Modulating autophagy to treat CV disease

Brought to you by the Fondation Leducq Transatlantic Network of Excellence

Levine Lab

Principal Investigator:

Beth Levine, M.D.

Leducq Lab Members:

Alvaro Fernandez, PhD (Leducq Fellow)
Salwa Sebti, PhD (Leducq Fellow)
Zhongju Zou

Contribution to the network:

The Levine lab has longstanding expertise in studying the molecular regulation of autophagy and its roles in physiological and pathophysiological processes. Our lab identified the autophagy protein Beclin 1; biochemical mechanisms underlying the regulation of Beclin 1 function; and roles of Beclin 1 and other autophagy proteins in tumor suppression, innate immunity, lifespan extension, exercise-regulated metabolism, and an autophagy, Na,K-ATPase cell death pathway called autosis. We have also identified new regulators of mitophagy and have developed a cell-penetrating autophagy-inducing peptide that has beneficial effects in a variety of preclinical disease models, including pressure overload-induced heart failure.

The goal of our studies in the network is to understand the role of autophagy and mitophagy in the regulation of death and survival of cardiomycoytes in both pathological stresses in the heart, such as ischemia/reperfusion, and normal physiological stresses, such as exercise. We also seek to identify new strategies to modulate autophagy to improve the survival of cardiomyocytes during stress, either by upregulating autophagy (in certain contexts) or preventing autotic cell death (in other contexts).

Our hypothesis is that autophagy and mitophagy play a protective role during many phases of cardiac stress, but that excessive induction of autophagy, such as that which occurs during ischemia reperfusion, can be detrimental.

Significance: We will (1) elucidate the molecular mechanisms by which mitophagy is regulated in cardiomyocytes; (2) elucidate the molecular mechanisms by which autosis is regulated in cardiomyocytes; (3) evaluate the role of enhanced autophagy in preventing cardiac aging; and (4) develop novel specific inducers of autophagy that function by increasing Beclin 1 activity. These studies should help clarify the role of autophagy and mitophagy in cardiac disease and help elucidate novel therapeutic strategies to improve cardiac health through autophagy modulation.