Projects

This page lists the projects realised by our group.

Deciphering the role of RNA editing in zebrafish development

RNA editing is a process of post-transcriptional alteration of transcripts. As such, RNA editing contradicts central biology dogma of transition of information from gene (DNA), through transcript (RNA), to protein, as due to RNA editing the primary sequence of particular transcripts can be altered, resulting in altered protein sequences that does not necessarily correspond to the sequence of the gene.

RNA editing was described for the first time in the 1980s, so it isn’t a new discovery. Since then, RNA editing was characterised in numerous organisms and it has been reported to function in an array of biological processes. RNA editing affects physiology and behaviour of animals from insect to human, by altering both, the sequence and structure of nervous system components. The most interesting roles of RNA editing described so far are: determination of castes in ants, adaptation to cold in octopuses. Most of all, RNA editing is crucial for correct development of the brain and nervous system of animals.
In addition, RNA editing was proposed to protect human (and other primates) genome against the expansions of Alu elements. Alu elements are repetitive sequences that are very abundant in our genome. What is more, Alu elements are believed to destabilise the genome by copying themselves across the chromosomes through the process of retrotransposition (transposition involving RNA). ADAR, one of the enzymes responsible for RNA editing, was found to bind Alu transcripts, edit their sequence and therefore block subsequent transposition to new genomic locations. 

Besides extensive research and multiple proposed functions in various organisms, there is still no consensus for the purpose of RNA editing. We would like to study the role of RNA editing in developing embryo. Obviously, we cannot conduct this study in human, therefore we will use zebrafish (Danio rerio), as it is easy to maintain in the lab and gives access to very early developmental stages, while being relatively close to human (human share most of the genes with zebrafish). 

We’ll to characterise RNA editing in zebrafish, by sequencing parental genomes and the transcriptomes of developing embryos at several stages of development. As RNA editing is expected to create difference between transcripts and genome sequence, subsequent comparison of transcripts with genome sequence will allow genome-wide detection of RNA editing. This will allow us not only to create most comprehensive RNA editing catalogue of developing embryo, but also to identify the changes in RNA editing throughout embryo development.

Summary of obtained results

During this project, I’ve developed novel bioinformatics methods to map RNA editing sites in the transcripts using data generated from next-generation sequencing (NGS) experiments. This method allowed us to identify transcripts edited by ADAR proteins. Many serve as key regulators of early development, responsible, for instance, for the normal definition of the anterior-posterior axis of the body. Interestingly, when we disturbed this protein in embryos, we obtained larvae with heavily affected body axis. Finally, we have created zebrafish mutant lacking Adar protein, that will allow further studies of this process. A detailed investigation into the role of RNA editing in early vertebrate development will contribute to a better understanding of gene expression regulation during embryonic growth. 

I have been working on my research at the Laboratory of Zebrafish Developmental Genomics, lead by Dr Cecilia Winata at the International Institute of Molecular and Cell Biology in Warsaw. Apart from giving me access to cutting-edge technologies in molecular biology and promoting my personal growth, the POLONEZ programme has provided me with great opportunity to cooperate with researchers from all around the globe.

Key achievements

  • Animal handling training according to Polish laws (PolLASA)
  • Identification of previously unannotated rRNA clusters in zebrafish genome
  • Protocol optimisation for rRNA depletion for Eukaryotes and Bacteria using TEX
  • Established protocols for direct RNA sequencing using Oxford Nanopore sequencer
  • Establishment of protocolos for Adar knock-down and overexpression
  • RNA-seq of control, Adar knock-down and overexpression at 2 hpf (maternal) and 5.3 hpf (zygotic transcripts)
  • Identification of Adar targets in maternal and zygotic transcrtipts
  • Establishment of novel transgenic line (Adar KO)
  • Rescue experiments with human Adar ortholog and enzymatically inactive Adar
  • Phenotypic characterisation of Adar knock-down and knock-out lines
  • Development of novel tool for accurate RNA editing detection from RNA-seq (REDiscover)
  • Adaptation of REDiscover to detect multiple types of RNA modifications from RNA-seq

