Research Areas

Heart Disease

Heart disease is the leading cause of death worldwide, affecting millions of lives each year and placing a tremendous economic burden on healthcare systems. In healthy patients, the heart functions as a pump, circulating oxygen-rich blood throughout the body to sustain life. This pumping action relies on the coordinated contraction and relaxation of cardiac muscle, driven by the sarcomere—the fundamental unit of muscle contraction.

Heart disease disrupts this critical function. Structural abnormalities, such as those caused by genetic variants in sarcomeric proteins, or impaired cell signaling and phosphorylation, can hinder the heart’s ability to contract and relax effectively. Over time, these disruptions weaken the heart’s pumping capacity, reducing blood flow to vital organs and tissues. This decline in function contributes to symptoms such as fatigue, shortness of breath, and fluid retention and can ultimately lead to heart failure, a severe and often fatal consequence of heart disease.

The Cardiac Sarcomere

The cardiac sarcomere is the fundamental contractile unit of cardiomyocytes, organized into a highly ordered structure composed of thin filaments (primarily actin), thick filaments (myosin), and accessory proteins such as myosin-binding protein C (cMyBP-C) and troponin-tropomyosin complexes. The sarcomere contracts by utilizing a sliding filament mechanism, where the thick and thin filaments interact to generate force and facilitate contraction and relaxation of the heart. This process is precisely regulated by calcium signaling and post-translational modifications such as phosphorylation, which modulate the activity and interactions of sarcomeric proteins. Structural or regulatory defects, such as mutations in sarcomeric proteins or dysregulation of signaling pathways, can impair sarcomere function, leading to myocardial dysfunction and development of heart failure.

Dysregulation of Sarcomere Phosphorylation

Phosphorylation of sarcomeric proteins, such as cardiac myosin-binding protein C (cMyBP-C) and troponin I, regulates key aspects of contractility, including force generation, calcium sensitivity, and relaxation. In heart failure, hypophosphorylation of these proteins is commonly observed, leading to reduced contractile efficiency, slowed relaxation, and increased diastolic dysfunction.

Mutations to the Sarcomere

Mutations in cardiac sarcomeric proteins are a known cause of certain types of heart disease, including hypertrophic cardiomyopathy (HCM), a genetic disorder that disrupts myocardial function. Proper cardiac function depends on the precise interaction and coordination of thin and thick filament proteins, which regulate the timing and strength of force generation and relaxation, ensuring balanced systolic and diastolic performance. Mutations in these proteins alter sarcomeric structure and function, often resulting in hypercontractility and excessive myocardial thickening. Over time, this pathological hypertrophy stiffens the heart, compromising its ability to pump effectively and leading to progressive cardiac dysfunction.

Gene Therapy

AAV gene therapy is a promising treatment for heart disease caused by mutations that result in cMyBP-C truncation. This therapy uses a harmless virus to deliver a healthy copy of the MYBPC3 gene to heart cells, restoring normal protein levels. By improving how heart muscles contract, it has the potential to prevent disease progression and improve heart function over the long term.

Small Molecule Therapy

Small molecules targeting myosin or cMyBP-C are emerging as innovative treatments for heart disease. Myosin-targeting compounds can modulate the motor protein's activity, either enhancing contractility in weak hearts or reducing excessive force in conditions like hypertrophic cardiomyopathy. Similarly, small molecules targeting cMyBP-C aim to stabilize the protein, enhance its phosphorylation, or restore its normal regulatory function within the sarcomere. These therapies offer precision in modulating heart muscle performance, providing new opportunities to treat various cardiac conditions by directly addressing the molecular drivers of dysfunction.

Metabolism

A healthy heart produces approximately six kilograms – or 15 times its own weight – of ATP per day to meet the tremendously large energy demands of its constant pumping action. This highly metabolic organ relies mostly on the efficient process of fatty acid oxidation to generate this amount of ATP. But, what happens to the metabolic pathways that support these energy demands with the onset of heart failure? And, can they be exploited as a way to treat maladaptive changes? Our ongoing projects aimed to address these questions include state-of-the-art respiratory equipment to measure oxygen consumption at the whole-body, cellular, and mitochondrial levels. We also use special diets to supplement mice with exogenous substrates to study systemic metabolism. With these approaches, we will develop a better understanding of both the cellular and systemic metabolic changes associated with heart failure and identify potential therapeutic approaches.

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