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.