Liang, Qiangrong , MD, PhD
Autophagy and cardiac homeostasis in diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes, Signal Transduction (Non-Insulin Action)\Transgenic Models
Type of Grant: Career Development
Project Start Date: January 1, 2009
Project End Date: December 31, 2013
Diabetic patients are more susceptible to heart failure. They have an especially poor prognosis following a heart attack. The reason for the increased risk for heart disease in diabetics is not entirely clear. A very popular theory is the increased generation of reactive oxygen species (ROS), the by-products of cellular powerhouse called mitochondria that are extremely toxic to heart muscle cells. However, heart failure is not reduced in diabetic patients by treatment with antioxidants, agents able to scavenge or antagonize ROS. This could be due to the inability of antioxidants to stop ROS generation in damaged mitochondria. Conceivably, a more effective method to reduce diabetic heart injury would be to remove injured mitochondria thereby preventing ROS generation. In normal heart, this role is played by a self-eating machinery termed autophagy that is extremely important for keeping cell healthy by degrading and recycling damaged cellular components including mitochondria. However, data from this laboratory show that autophagy is dysfunctional in diabetic mouse heart, leading to mitochondrial aggregation, dead muscle cells and poor cardiac function. These results suggest that dysfunctional autophagy may be one of the reasons that cause heart problem. To prove this, this laboratory will restore autophagy function in the diabetic mouse heart by drug or genetic gene transfer, and then examine if the injured mitochondria could be removed, ROS generation stopped, the number of dead cells reduced, and heart function improved. The study will provide novel insight into the pathogenesis and potential treatment of heart failure in diabetic patients.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research is focused on diabetic cardiac complications. A majority of diabetic patients die from cardiovascular disease. These patients are more susceptible to heart failure even in the absence of vascular pathology, and they demonstrate a worse prognosis subsequent to heart attack. Although many cellular and molecular changes have been proposed to contribute to diabetic cardiac damage, strategies to effectively prevent or treat diabetic heart failure are still lacking, underscoring the need for a more comprehensive understanding of the underlying pathogenic mechanisms. This project will examine the role of autophagy in the progression of diabetic heart failure. Autophagy is the only cellular machinery that 'eats' and destroys garbage produced in a cell.
It thus plays an important role in the maintenance of a healthy heart by removing damaged organelles including mitochondria from the heart cells. Unfortunately, autophagic function is impaired in the advanced diabetic heart. This causes increased aggregation of injured mitochondria, which may lead to unopposed generation of reactive oxygen species (ROS). These highly toxic free radicals can damage heart muscle cells, weakening cardiac contractile force eventually resulting in overt diabetic heart failure. It is believed that normalization of autophagy would facilitate the rapid removal of injured mitochondria, reducing ROS generation and cardiac damage. This project will utilize pharmacologic and genetic manipulations in diabetic animal models to examine the effectiveness of normalizing or enhancing autophagic activity in the treatment of diabetic heart failure. The study will provide novel insights into the pathogenesis of diabetic cardiac damage and suggest potential therapeutic strategies to repair specific defects in diabetic heart and decrease the mortality in diabetic patients.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetic patients do not die from high blood sugar per se. Rather, most of them die from diabetic complications, especially cardiovascular complications that account for more than two thirds of deaths in diabetic population. Thus, in addition to a cure for diabetes, it is important to prevent and/or treat the associated cardiac complications that culminate in heart failure to reduce the high mortality in diabetic patients. However, to design rational therapies, we must first understand the pathways that predispose diabetic patients to a high risk of developing heart failure. To this end, the present project will investigate the pathogenesis of diabetic heart failure using a number of animal models. The significance of this project resides within its potential to provide a deeper understanding of the mechanisms underlying diabetic heart failure and to suggest novel strategies for clinical therapy.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
It was during my PhD training period that I developed an interest in diabetic research. My mentor, Dr. Paul Epstein, was investigating both pancreatic ß cell function and cardiac function in diabetic animal models. I chose to focus my thesis research on cardiac glucose metabolism and the antioxidant therapy of diabetic cardiomyopathy. Although my work during postdoctoral training with Dr. Jeff Molkentin was not directly related to diabetes, it dealt with cardiac signal transduction mechanism in general, which is extremely important for understanding diabetic heart disease at cellular and molecular levels. I also had medical training before. As a result, the combination of my training in medicine, diabetes and molecular cardiology has helped shaping my academic career in diabetic research.
Due to the increasingly epidemic nature and severe consequence of diabetes, it is likely that a majority of United States citizens are or will be impacted by diabetes within their lifetime, either by personal experience with a family member or a friend. Diabetes is a chronic disease that requires life-long treatment, and most diabetic patients die from complications. The health care costs associated with treating diabetes and its complications are exceedingly high. Thus, it is imperative that we dedicate our scientific efforts to discover new therapies that will improve the quality of life for patients. In this respect, I was honored to receive the ADA award that would enable me to continue my research into the pathogenesis of diabetic cardiac complications. The ultimate goal of my research career is to find a cure for the various forms of heart failure including that induced by diabetes. I believe that the ADA award will initiate a major advancement in my research career. This support will allow me to test my ideas and establish a solid foundation for my long term pursuit of diabetes research.
In what direction do you see the future of diabetes research going?
A cure for type 1 diabetes requires a research effort that is devoted to investigations of beta cell regeneration from various progenitor cells and stem cells, including induced pluripotent stem cells. Equally important is the modulation of host immune responses to prevent the destruction of beta cells or to enhance beta cell survival. The control of type 2 diabetes requires both preventive measures that include life style changes and effective control of the risk factors that comprise metabolic syndrome. Last but not least, a reduction in the death rate of diabetic patients requires continued investigations into the cellular and molecular mechanisms that mediate diabetic cardiovascular complications, the major cause of mortality in diabetics.
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