 

Project dissemination

Communications

  • Polish Illumina User Symposium, Poznań, Poland (11-12 Oct 2018) - invited lecture: “NGS tips & tricks”
  • European Epitranscriptomics Network meeting, Malaga, Spain (8-11 Oct 2018) - invited seminar: “Toward new methods for detection of RNA modifications using second and third generation sequencing”
  • #NGSchool2018 Summer School, Lublin, Poland (16-23 Sep 2018) - lecture: “MinION explained: principles, running & hacking it.”
  • 6th Central European Summer Course on Mycology, Szeged, Hungary (6-11 Jul 2018) – invited lecture: “Evolutionary innovations as a result of inter-species genome hybridisation.”
  • Genome Bioinformatics for Health, Großbothen, Germany (25-27 Jun 2018) – invited seminar: “NGS in Biomedicine: Are we ready for SMRT revolution?”
  • EMBL Conference: The Epitranscriptome, Heidelberg, Germany (25-27 Apr 2018) – poster: “RNA editing in embryonic development
  • 10th European Zebrafish Meeting 2017, Budapest, Hungary (3-7 Jul 2017) - poster: “Deciphering the role of RNA editing in vertebrate development”

Organisation of scientific events


Detailed information about the project

  • Project Duration: 01.01.2017-31.12.2018
  • Project number: 2015/19/P/NZ2/03655
  • Project title: “Deciphering the role of RNA editing in zebrafish development”
  • Project leader: Dr. Leszek Piotr Pryszcz
  • Source of funding: National Science Centre, Poland, POLONEZ
  • Budget: 921 064 PLN

 

This project has received funding in National Science Centre (Poland) Polonez-1 framework from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 665778.

Genomic profiling of zebrafish cardiac pacemaker cells

Detailed information about the project:
Project Duration: 01.09.2016-31.08.2018
Project number: 2015/19/P/NZ3/03613
Project title: “Genomic profiling of zebrafish cardiac pacemaker cells”
Project leader: Dr. Rashid Minhas
Source of funding: National Science Centre, Poland, POLONEZ
Budget: 921 064 PLN

Objective:

The cardiac conduction system (CCS) is an essential component of the heart. It is responsible for initiating and coordinating the electrical signals that cause rhythmic and synchronized contractions of the atria and ventricles. The CCS is evolutionarily conserved in the building plan of the heart, and it indicates that the cellular and molecular mechanisms that drive the formation of pacemaker tissues are almost similar among vertebrates. Components of the mammalian conduction system are morphologically well defined in mouse and human. However, the molecular mechanisms by which the CCS cells are set apart and specified from a common cardiomyocyte cell are not thoroughly understood to date.

The study of heart development is often hindered by the fact that the organ is absolutely required for survival in most organisms. In zebrafish (Danio rerio), a functioning cardiac system develops at 24 hpf, but is not essential for the survival of early embryos and thus zebrafish poses a unique advantage in this respect. Furthermore, zebrafish is highly amenable to genetic modifications, and has a short generation time, which allows convenient and rapid analysis of gene function and modelling of human genetic defects. Using zebrafish as an in vivo system, we would like to carry out transcriptomic profiling of these highly specialized cells, coupled with profiling of chromatin state, to indicate important regulatory regions implicated in CCS development. Expression profiling of these cells would help us identify key genes expressed specifically in pacemaker cells. While profiling of chromatin state will allow us to identify regulatory regions active specifically in the CCS. A combination of these profiles will thus become the basis for the assembly of a gene regulatory network underlying the development of the CCS.

