Our Research

The significance of lysosomes in the cardiac disease pathology

The ultimate goal of our research is to understand the process that promotes cardiomyocyte injury or loss that eventually leads to cardiac dysfunction and heart failure. The Autophagy-Lysosome system plays a key role in protecting the heart and maintaining its contractile function. Dysregulation of this system leads to intracellular Ca2+ dysregulation, increased oxidative stress, mitochondrial injury, apoptosis and overall cardiac dysfunction. Recent studies have demonstrated an association between cardiac injury and lysosomal dysfunction. Lysosomal membrane permeabilization (LMP) occurs in response to a variety of stresses that promote the release of lysosomal enzymes such as cathepsin D (CTSD) from the lysosomal lumen into the cytosol where these enzymes then participate in apoptotic signaling. Elucidating the spatiotemporal regulation of these intracellular events will help to delineate the essential processes that are necessary for maintaining cardiac muscle cell homeostasis. Understanding this regulation will allow for the development of new therapeutic strategies to prevent cardiac dysfunction under various stresses.

Projects:

  1. Lysosomal dysfunction in the diabetic heart

We are investigating the pathological significance of LMP and CTSD in the diabetic heart injury using pharmacological and genetic gain- and loss-of-function approaches in both in vitro cultured cells and in vivo mouse models. Successful completion of this project will provide novel insight into the mechanisms that mediate diabetic cardiac injury, thus facilitating drug design for preventing or treating cardiomyopathy and heart failure in diabetes.

1a. Evaluate the level of lysosomal injury

“Physician, heal thyself”. Lysosomes, the ER physician in cells, do. There is a way to repairing or fixing damaged lysosome. They can take care of themselves while they are also maintaining the other parts of cell. But, once the job is overwhelmed, this lysosome-based cellular healthcare system easily falls. So far, we have no good panel to monitor the health condition of lysosome itself. We are trying to develop a comprehensive review panel/index for evaluating the health condition of lysosomes (such as the structure, size, number, biogenesis, LMP, intracellular distribution, kinetics of lysosomal degradation) in various stresses.

1b. How to protect the lysosomes

We are seeking the ways to limit or to repair LMP. There are some ways such as strengthen the lysosome membrane, or backing up the hole of injury. There are some candidates (drugs and genes) potentially protect lysosomes. The beneficial effect and the optimal application requirements are currently under investigation.

There is Plan B. Diabetes is a slow death process. So, lysosomes don’t know they’re in danger like boiling frogs. What if we give a shock to wake them up and get them ready to react to the sneaking stress? This plan B might sound counterintuitive, but this may be more effective like taking a vaccine shot for training your body defense system even before the situation gets more serious. We have some ideas for giving a minimal but sufficient shock to wake the lysosomes. The concept should be tested in culture dish and practical way will be designed in near future.

  1. The communication between lysosomes and mitochondria

Recent technological advances revealed that the organelles are communicating by contacting, forming micro-environment or exchanging the conponents for making the orchestrated inter-orgenelle signal transduction. It has been shown that lysosomes and mitochondria are also contacting each other for many reasons. By using super-resolution microscopy technique, we will demonstrate how they communicate in the cardiomyocytes.

2a. Determine if diabetic stresses (hyperglycemia and dyslipidemia) alter lysosome-mitochondria communication

2b. Determine if mitochondria are released or transferred from cardiomyocytes