translational research in the field. VascmiR will envelop these concepts in a broad, cutting edge portfolio of high risk and in-depth studies that encompass fundamental research, mouse genetics to create novel models and miR intervention studies in small and large animal models coupled with targeted miRNA therapeutics. Collective synergy by assessing pulmonary as well as peripheral venous and arterial pathological vascular remodelling models of disease under a single funding mechanism will afford substantial scientific advancement. VascmiR will go beyond current state-of-the-art and create new knowledge of miRNA in vascular pathologies, all of which have important unmet clinical need. VascmiR will streamline fundamental new opportunities for targeted miRNA-based therapeutics to improve human health in cardiovascular setting. I envisage that a co-ordinated, multifaceted and integrative programme in these vascular pathology settings to better understand the mechanistic role of miRNA in vascular remodelling will have a major impact on the field, leading to early translation of advanced miRNA therapeutics in the vasculature.

 

Links to our recent reviews on non-coding RNA in the vascular system:

http://onlinelibrary.wiley.com/doi/10.1002/cpt.355/full

http://www.sciencedirect.com/science/article/pii/S1471489216300078

http://journals.lww.com/co-lipidology/Abstract/2016/10000/Role_of_noncoding_RNA_in_vascular_remodelling.3.aspx

Non-Coding RNA Biology and Function in Vascular Remodelling

With only 1.2% of the human genome coding for proteins, focus is now shifting towards the possible functional roles for the other 98.8% of the genome with little to no protein-coding capacity. While their function is still debated, ncRNA transcripts compose approximately 70 to 80% of our genome and include thousands of operationally significant RNAs implied in all manner of biological processes. As novel ncRNA categories emerge, the microRNA and long non-coding RNA gene families have sparked great interest within the research community as they have been found to be critical during development and often dysregulated in disease.

Ubiquitously expressed in all human cells, miRNAs regulate mRNA translation by binding to their complementary base-pair sequences on the 3’UTR of mRNA transcripts, eventually suppressing protein synthesis. Due to their prevalence, they have been put forward as possible biomarkers and treatment targets for a variety of pathologies. This is of particular significance in the within the vasculature, with multiple miRNAs identified in endothelial and smooth muscle cells, regulating their behaviour and ultimately affecting the process of vascular remodelling.

Previously published work by our group as described a novel miR-143-3p-mediated cell-to-cell communication pathway between pulmonary vascular cells which contributes to altered cell migration in PAH. Inhibition of this pathway, by miR-143-3p knock-down, effectively blocked experimental PAH in mice exposed to chronic hypoxia (Deng et al, 2015; add link https://www.ncbi.nlm.nih.gov/pubmed/26311719 ). Outside of PAH, we have elucidated some of the key regulatory roles of various miRNA in other vascular remodelling scenarios such as in-stent restenosis (McDonald et al, 2015 https://www.ncbi.nlm.nih.gov/pubmed/26022821 ) and vein graft remodelling (McDonald et al, 2013 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675389/ ).       

In addition to miRNAs, lncRNAs have also gained widespread attention as a novel layer of biological regulation. Defined as RNA transcripts longer than 200 nucleotides, they do not code for any proteins but instead function as direct and indirect gene regulators able to carry out both gene inhibition and activation, among others. At a post-transcriptional level, a growing number of studies have also implicated lncRNAs at various stages of control, regulating mRNA stability, enhancing mRNA translation and acting as miRNA sponges. Recent publications also point towards the existence of widespread cross-regulatory interactions between noncoding RNAs classes, adding a further functional role for lncRNAs.

While examples of miRNA-mediated vascular remodelling are vast, they are not the only ncRNAs implicated throughout the pathological process.  It is now becoming clear that abnormal lncRNAs levels are linked to aberrant cell migration, proliferation, and function.  For example, recent data from our lab identified the lncRNA SMILR as a driver of vascular smooth muscle cell proliferation, often linked to atherosclerosis and other vascular remodelling diseases (Ballantyne et al, 2016 https://www.ncbi.nlm.nih.gov/pubmed/27052414 ).

