Projects and Activities
Molecular dissection of valve and outflow tract development
In human, congenital heart malformations represent the single largest class of birth defects with an estimated frequency of 4-5 percent of live births. Defects of the septa and valves account for the majority of congenital heart disease. Thanks to advances in surgical repairs, over 1 million adults in North America are living with CHD but face a lifetime of problems including arrhythmias, ventricular dysfunction, one or more re-operations and premature death from myocardial infarction, sudden death or stroke. Late referral and intervention have a deleterious effect on long term and event free survival. For example, the more subtle defects like atrial septal defects or subclinical valve defects, cause progressive degeneration leading to early adult requirement for valve replacement and other major interventions. Even benign defects like persistent foramen ovale, a form of ASD affecting 25 per cent of the population are associated with significant cardiovascular risks including a 3 to 6 fold increase in stroke, the major cause of morbidity in industrialized countries. Identification of the genes responsible for CHD will enhance early diagnosis, care and follow up of patients which will significantly decrease cardiovascular complications.
It is the objective of the present grant proposal to identify the regulatory circuits and genes essential for valve and septal formation and test the consequences of their dysfunction on heart development using molecular genetics and biochemical studies. The experiments proposed are likely to identify potential disease causing genes and to produce animal models of human birth defects that will accelerate development of preventive and therapeutic approaches of heart disease.
Transcription networks in cardiac hypertrophy
In recent years, the incidence of heart failure has reached epidemic levels with more than half a million new cases being diagnosed each year in North America alone. Heart failure is a progressive condition characterized by contractile dysfunction and profound changes in cardiac structure that include enlargement of myocytes (the contractile cells of the heart), loss of myocytes and increased fibrosis. In response to increased pressure or workload, the heart initially mounts an adaptive response to help maintain cardiovascular homeostasis. This involves genetic reprogramming and increased cell size. However, this compensated state is not maintained and the heart undergoes remodeling that involves loss of myocytes and increased fibrosis which ultimately leads to cardiac dysfunction. The mechanisms responsible for the transition from a compensated state to heart failure remain poorly understood. We are interested in understanding the molecular events that are responsible for maintaining cardiac function in order to prevent progression to heart failure. The experiments proposed could open the way for improved therapies for preventing or treating cardiomyopathies and heart failure.
Mechanisms of TBX5 Action in the heart
Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by cardiac abnormalities and upper limb malformations. Its cardiac defects include Atrial Septal Defects (ASD), Ventricular Septal Defects (VSD), conduction system defects, endocardial cushion defect and mitral valve disease. Linkage analysis mapped the disease to TBX5 gene at 12q24., which is a member of the newly identified family of T-box transcription factors is a dosage-sensitive regulator of heart development. Over Mutations in TBX5 were found in a large spectrum of cardiac defects ranging from isolated ASD to the complex heart and limb malformations associated with HOS. The pattern of Tbx5 expression in upper limb, atria and left ventricles together with the finding that mice with heterozygous deletion of Tbx5 recapitulate HOS have further supported the causative link between mutations in TBX5 gene and HOS.
However, mutations in either the coding sequences or splice junctions are not found in 35% of HOS patients. This has raised debate on the existence of another-as yet unknown- HOS causing locus. Alternatively, unscreened mutations in regulatory or intragenic regions of TBX5 gene might be an explanation.
The overall objective of this grant was to elucidate the mechanisms of TBX5 action in the heart. In particular, we aimed to:
- Analyze the function of TBX5 in endocardial cells.
- Characterize novel Tbx5 alternatively spliced isoforms.
Role of GATA transcription factors in the heart
Congenital heart disease (CHD) affects 1-2% of the population and represents the largest class of birth defects. It is the leading cause of death in infants during the first year of life. It is also an independent risk factor for premature onset of adult cardiovascular disease including degenerative valve disease, myocardial infarction and sudden death. It is well established that CHD is a heritable trait, i.e. it ‘runs in the family’. However, its transmission does not follow simple Mendelian inheritance and is influenced by other genetic as well as environmental factors. Despite great advances over the past decade, the causative genes responsible for the majority of human CHD remain unknown.
A better understanding of the genes and circuits required for normal heart development will immensely advance our understanding, detection and care of CHD. During the past decade, our lab has proudly contributed to this thru our discovery and characterization of several genes essential for normal heart development such as GATA4 and GATA5. Alterations in these genes are associated with several type of human CHD, including bicuspid aortic valve, atrial and ventricular septal defects as well as rhythm abnormalities. Using our unique tools and animal models of human disease, we wish to pursue our studies aimed at understanding the essential role of these GATA proteins at various stages of heart development and in different cardiac cells. We also intend to use our animal models of CHD to elucidate the degenerative nature of CHD in the hope of preventing cardiac dysfunction and associated complications such as the need for valve replacement. Lastly, our animal models offer the possibility to explore the impact of environmental factors on CHD manifestation and progression. The results of this study will continue to impact diagnosis and care of individuals with heart disease or with a family history of the disease.