Megan Holt

Program: Developmental Regenerative and Stem Cell Biology

Current advisor: Kory J. Lavine, MD, PhD

Undergraduate university: St. Mary’s College-California, 2020

Enrollment year: 2022

Research summary
Investigating the role of focal adhesion kinase (FAK) in cardiac resident macrophages in cardiac development and response to injury

Cardiac resident macrophages (CRMs) are among the earliest immune cells to populate the developing heart and are increasingly recognized as key regulators of cardiomyocyte (CM) maturation, heart development, cardiac homeostasis, adaptive myocardial remodeling, and repair. Gaps remain in our understanding of the precise mechanisms by which CRMs govern these processes. Recent work has uncovered that CRMs interact with CMs through focal adhesion complexes and that transduction of mechanical signals regulates the activation of CRMs. Among the many proteins that interact with focal adhesion complexes, focal adhesion kinase (FAK, encoded by PTK2) represents a critical mediator of downstream mechanically responsive signaling. I am testing the hypothesis that FAK is a central regulator of interactions between CRMs and CMs and is essential for the reparative effector functions of CRMs. Consistent with this hypothesis, conditional knockout (KO) of FAK in CRMs resulted in retraction of macrophage processes and disrupted physical interactions between CRMs and CMs. Absence of FAK in CRMs potentiated the development of cardiac fibrosis and significantly increased the expression of proinflammatory mediators in the setting of cardiac injury. Moreover, single cell RNA sequencing (scRNA seq) revealed that loss of FAK in CRMs influenced the specification and phenotypes of monocyte-derived macrophages recruited to the injured heart. I am seeking to define the role of CRM FAK in cardiac development and mechanisms by which FAK signaling modulates CRM activation during development and following cardiac injury.

Graduate publications