Abstract
Congenital heart disease (CHD) is one of the most common type of birth defect, accounting for one-third of all major congenital anomalies. Among CHDs, one of the major group of cardiac patients have disorders of the cardiac conduction system (CCS) and its associated tissues, causing life threatening severe arrhythmias. CCS cells are present in two different locations in the heart: the sinoatrial node (SAN) and the atrioventricular node (AVN). The zebrafish is a well-established vertebrate model for cardiovascular studies. To understand the molecular mechanism underlying the development of the pacemakers cells, we use a zebrafish transgenic line with GFP expression in CCS cells. Zebrafish hearts were isolated at 72 hpf and GFP positive cells were sorted using FACS. High quality RNA was extracted and subjected to RNA-Seq to profile their transcriptome.  This study will shed light on novel CCS-specific molecular markers and highlight the active regulatory regions responsible for the specialized function of these cells. This knowledge will further improve the understanding of sinus node dysfunction and facilitate the development of novel therapies.

Posters at the international conferences:

(1) Genomic interaction responsible for pacemaker-specific GFP expression in zebrafish heart

Gene-regulatory systems in development Parador de Carmona, Spain 


(2) Genomic profiling of zebrafish cardiac pacemaker cells
Fishmed 2018 (International Institute of Molecular and Cell Biology (IIMCB), Warsaw, Poland


(3) Deciphering the zebrafish cardiac pacemaker development with RNA-Seq
18th International Zebrafish Conference University of Medicine Wisconsin, Madison, USA

Activities towards the general public:
(1) Be Heathy as a Fish workshop, 10-14 July 2018
Be Heathy as a Fish workshops as a part of the International Biology School for young, talented students from Ukraine. The objective of the educational program is to teach children basic knowledge about the life of fish and about possibilities of their use in studies on certain human diseases. During the workshops children watch the Healthy as a Fish movie, perform simple biological experiments, take part in a discussion about the genetic similarities of humans and fish, and receive a copy of the Be Healthy as a Fish book.
Since December 2012, our Institute has been implementing the FishMed project, supported by the European Union. Within this project, IIMCB has opened one of the largest facilities to grow and breed lines of zebrafish as research models in this part of Europe. We are pioneering research, in which we use zebrafish as an attractive alternative to studies in which higher vertebrates are used as the model organisms. Using this species as an example, children have the opportunity to learn how important fish are for us, as well as discover what we as a society can gain through the work of biologists in the future.
(2) The Biologists Night, 12 January 2018
The event was held on January 12, 2018 at the Faculty of Biology University of Warsaw, and at the Center of Biological-Chemical Sciences University of Warsaw. The program included lectures, laboratories, workshops and exhibitions. About 600 participants attended the event. It was a great opportunity to present zebrafish to broader audience.

Publications:

Minhas, R., Paterek, A., Łapiński, M., Bazała, M., Korzh, V., Winata, C.L. 2018. A novel conserved enhancer at zebrafish zic3 and zic6 loci drives neural expression. Developmental Dynamics. Manuscript Submitted.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 665778 (National Science Centre (NCN), Poland).

 

Approaching integrative genomics to identify molecular drivers of congenital heart disease

Detailed information about the project:

Project Duration: 01.03.2019-28.02.2022
Project number: 2018/29/B/NZ2/01010
Project title: “Approaching integrative genomics to identify molecular drivers of congenital heart disease ”
Project leader: Michal Pawlak, PhD; Investigators: Costantino Parisi, MSc
Source of funding: National Science Centre, Poland, OPUS
Budget: 1 880 050 PLN

Project decription:

