Research Areas

Autophagy and Mitophagy

Researchers in the Gottlieb Lab are exploring the roles of autophagy and mitophagy in the heart in both health and disease settings. We have found that autophagic removal of damaged mitochondria (mitophagy) is important for protecting the heart against ischemia/reperfusion injury. Interventions such as ischemic preconditioning and statin therapy activate mitophagy that depends on the participation of specific proteins, including Parkin and p62/sequestosome1, and on depletion of coenzyme Q10. We have developed tools for studying mitochondrial turnover, notably a fluorescent protein we call MitoTimer. This fluorescent protein serves as a molecular clock, allowing us to "time-stamp" mitochondria to monitor their removal and subsequent replacement in cells and transgenic mice.

This confocal image of a heart cryosection from a mouse expressing MitoTimer reveals evidence of synchronized mitochondrial turnover among neighboring cardiomyocytes. This novel tool animal allows us, for the first time, to visualize mitochondrial turnover in vivo.


Impact of Obesity on Autophagy and Cardioprotection

We are interested in understanding how metabolic syndrome disrupts autophagy and increases ischemia/reperfusion injury in the heart, using cell, mouse, and porcine models. One of our goals is to identify agents that can restore autophagy and cardioprotection. Using proteomics to develop a detailed portrait of the heart in animals fed standard chow or a high-fat diet, we have discovered that obese mice show remarkable dysregulation of the response to nutrient stress that may parallel and shed new light on their exaggerated response to ischemic stress.


Cardiomyopathy in Stem Cell Depletion Syndromes

We established a mouse model that recapitulates the features of the clinical syndrome of heart failure that develops years after childhood exposure to anthracyclines. We showed that this failure was due to depletion of cardiac-resident c-kit+ cells, which resulted in impaired rarefaction of the capillaries of the coronary bed. Currently, we are developing a treatment to restore c-kit+ cells to the heart and are interested in identifying whether patients who received anthracyclines in childhood have limited coronary flow reserve that might predict increased risk for late-onset heart failure. We have also published evidence that exposure to coxsackievirus B in early childhood has very similar effects and could explain some cases of idiopathic heart failure in adults. We are hoping to study patients receiving chemotherapy to determine if we can identify early markers of microvascular disease.


Shown are comparable regions of mouse hearts stained with anti-CD31 to label capillaries. The control animal received saline injections (S-P) and shows a normal capillary density, whereas the mouse that received the chemotherapy drug doxorubicin (D-P) as a pup shows fewer capillaries. Interestingly, coronary flow is normal under basal conditions, but the doxorubicin-exposed animals cannot increase coronary flow in response to a challenge, resulting in exercise-induced ischemia. This may shed light on the cardiac microvascular disease that is recognized to be more common in women and which may eventually lead to heart failure with preserved ejection fraction (HFpEF). Thus this animal model will allow us to examine potential therapies to reverse microvascular disease.

Mitochondrial Function in Health and Disease

Using Seahorse respirometry and a variety of complementary approaches, we are analyzing mitochondrial function in various disease states. We are just beginning a study of mitochondrial alterations in biopsies from heart transplant patients, with the goal of identifying early markers that will predict graft rejection. This work is done in collaboration with Lawrence Czer, MD, and the heart transplant team.

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