Projects
In humans, cardiac malformations represent 25% of all birth defects and, in adults, cardiac dysfunction is the leading cause of death in industrialized countries. A better understanding of the molecular mechanisms involved in normal and pathologic heart development will greatly improve diagnosis, prevention and treatments of heart disease.
Today, over 1 million adults in North America are being successfully treated for congenital heart disease (CHD) thanks to advances in imaging and surgical techniques. However, these people face a lifetime of problems including arrhythmias, ventricular dysfunction, stroke and premature death. Subclinical heart defects that exacerbate with age such as valve defects (ultimately requiring valve replacement) are present in 1-2% of the population. Moreover, it is estimated that in 25% of the population, the wall separating the two atrial chambers of the heart does not close properly after birth. Although this condition does not affect normal hemodynamics, it increases the risk of stroke by 3 to 6 times.
The causes of ischemic heart disease include cardiac malformation, high blood pressure, diabetes, vascular problems, infection and chemotherapy. This is characterized by a loss of myocytes, the contractile cells of the heart. Unlike other cells of the body, cardiac myocytes do not regenerate spontaneously and their irreversible loss leads to heart failure. Understanding the molecular basis for survival and proliferation of myocytes as well as the mechanisms that govern differentiation of stem and progenitor cells into cardiac myocytes holds great promise for cardiac repair and regeneration therapies.
During the past 15 years, Dr Nemer has been investigating the genetic pathways involved in normal and pathologic heart development. She has identified several genes required for myocyte survival and/or the proper formation of the heart.
Her research aims are to elucidate the pathways involved in cardiogenesis with a particular focus on determining the mechanisms underlying cardiac lineage differentiation and heart morphogenesis. Another major aim is to define the pathways essential for the survival of postnatal cardiomyocytes and the adaptive responses of the heart. Such studies of the molecular pathways underlying normal heart development are a prerequisite to elucidating the genetic basis of congenital heart disease (CHD) and to developing appropriate preventive procedures and therapeutic interventions.
A major part of this project is aimed at understanding disease mechanism. This will involve extensive structure-function and biochemical studies to test the effect of mutations on DNA binding, protein:protein interactions and transcriptional activities. In parallel, in vivo functional properties will be tested to determine the effect on cell fate regulation (survival, proliferation, differentiation). Additionally, causative links can only be established definitively through direct testing of the effect of mutations in vivo using targeted mutagenesis in ES cells and thru generation of genetically engineered mice. The lab is concentrating its efforts on analyzing the critical regulators of cardiac genes including GATA-4, Nkx2.5 and Tbx5 mutations which are linked to CHD.
Fig. 1. Schematic representations of the major stages of heart development. The indicated embryonic days correspond to mouse embryos. Except for GATA-5 (zebrafish), the role of the indicated TFs was identified mostly through mouse genetics. a, atria; ao, aorta; la, left atrium; lv, left ventricle; ot, outflow tract; pa, pulmonary aorta/trunk; ra, right atrium; rv, right ventricle; sv, sinus venosus; v, ventricle.
This research combines state-of-the-art functional genomic approaches with molecular genetics in animal models of human disease aimed at deciphering the intricate regulatory circuits that control heart development. The end in view is to reveal the basis of structural and/or functional cardiac defects in humans and identification of disease causing genes and development of new screening and diagnostic tools, and novel, druggable targets.
to come...