Ultimately, as new compelling evidence showing that ncRNAs play an active role during pathological vascular remodelling continues to emerge so will new therapeutic strategies. VASCMIR is working at the interface of miRNA and lncRNA function in vascular remodelling – we focus on vein grafting, in stent restenosis and pulmonary arterial hypertension.

More information on vein grafting: https://en.wikipedia.org/wiki/Vascular_bypass

More information on coronary stenting: https://en.wikipedia.org/wiki/Coronary_stent

Pulmonary arterial hypertension (PAH) is a rare, severe and progressive disease with an estimated prevalence of ~15 cases per million characterised by vasoconstriction and remodelling of the pulmonary vasculature, resulting in right heart failure and eventual death. PAH is currently defined by a mean pulmonary arterial pressure (mPAP) is greater than 25 mmHg at rest. The pathogenesis of PAH includes sustained vasoconstriction and abnormal progressive fixed vascular remodelling. This is accompanied by endothelial dysfunction and activation of fibroblasts, smooth muscle cells and inflammatory cells (Figure 1). PAH may be initiated by loss of endothelial integrity and dysfunction resulting in exposure of underlying cells to circulating factors, leading to proliferation and apoptosis resistance in the adventitia, smooth muscle media and the formation of a neointima. Clinically, PAH is subdivided into several groups, including: idiopathic (IPAH), heritable (HPAH) and PAH associated with other diseases (APAH). Female gender is considered a risk factor per se for all PAH subtypes, since it is more frequent in women than men. Most cases of HPAH (>70%), and some IPAH cases (approximately 20%), are caused by mutations in the bone morphogenetic protein type II receptor gene (BMPR2) that impairs BMP signaling pathway via Smad1, Smad5 and Smad8, and leads to an increased activity of TGF-β pathway via non-canonical and canonical Smad2/3 signaling. However, since PAH is incompletely penetrant, BMPR2 mutations alone may not be sufficient to cause disease, so that a ‘second hit’ including other genetic and/or environmental factors may be required for the clinical manifestation of PAH. Triggers for disease may include inflammation, hypoxia and shear stress or vascular injury.

Figure 1 Schematic showing the different cells types involved in pulmonary vascular remodeling In PAH, the pulmonary artery undergoes changes to all three layers of the vessel, including adventitial thickening with fibroblast proliferation and inflammatory cells recruitment (macrophages, dendritic cells, mast cells, B cells, and T cells), proliferation, resistance to apoptosis and hypertrophy of pulmonary artery smooth muscle and endothelial cells result in medial and intimal thickening of the pulmonary vessel wall.

More information on PAH -  http://www.mayoclinic.org/diseases-conditions/pulmonary-hypertension/symptoms-causes/dxc-20197481

 

Projects in VASMIR

We aim to study the following:

1. The role of miR-143/145 and its associated lncRNA in vascular remodelling

Here, we are interested in improving our knowledge of how the interplay between the lncRNA and miRNA control vSMC biology and pathology, using in vitro and in vivo models. Researchers: Francesca Vacante, Judith Sluimer, Paddy Hadoke, Laura Denby, Fatma Kok, Andrew Baker

2. To understand the function of non-coding RNA in endothelial-to-mesenchyme transition (EndMT).

Here, we use an in vitro model system to recreate the in vivo phenotype (Figure 2). We are interesting in using new technologies to improve our understanding of how the non-coding landscape can control EndMT. Researchers: Joe Monteiro, Lin Deng, Axelle Caudrillier, Fatma Kok, Andrew Baker

3. To understand the function of lncRNA in endothelial cell function.

Here, we use RNAseq and other informatics approaches to indentify functions of lncRNA and miRNA in endothelial cell biology relating to vascular injury and repair.  Researchers: Julie Rodor, Helen Spencer, Fatma Kok, Andrew Baker

Figure 2: Model system for assessing EndMT in vitro.