Congenital heart defect (CHD) is the most common birth defects and a major cause of heart diseases. In Europe, CHD occurs in about 8 of 1000 live births. Among CHD cases, 10% result in fetal death or termination of pregnancy. In a survey of CHD cases between 2001 and 2005 in the European population, close to 90% of patients with CHD can survive, in many cases through adulthood, however, need continual treatment and monitoring. Notably, thanks to medical advances over the past 75 years, many of fatal childhood heart problems have changed to chronic medical conditions. Social burdens including education, employment and insurability, which increase the societal costs of adult CHD, are now being recognized for adults living with CHD (Seckeler M. et al. 2016). Further research studies are therefore needed to hamper the morbidity and mortality of CHD patients in Poland and EU. As prognosed by Centre for Economics and Business Research (UK, cebr.com) the cost of cardiovascular disease (CVD), which includes coronary heart disease, heart failure, CHD and strokes, will increase in Europe to around 102.1 billion euros annually by 2020. According to European Heart Network (Townnsend et al. 2016), of the total cost of CVD in the EU, around 54% is due to health care costs, 24% due to productivity losses and 22% due to the informal care of people with CVD. Therefore, research on different aspects of CVD are constantly supported by the European Commission's framework programmes (FPs). Research on this is estimated to be over € 163 million (ec.europa.eu) under Horizon2020.

Figure 1. The outline of the project.

The increasing survival rate of CHD patients, necessities better diagnosis and understanding of pathophysiology to improve preventive strategies and develop new treatments. CHD is caused by abnormalities in the process of heart development. Genetic determinants of CHD are largely components of molecular pathways regulating cardiogenesis. A comprehensive knowledge of heart development is therefore an essential step in understanding the mechanism of CHD. The lack of understanding on the regulatory network driving heart development, often hinders the diagnosis of CHD and development of novel therapeutic strategies.

Therefore, the main scientific goals of the project are to identify novel functional transcripts and changes in gene regulatory networks of heart development to understand molecular mechanism of CHD and help in designing novel diagnostic and therapeutic strategies. The projects engages multiple approaches including in vivo biological models, modified organisms, bioinformatics algorithms and clinical data. Our preliminary data in zebrafish allowed to establish the regulatory networks responsible for heart development. By using modified individuals of zebrafish we also characterized genes which become affected in zebrafish with malformed hearts. In current project we plan to integrate this data with results obtained by applying genome-wide association studies (GWAS) and whole-exome sequencing (WES) in patients with CHD. This kind of approach called integrative genomics, allows to maximize the output of clinical data and data obtained from model organisms. The expected output of the study is to identify novel genes and their regulatory regions associated with CHD and further test their function in heart development of zebrafish. The long-term output of the project is to help identifying novel biomarkers of CHD enabling early non-invasive diagnosis of cardiovascular anomalies and lower risk treatment. The project aims to provide novel diagnostic and therapeutic strategies which will decrease the cost related to CHD healthcare. The knowledge resulting from this study is therefore envisaged to significantly contribute to the advancement of the understanding of CHD biology and the applicability of the gained knowledge in clinics including accurate prenatal genetic tests. Further eventual commercialization processes, depending on the output of the project, including patent application, will ensure the involvement of the research partners.

Finally, the project will ensure development of highly-qualified researchers familiar with cutting-edge research technologies such as next-generation sequencing, live in vivo imaging, bioinformatics and personalized medicine. The engagement of national and international partners both from academia and enterprise will prepare young researchers to work in innovative R&D projects thus contributing to development of this field of economy both in Poland and Europe.

 

Elucidating the gene regulatory network of zebrafish heart development using genomics

Detailed information about the project:


Project number: 2014/13/B/NZ2/03863
Project title: “Elucidating the gene regulatory network of zebrafish heart development using genomics”
Project leader: Cecilia Winata, PhD, Investigators: Katarzyna Nieścierowicz PhD, Michal Pawlak PhD
Source of funding: National Science Centre, Poland, OPUS
Budget: 955 500 PLN

Project decription:

