Researchers at the UCLA cardiovascular theme are investigating and contributing to our understanding of the genetic basis of cardiac disease. Heart failure is the epidemic of the 21st century with almost 20 million people globally and more than 6 million people in the United States carrying the diagnosis. More than 600,000 individuals are annually diagnosed with heart failure in the US alone and once a diagnosis is made, the 5 year survival is close to 50% despite optimal medical therapy. Despite major advances in medical technology and science, little is known about hope genes can affect survival or denote accelerated progression of diaease. The UCLA cardiovascular theme uses comprehensive genomics, systems biology and multi -omics approach hes to solve such questions.
One example of a condition caused by genetic mutations that run in families is hypertrophic cardiomyopathy. This is the disorder often associated with sudden death in young athletes.
Dr. Jessica Wang, assistant professor of medicine in the Division of Cardiology, leads an effort to understand how variation in the DNA sequence causes disease.
The laboratory of Jake Lusis in the department of cardiology and human genetics uses a multi-omic approach to identify key genetic pathways that affect cardiac disease. The laboratory uses the combination of genetics, molecular biology, and informatics to investigate pathways underlying common cardiovascular and metabolic disorders. They exploit natural genetic variation among inbred strains of mice or human populations to identify novel targets and formulate hypotheses, and we perform validation using experimental perturbations in mice.
The lab has taken advantage of high throughput biologic technologies, such as transcriptomics, metabolomics, and proteomics, to help develop new approaches to understand complex traits. They have shown that when integrated with natural genetic variation, such multi-omics analyses can be used to model biologic pathways and uncover regulatory mechanisms, an approach known as “systems genetics”.During the past 10 years, they have developed a unique mapping approach in mice that is analogous to genome-wide association studies in humans. This approach utilizes a well-characterized population of 100 inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). A major advantage of this approach is that the resolution is much better than with traditional genetic crosses. It also facilitates studies of gene-by-environment interactions, which are very difficult to address in human populations, and it has important advantages for systems-based approaches which require analysis of relevant tissues. (Figure at right shows integration of multi-omic data using natural variation.)
The laboratory of Dr Yibin Wang (Anesthesiology, Physiology and Medicine) investigates how stress signaling leads to pathological changes in the heart and metabolic system. Dr. Wang’s laboratory utilizing systems genetics approaches and related genomic tools is trying to understand how epigenetic regulators such as lncRNAs and RNA binding proteins affect the phenotype of stress induced cardiac disease and remodeling.
They are investigating novel regulators of metabolism that modulate cardiac phenotype and are identifying novel therapeutic targets for heart failure with a special emphasis on branched amino acid regulation and nutrient signaling.