DISCOVERY of the Mechanisms that Underlie Cardiac Growth.

Image of a cycling cardiomyocyte and endothelial cell directly adjacent to each other.

Myovascular growth niches.  We have shown that the master angiogenic factor Vegfa can induce growth and regeneration in zebrafish and neonatal mice.  We have also spatiotemporally linked proliferating cardiac endothelial cells to proliferating cardiomyocytes, providing evidence for concentrated growth niches in the mammalian heart.  Current projects include 1) defining the molecular intermediaries that synchronize growth of cardiomyocytes and endothelial cells during regeneration and disease and 2) defining the cellular and molecular constituents of cardiac growth niches during regeneration and disease.

Regulators of human cardiac growth.   We use advanced genetic techniques to model therapeutic effects of growth factors on human heart size .  For example, we used Mendelian Randomization to link higher circulating VEGFA levels with human heart size.  Current projects in the lab include 1) the identification of new growth intermediaries that causally regulate human heart size; and 2) defining common genetic variants that determine human heart size.

A) Schematic of MR approach to model VEGFA effects on the human heart; B) GWAS identifying pQTLs to serve as genetic instruments of VEGFA levels; and C) Results of MR studies applied to the UKBiobank showing that VEGFA increased left ventricular mass in the human heart.

DELIVERY of therapeutics to the mammalian heart.

Reactive oxygen species - responsive SPION hybrid nanogels

Reprogramming human cardiac growth responses to recover function requires tools that specifically work in diseased myocardium, that “turn off” after successful repair, and that can be repeatedly dosed.  Through collaborative work, we have identified enhancer sequences that can spatiotemporally regulate gene expression in injured myocardium.   Current projects include 1) the discovery of new tools for spatiotemporal control of growth factor expression in diseased myocardium; and 2) engineering new delivery vehicles for genetic cargo to target the heart.

DETECTION of diseased and recovered myocardium.

Prognostic effects of circulating angiokine levels in patients with HFrEF.

Successful implementation of restorative therapies to the failing heart requires tools for accurately detecting dysfunctional and recovered myocardium.  We have defined tools for assaying recovery in LVAD recipients and new biomarkers for determining the potential for functional recovery in patients with heart failure.  Ongoing projects are 1) developing new tools for assaying human cardiac recovery and 2) evaluating the robustness of our tools in new patient populations.

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