The heart muscle or myocardium makes up most of the heart tissues and is mainly responsible for its function. Upon completion of gastrulation, heart muscle cells or cardiomyocytes (CMs) are specified from a pool of mesodermal progenitors at the anterior portion of the embryonic lateral plate mesoderm (Stainier et al. 1993; Stainier and Fishman 1994; Kelly et al. 2014). As development proceeds, heart progenitors migrate to the midline and form a tube structure known as the primitive heart tube (Stainier et al. 1993). This structure subsequently expands through cell division and addition of more cells originating from the progenitor pool (Kelly et al. 2014; Knight and Yelon 2016). Looping of the heart tube then gives rise to distinct chambers of the heart, namely, the atria and ventricles. Although the vertebrate heart can have between two to four chambers, the step-wise morphogenesis of progenitors specification, migration, tube formation, and looping, are highly conserved between species (Jensen et al. 2013).

CMs are specified early during embryogenesis and undergo various cellular processes of proliferation, migration, and differentiation which collectively give rise to a fully formed and functioning heart. Crucial to regulating each step of heart morphogenesis are cardiac transcription factors (TFs) which include Nkx2.5, Gata5, Tbx5, and Hand2 (Clark et al. 2006; Nemer 2008). These TFs are known to play a role in establishing the CM identity of mesodermal progenitor cells, regulating the formation and looping of the heart tube, as well as the specification of atrial and ventricular CMs. Specification and differentiation of the cardiac progenitors are regulated by the interactions between several key TFs - Nkx2.5, Gata5, Tbx5, and Hand2. Members of the GATA family of TFs, Gata4, Gata5, and Gata6, are responsible for the earliest step of cardiac progenitor specification (Jiang and Evans 1996; Jiang et al. 1998; Reiter et al. 1999; Singh et al. 2010; Lou et al. 2011; Turbendian et al. 2013). Gata factors activate the expression of nkx2.5, another early marker of CMs (Chen and Fishman 1996; Lien et al. 1999). Although not essential for specification of CMs, Nkx2.5 plays an important role in initiating the expression of many cardiac genes in mouse and regulating the numbers of atrial and ventricular progenitors (Searcy et al. 1998; Targoff et al. 2008). Similarly, another TF expressed in CM progenitors, Hand2, is responsible for proliferation of ventricular progenitors (Yelon et al. 2000). Hand2 also induces and maintains the expression of Tbx5, which is necessary for atrial specification in the mouse (Liberatore et al. 2000; Bruneau et al. 2001).

Despite the established knowledge of key TFs regulating the various steps of heart morphogenesis, considerable challenges to understand the mechanism of heart development still exist as little is known about their molecular mechanism and downstream targets. Transcription is modulated by cis regulatory elements that are located in non-coding regions of the genome, which serve as binding sites for TFs (Farnham 2009; Shlyueva et al. 2014). Although these regulatory elements equally contribute to the molecular mechanism controlling development, there is still a lack of systematic resources and understanding of their roles in heart development. Moreover, cardiac TFs have been shown to interact with chromatin-modifying factors, and the loss of function of several histone-modifying enzymes has been found to affect various aspects of cardiac development (Miller et al. 2008; Nimura et al. 2009; Lou et al. 2011; Takeuchi et al. 2011). Therefore, the chromatin landscape is another factor which needs to be considered when studying the process of heart development. Importantly, the lack of understanding how heart development proceeds makes it difficult to determine the cause of different forms of congenital heart disease (CHD). Here we seek to understand the nature of interaction between TFs and epigenomic landscape, how this landscape changes throughout development, and how it affects heart development.

The study of heart development poses a unique challenge due to the importance of the organ for survival. The disruption of factors regulating the early steps of heart formation can result in early embryonic lethality. The use of zebrafish as a model organism alleviates this problem by allowing access to developing embryos immediately after fertilization and its ability to survive without a functioning heart up to a comparatively late stage of development (Stainier 2001; Staudt and Stainier 2012). To elucidate the dynamics of the transcriptional regulatory landscape during heart development, we isolated CMs directly from the developing wild-type zebrafish heart at three key stages of morphogenesis: linear heart tube formation (24 hpf), chamber formation and differentiation (48 hpf), and heart maturation (72 hpf). Similarly, we isolated CMs from cardiac TF mutants of gata5, tbx5a and hand2 at 72 hpf. We then combined transcriptome profiling (RNA-seq) with an assay for chromatin accessibility (ATAC-seq) (Buenrostro et al. 2013) to capture the dynamics of regulatory landscape throughout the progression of heart morphogenesis in vivo. Our results unravelled the gene regulatory network driving key processes of heart development.

