Dr. Sherry Sun

Signaling mediated by bioactive lipids constitutes an integral component in the pathogenesis of inflammation, which in turn amplifies tissue injury and correlates with the progression of cardiac failure in cardiac stress. Specifically, lysophosphatidic acid (LPA) signaling, predominantly generated by the extracellular lysophospholipase D enzyme, autotaxin, facilitates detrimental cardiac remodeling. Autotaxin, primarily derived from adipose tissue, contributes substantially to plasma LPA levels, elucidating the association between obesity and cardiac failure.

Our preliminary investigations indicate a correlation between the upregulation of pro-inflammatory macrophages and the escalation of heart failure, a process that appears to be aggravated by autotaxin. The nexus between macrophage signaling, obesity, autotaxin/LPA signaling, and the development of heart failure, along with its potential therapeutic implications, is an active research area in the lab.

We are dedicated to elucidating the molecular mechanisms underlying heart failure and investigating the intricate involvement of the immune system in this process. To accomplish this, we employ a combination of animal models and clinical studies, which serve as the foundation for our experimental investigations. In particular, our research highlights the critical role played by key components of the immune system, such as neutrophils and macrophages, in both cardiac inflammation and the subsequent recovery phase.

Macrophages, in particular, are indispensable for promoting tissue healing following injury, extending their influence to almost every organ within the body. However, in the context of a heart attack, prolonged pro-inflammatory activation of macrophages can instead contribute to cardiac damage. Therefore, a highly promising strategy to mitigate the initial extent of cardiac injury (preservation) post-heart attack involves modulating the activation state of macrophages, steering them towards an anti-inflammatory phenotype referred to as alternative polarization.

In our laboratory, we pursue diverse approaches aimed at enhancing alternative macrophage polarization. These methodologies encompass not only cell therapy interventions, but also the exploration of various novel and repurposed pharmaceutical agents. Through these comprehensive investigations, we aim to expand our understanding of the immune response in cardiac pathology and identify potential therapeutic avenues to improve patient outcomes in the context of heart failure.

Animal models of cardiac tissue injury and repair

We are focused on understanding the immune response to heart attack, specifically the role of neutrophils and macrophages. We examine the innate mechanisms responsible for their production, mobilization, and homing to the heart after a heart attack. We also examine how to modulate their state towards the anti-inflammatory (reparative) state using cell therapy as well as repurposed pharmaceuticals. We use a multi-modality approach to study these phenomena including animal models, in vivo imaging, microscopy, and molecular biology techniques, among others.

Comparative biology studies to examine novel innate mechanisms of myocardial tissue preservation

Although neonatal rodents and pigs can regenerate cardiac tissue, their neonatal regenerative capacity is lost shortly after birth, with adults exhibiting negligible cardiac regeneration or resistance to AMI. To date, only non-mammalian vertebrates, such as zebrafish and newts, have been identified with the ability to regenerate cardiac tissue after injury in adulthood. However, these aquatic vertebrate models have limited translational appeal from the standpoint of human physiology and immunology.

The Acomys (African Spiny) mouse represents a novel model of complex tissue regeneration after injury. Our work documented significantly reduced mortality, smaller scar size, and restored cardiac function in Acomys compared with Mus and was published in parallel with an independent study showing similar findings. Work in the lab focuses on understanding the underpinnings of cardiac ischemic resilience in Acomys with a focus on unique cell populations in the heart such as cardiomyocytes and immune cells.

Translational studies in patients with cardiovascular disease

We also have several integrated translational projects that focus on the immune response to heart attack in humans. We have initiated a biobank of sequential peripheral blood samples collected from heart attack patients to further explore the mechanisms regulating these immune responses and their clinical consequences.