Novgorodov, Sergei Alexander, PhD
Mitochondrial ceramide producing pathways in diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Integrated Physiology\Muscle
Type of Grant: Innovation
Project Start Date: July 1, 2012
Project End Date: June 30, 2014
The incidence of diabetes is increasing globally. The death rate linked to cardiovascular complications and heart failure is up to 4 times higher in diabetic adults, as compared to adults with no disease. Diabetic cardiomyopathy plays a primary role in heart failure independently of other risk factors, such as coronary disease and hypertension. The underlying mechanisms for the development of diabetic cardiomyopathy are not entirely understood, however excessive accumulation of lipids and mitochondrial dysfunction were implicated as major factors.
The sphingolipid ceramide has been established as a key mediator of cell-stress responses and its involvement in diabetic/lipotoxic cardiomyopathy has been suggested. Moreover, ceramide-mediated deregulation of mitochondrial functions and the presence of ceramide metabolizing enzymes in mitochondria are well documented. This emphasizes the intimate connection between ceramide metabolism and mitochondrial physiology. Key questions remain about putative mechanisms of ceramide generation in mitochondria of diabetic heart and the role of ceramide in mitochondrial dysfunction in this disease. We will fill this gap in knowledge by establishing a biological relationship between the aberrant sphingolipid profile in diabetic heart disease and mitochondrial deregulation. The proposed studies focus on the novel mechanism of ceramide generation in mitochondria of the diabetic heart, and contribution of ceramide generation to mitochondrial dysfunction. Collectively, the expected results should generate a more coherent and unified view on the role of ceramide in diabetes, and identify novel targets for more effective therapies.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Cardiovascular disease remains the leading cause of mortality and morbidity in individuals with diabetes. Compelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independent of other risk factors such as coronary disease and hypertension. Recent advances in the studies of diabetic cardiomyopathy highlighted the role of mitochondrial dysfunction as an important factor to the decreased energy production and accelerated cardiomyocyte cell death in diabetes and obesity.
Cytotoxic lipid ceramide has been linked to the disruption of mitochondrial function and the potentiation of cell death in a variety of models. However, there is a gap in our knowledge regarding how ceramide is produced and the role ceramide plays in the mitochondrial dysfunction of a diabetic heart. Thus, the overall objective of this proposal is to establish and characterize these ceramide generating pathways. Therefore, the current project covers the areas of research related to the disturbance of cardiac bioenergetics and lipid signaling in diabetes. The proposed project will reveal mitochondrial targets that can provide the basis for developing new approaches for therapeutic interventions without disturbing the global ceramide metabolism of the cell.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes is dangerous due to serious long-term complications, especially cardiovascular diseases. Disease of heart muscle was highlighted in recent studies as an important contributor to diabetic complications. 68% of diabetes-related death among the elderly population (65 years or older) was attributed to heart disease. Such alterations in heart muscle include a decreased capacity to produce energy for heart contraction/relaxation and increased sensitivity of cardiac cells to stress stimuli. In this current project, we will establish the mechanism by which toxic lipids accumulate in diabetic cardiac cells, suppress energy production, and accelerate cardiac cell death. It will advance our understanding of lipid-induced toxicity in a diabetic heart and reveal specific targets for developing new therapeutics for the disorder. Because this project considers the basic mechanisms of cell dysfunction, the outcomes will have wide applicability to a variety disorders associated obesity and diabetes, including chronic renal failure, nerve damage, and retinal damage.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
My predominant area of research has been mitochondrial bioenergetics and lipid signaling. Diabetes research continues to be a comprehensive and synergistic effort by experts of diverse fields working toward a common goal that is now within reach. To be a part of and break new ground in this multifaceted collaboration would be a tremendous honor. The idea that the outcomes of my studies are applicable to such a devastating and wide-spread disease as diabetes is exciting for me. Knowing that your work will help decrease the suffering of other people is very satisfying. This award will act as a foundation, allowing me to accumulate and rationalize new knowledge, develop new tools, and create a framework for a lipid signaling centered approach to diabetic cardiomyopathy, which currently remains an understudied area of diabetes research.
In what direction do you see the future of diabetes research going?
Identification of the causes of diabetes and ways to manage, prevent, or cure the disorder will remain the main directions of research. I think that general research aimed on the intensive management of blood glucose, lipids and insulin through novel insulins, transplantation of islets, life style changes, etc. will provide a significant contribution in diabetes management and prevention. Studies aimed at the identification of the genetic markers of diabetes will allow earlier intervention aimed at prevention of diabetes. The long-term complications of diabetes affect every organ in the body. Each organ/cell has it own specific metabolic signature/signaling in response to diabetes. Therefore, the intensification of mechanistic studies aimed at the identification of these specific pathways should provide the basis for the development of novel, specifically targeted drugs which will allow us to decrease overall drug toxicity.
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