Publications:

Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development. Pawlak M, Kedzierska KZ, Migdal M, Nahia KA, Ramilowski JA, Bugajski L, Hashimoto K, Marconi A, Piwocka K, Carninci P, Winata CL. Genome Res. 2019 Mar;29(3):506-519. doi: 10.1101/gr.244491.118. Epub 2019 Feb 13.

Decoding the Heart through Next Generation Sequencing Approaches. Pawlak M, Niescierowicz K, Winata CL. Genes (Basel). 2018 Jun 7;9(6). pii: E289. doi: 10.3390/genes9060289. Review.

Functional characterization of non-collagenous extracellular matrix proteins as a potential molecular target and novel biomarker of liver fibrosis

Detailed information about the project:

Project Duration: 01.09.2015-28.08.2019
Project number: UMO-2014/15/D/NZ5/03421
Project title: “Functional characterization of non-collagenous extracellular matrix proteins as a potential molecular target and novel biomarker of liver fibrosis”
Project leader: Michal Pawlak, PhD; Investigators: Eugeniusz Tralle, MSc
Source of funding: National Science Centre, Poland, SONATA
Budget: 541 875 PLN

Project decription and main findings:

Fibrosis characterized by exaggerated synthesis and accumulation of connective tissue in the organ leading to its progressive dysfunction are associated with a wide range of chronic diseases. Among them liver fibrosis and its final stage liver cirrhosis is the major and the most severe hallmark of chronic liver disease leading to cancer development and organ failure. Liver cirrhosis affects nearly 0.1% of European population. The predominant cause of liver fibrosis are excessive alcohol consumption, hepatitis B and C virus and non-alcoholic fatty liver disease (NAFLD), which prevalence is drastically increasing over last decades due to epidemic of obesity.

Currently, no approved and efficient liver fibrosis therapy is approved, therefore liver transplantation is often needed in individuals with high grade of pathological changes. Despite growing understanding of the mechanisms driving liver fibrosis, there is lack of specific molecular biomarkers and molecular targets providing non-invasive diagnosis and safe targeted therapy. Transcriptomics, proteomics, metabolomics and other ‘omics’ have emerged as valuable tools to elucidate the mechanisms of multiple diseases and search for novel molecular markers and therapy targets.

By applying transcriptomics of liver biopsies from healthy patients and patients with liver fibrosis, we have identified genes related to this pathological condition including dermatopontin (DPT), a gene encoding extracellular matrix protein with yet unknown role in fibrogenesis. Functional tests in model organisms such as zebrafish and mouse established a clear association between DPT expression and liver fibrosis. DPT gene loss-of-function experiments including CRISPR-Cas9 genome editing, revealed that the lack of functional Dpt protein protects the animals from liver fibrosis development. Moreover, next-generation sequencing (NGS) techniques such as RNA-seq and ATAC-seq performed at single-cell type resolution in zebrafish model allowed to identify genes and epigenetic landscapes related to physiological conditions and liver injury.

Finally, we have identified novel protein associated with liver fibrosis both in human and in animal models of chronic liver injury. DPT appears as a promising molecular marker of liver fibrosis with a strong potential in  development of non-invasive diagnostics of liver fibrosis. Moreover, DPT is a potential molecular target of liver fibrosis therefore our findings can contribute in identifying novel preventive and therapeutic strategies of liver fibrosis.

