HCM is an inherited disorder in which the primary abnormality is overgrowth of the cardiac muscle. HCM occurs in 0.2% to 0.5% of the population and may cause complications like sudden death, arrhythmias, and heart failure. While HCM is caused by mutations in genes coding for proteins in the heart’s muscle fibers, patients often also have abnormalities of the valves. For example, the leaflets of the mitral valve (MV) may be elongated and obstruct blood flow out of the heart, thereby causing some of the complications of HCM. To investigate how mutations in muscle proteins might affect valve tissue, Dr. Judge will study a mouse model of HCM with a mutation in the gene for cardiac myosin binding protein C (Mybpc3). Humans with mutations in the gene have abnormally long mitral leaflets, even prior to the onset of muscle hypertrophy. Dr. Judge will compare the gene expression patterns in MV tissue of the HCM mice with those in normal mice and mice with MV disease from conditions unrelated to HCM. He will also determine whether replacement with a normal form of Mybpc3 in the HCM mice can normalize their valves. Finally, because the growth factor TGF-ß has been implicated in MV abnormalities, Dr. Judge will test whether TGF-ß-blocking strategies are effective against MV disease in the HCM mice. This work will provide important insight into how MV disease develops in the context of HCM and how it may be prevented or treated.
 

Dr. Kaikkonen received her PhD in molecular medicine in 2008 from the University of Kuopio, Finland, in the laboratory of Dr. Seppo Ylä-Herttuala, European coordinator of the Immune Modulation of Cardiovascular Disease network. In August 2009, she began a post-doctoral fellowship with network member Dr. Christopher Glass at the University of California, San Diego. With her Career Development Award, she will extend her stay in San Diego for another year before returning to the University of Kuopio.

Macrophages are white blood cells that engulf and digest cellular debris and pathogens and stimulate other immune cells to respond to the pathogens. They play a key role in the development of atherosclerosis through their accumulation of cholesterol and production of inflammatory factors. Macrophages are activated by a family of vascular endothelial growth factors (VEGFs) produced by the endothelium, the inner lining of blood vessels. Regulation of the gene expression of VEGFs and of their receptor on the surface of macrophages therefore represents a potential strategy for the prevention and treatment of atherosclerosis.

Gene expression may be modulated not only by direct changes in the DNA sequence but by epigenetic mechanisms beyond the DNA sequence, which may be more accessible for therapeutic intervention. One epigenetic mechanism utilizes short strands of RNA, which may be naturally occurring (non-coding, or ncRNAs) or synthetic (small interfering, or siRNAs). Dr. Kaikkonen will study how natural RNA epigenetic mechanisms modulate the expression of different VEGFs and the VEGF receptor. Furthermore, based on recent work generating siRNAs that induce epigenetic changes in VEGFs, she will determine whether this siRNA effect is due to direct interaction with the gene expression machinery of the cell or with ncRNAs. Ultimately, Dr. Kaikkonen will test whether the siRNAs are an effective treatment in a mouse model of atherosclerosis. With this project, she will develop expertise and insight into using contemporary molecular biology methods for the modulation of gene expression.

Lee Roberts is a PhD student in biochemistry at King’s College, University of Cambridge, UK, where he studies lipid metabolism. He will spend two years at the Broad Institute with Dr. Robert Gerszten of the Integrative Networks Regulating Cardiomyocyte Metabolism and Survival in Heart Failure and Insulin Resistance network. He will build upon his analytical and technical background with a translational research project on diabetes.

One approach to identifying new risk predictors lies in metabolomics, the large-scale study of cellular metabolites, analogous to such study of genes (“genomics”) and proteins (“proteomics”). The human metabolome is estimated to include approximately 2500 small molecules. Techniques such as mass spectrometry enable the characterization of metabolites from blood and other biological samples.

Mr. Roberts will study patients from the Framingham Heart Study who have been followed for up to 14 years after an oral glucose tolerance test. This test, in which the blood glucose level is measured before and after ingestion of a load of glucose, determines how quickly glucose is cleared from the blood and is used to diagnose insulin resistance and diabetes. While all the participants had normal test results at baseline, many went on to develop insulin resistance or diabetes over time. Mr. Roberts will perform a metabolomic analysis of the blood samples from the baseline test to see if any metabolites would have accurately predicted these developments. This analysis will cover a vast array of metabolic pathways. The metabolites identified as risk predictors will then be tested in in vitro and in vivo models to evaluate their effects on cardiac cells, to provide insight into how diabetes causes cardiac complications. This Career Development Award allows Mr. Roberts to take advantage of the unique combination of the Framingham Heart Study and the metabolomics platform at the Broad Institute to potentially make an impact on an illness of worldwide importance.