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Our group aims to understand the microRNA-mediated mechanisms fundamental to cardiac fibrosis and electrical remodelling that are associated with atrial fibrillation (a very common rhythm disorder). We are particularly interested in functional cross-talk between two major cell types in the heart – myocytes and fibroblasts.

Atrial fibroblasts
Human atrial fibroblasts under basal (left panel) & activated conditions (right panel); calcitonin receptor (green), filamin A (red), DAPI (blue), merge (yellow).

 Atrial fibrillation (AF) is an increasingly common arrhythmia that is associated with significant morbidity and a two-fold increase in mortality. Treatment of AF remains a challenge, as AF induces electrical and structural changes in the atrial myocardium. The mechanisms of  remodelling are not well understood; however, microRNAs (small non-coding RNAs) have emerged as important players in this process. We are very interested in uncovering patho- and physio-logical role of long non-coding RNAs and microRNAs in AF, with a particular focus on studying microRNA-mediated function of cardiac myocytes and fibroblasts.

1. Investigating microRNA-mediated mechanisms of cardiac fibrosis.

Human atrial fibroblasts isolated from control patients (left panel) & patients with atrial fibrillation (right panel); calcitonin receptor (green), filamin A (red), DAPI (blue), merge (yellow). Figure 1: Human atrial fibroblasts isolated from control patients  (left) & patients with atrial fibrillation (right); calcitonin receptor (green), filamin A (red), DAPI (blue), merge (yellow). 

Cardiac fribroblastsFigure 2: Migration assay in human cardiac fibroblasts at 0 hours (left panel) and at 24  hours (right panel).

Cardiac fibrosis is a prominent feature of cardiac pathology (including AF) and is a major unmet clinical problem. Through our research we are trying to understand the mechanisms causing and underlying atrial fibrogenesis so as to inform new tools to control excessive fibrosis. Our pilot results show that microRNA-31 is upregulated in atrial fibroblasts in AF. Thus, we aim to uncover fibroblasts-specific targets of microRNA-31 and investigate the impact of microRNA-31 on fibrogenesis in AF using isolated human and murine cardiac fibroblasts (Fig.1). We will employ functional assays to assess cell viability, migration (Fig.2), stress fibre formation and proliferation, collagen production (Fig.3) and calcification of extracellular matrix (Fig.4). As a part of this work, we are also interested in exploring the interplay between cardiac myocytes and fibroblasts using isolated cardiomyocytes.

CollagenFigure 3: Collagen production by human atrial fibroblasts in culture (assessed by scar-in-a-jar assay, curtesy of Dr Angela Lee)

ECM calcificationFigure 4: Calcification of extracellular matrix (in red, as indicated by arrows) in a culture of human atrial fibroblasts.

2. Regulation of ion channels by microRNAs.

It is well established that AF-induced electrical remodelling is associated with altered function and abundance of ion channel associated subunits. MicroRNA-31 is predicted to target a number of potassium and calcium ion channel subunits. Some of these subunits (eg L-type calcium channel α1C) are downregulated in AF and play a critical role in the progression of the arrhythmia. As the same microRNA can frequently share microRNA recognition elements with a number of functionally related genes (ie ion channels), we are planning to investigate a complex interaction of microRNA-31 with ion channel subunits in human atrial myocytes.

This study will initially employ an RNA deep-sequencing approach to interrogate changes in the transcriptome secondary to microRNA-31 overexpression and inhibition; this will be further validated by qRT-PCR, reporter assay, and loss-/gain-of-function experiments in the relevant cell type.

3. Uncovering the mechanisms causing upregulation of microRNA-31 in atrial fibrillation.

To date, therapeutic strategies to manipulate microRNAs expression and function with antagomirs or microRNA mimics are hampered by the lack of organ-specific delivery and by a short-lasting effect. Thus, we are dedicated to investigating the mechanisms that cause changes in microRNA levels in relevant cells (ie cardiac fibroblasts and myocytes). In this work we aim to explore cell-specific mechanisms leading to up-regulation of microRNA-31 and of other microRNAs of interest that have been flagged up in AF. Ultimately, this work may inform the development of safer therapeutic strategies to inhibit microRNA-31 in a cell-specific manner. In this work, we are planning to employ immunoprecipitation of cross-linked chromatin (ChIP), an electrophoretic mobility shift assay (EMSA), qRT-PCR, reporter assay, and loss- and gain-of-function experiments.

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