Conferences:

1. Fishing for novel targets of liver fibrosis by using danio rerio model. Michal Pawlak, Katarzyna Kedzierska, Cecilia Winata. Liver fibrosis: The next goal of targeted therapy? European Association for the Study of the Liver, 17-18 JUNE 2016 Porto, Portugal. Poster presentation

2. The role of a novel extracellular matrix protein in zebrafish liver development and repair. E Tralle. M Pawlak, C Winata. 10th European ZebraFish Meeting, Budapest, Hungary, 3-7 July 2017. Poster presentation

3. Establishing a zebrafish liver fibrosis model. E Tralle. M Pawlak, C Winata. 2nd International FishMed Conference on Zebrafish Research, FishMed2018, March 25-27, 2018. Poster presentation

Publications:

1. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Gross B, Pawlak M, Lefebvre P, Staels B. Nature Reviews Endocrinology. 2017 Jan;13(1):36-49. doi: 10.1038/nrendo.2016.135. Epub 2016 Sep 16

2. Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin. Lefebvre P, Lalloyer F, Baugé E, Pawlak M, Gheeraert C, Dehondt H, Vanhoutte J, Woitrain E, Hennuyer N, Mazuy C, Bobowski-Gérard M, Zummo FP, Derudas B, Driessen A, Hubens G, Vonghia L, Kwanten WJ, Michielsen P, Vanwolleghem T, Eeckhoute J, Verrijken A, Van Gaal L, Francque S, Staels B. Journal of Clinical Investigation Insight. 2017 Jul 6;2(13). doi: 10.1172/jci.insight.92264. [Epub ahead of print].

3. Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development. Pawlak M, Kedzierska K, Migdal M, Abu Nahia K, Ramilowski JA, Bugajski L, Hashimoto K, Marconi A, Piwocka K, Carninci P, Winata CL. Genome Research, Accepted article, 2019 Jan 9.

4. Transcriptome and chromatin landscapes of hepatocytes, stellate cells and endothelial cells in vivo during liver injury. Pawlak et al. [Manuscript in preparation].

 

 

Genomics dissection of the heart pacemaker in Zebrafish

Heart arrhythmia is a condition where the rhythm of heart contraction becomes irregular. This can lead to the formation of blood clots with devastating consequences such as heart attack and stroke. However, despite its seriousness, heart arrhythmia is very little understood compared to other types of heart diseases. The genetic factors which cause the condition is not well known and there is very little medical treatment available to treat such conditions, the most common being surgery and artificial pacemakers. Therefore, heart arrhythmia patients often have to live with the condition and experience a decrease in quality of life and often need to undergo continuous and costly medical procedures due to common recurrence of the condition. Our research aims to improve the understanding of the genetic mechanism causing heart arrhythmia, and with this knowledge, we hope to contribute to the medical field in improving the diagnosis as well as treatment methods of heart arrhythmia.

The pacemaker is a group of cells in the heart which spontaneously generate small electrical current at a regular rhythm and propagate this current throughout the heart, causing its rhythmic contraction. If the pacemakers develops abnormally, the rhythm of heart contraction is affected, leading to different types of arrhythmia depending on which pacemaker is affected and the nature of the defect. To study how the pacemaker develops and functions, we use the zebrafish as a model organism due to its similarity in heart physiology and genetics to that of humans. Using a genomics approach, we will perform a study to elucidate the molecular mechanism underlying pacemaker development in the zebrafish, followed by initiating the groundworks for establishing the zebrafish as a model organism to study pacemakers function and diseases associated with their dysfunction. Besides identifying factors in common between human and zebrafish, our results will also suggest novel genetic factors with potential implications in heart arrhythmia. This knowledge is envisaged to contribute to future development of molecular diagnosis as well as inform the design of future clinical therapies for heart arrhythmia.

 

The project is carried-out within the First-TEAM programme of the Foundation for Polish Science and is co-financed from the European Union under the European Regional Development Fund.