Symons, John David, PhD
Protein phosphatase 2A activation is required for lipid-induced, ceramide-mediated arterial dysfunction
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications, Complications\Macrovascular-Cellular Mechanisms of Atherogenesis in Diabetes, Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Obesity, Obesity\Animal Models
Type of Grant: Minority Undergraduate Internship
Project Start Date: January 1, 2013
Project End Date: December 31, 2013
Cardiovascular complications are the leading causes of morbidity and mortality in individuals with diet-induced obesity (DIO), type 2 diabetes mellitus (T2DM), and insulin resistance (IR). Complications include pathologies specific to large (e.g., atherosclerosis) and small (e.g., retinopathy) blood vessels. Common among all of these pathologies is endothelial dysfunction. Blood vessels are composed of an inner (the endothelium), middle (the vascular smooth muscle) and outer (the adventitia) layer. A crucial aspect of endothelial dysfunction is a disrupted ability of an enzyme located in the endothelium (i.e., endothelial nitric oxide synthase; eNOS) to synthesize and produce nitric oxide (NO). NO causes blood vessels to relax, which contributes to improved blood flow and reduced blood pressure.
Work from our laboratory indicates that elevated free fatty acids in experimental models of DIO, T2DM, and IR cause a toxic substance called ceramide to become elevated in blood vessels. Elevated ceramide disrupts the ability of eNOS to produce NO. The MUI (Ms Uzoigwe) will test a mechanism whereby ceramide might disrupt the eNOS enzyme. Specifically, Ms Uzoigwe will determine whether ceramide disrupts eNOS enzyme function and causes endothelial dysfunction secondary to activating an intracellular protein called protein phosphatase 2A (PP2A). Obesity is an epidemic in both genders and among all age groups. Results from the proposed experiment will provide important, novel, mechanistic insight into mechanisms whereby lipotoxicity associated with DIO, T2DM, and IR might contribute to vascular dysfunction. This information will aid in designing new therapeutic intervention strategies for treating DIO, T2DM, and IR.
Mentor: John Symons
Undergraduate: Emmanuella Uzoigwe
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and curing diabetes?
The prevalence of obesity in the United States exceeds 30% for both genders in most age groups. Obesity predisposes individuals to type 2 diabetes and insulin resistance. Of the ~24 million people in the United States with diabetes, 90-95% have type 2 diabetes. Cardiovascular complications are the leading cause of death in diabetics. One cardiovascular complication is impaired blood vessel function. Consequences of impaired blood vessel function include high blood pressure, peripheral limb pain upon exertion, poor wound healing, and in extreme cases, blindness or amputation. The precise mechanisms responsible for vascular dysfunction associated with type 2 diabetes are unclear. Obesity and type 2 diabetes are associated with elevated circulating concentrations of free fatty acids (FFAs). When FFA accumulation exceeds adipose storage and oxidative capacity they are deposited into tissues not suited for lipid storage. Lipid oversupply can lead to the accumulation of metabolites that are associated with cardiovascular risk. With previous support from the ADA we showed that one biologically active lipid metabolite that contributes to vascular dysfunction is ceramide. At present, studies in my laboratory are designed to determine the precise mechanisms whereby this toxic substance impairs the ability of blood vessels to function properly. It is important to understand mechanisms that precipitate vascular dysfunction so that therapeutic targets and intervention strategies can be designed. Information generated by testing our hypotheses will provide important insight into understanding the contribution from ceramide to cardiovascular defects that exist in our clinically relevant experimental animal model of diet-induced obesity and the metabolic syndrome
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Individuals with diabetes often develop cardiovascular complications. One cardiovascular complication is impaired blood vessel function. Consequences of impaired blood vessel function include, but are not limited to, high blood pressure, peripheral limb pain upon exertion, poor wound healing, and in extreme cases, blindness or amputation. The precise mechanisms responsible for vascular dysfunction associated with type 2 diabetes are unclear. My laboratory hopes to determine mechanisms whereby vascular dysfunction occurs in the context of diabetes. It is hoped that our results will provide mechanistic insight linking one potential mechanism i.e., endogenous vascular ceramide biosynthesis, to cardiovascular defects in a clinically relevant murine model of diet-induced obesity and type 2 diabetes, and present new targets for the treatment of vascular dysfunction in these prevalent conditions.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
I am interested in cardiovascular physiology in general, and vascular biology in particular. Type 2 diabetes is an epidemic that does not discriminate regarding gender or age. Vascular function is impaired in individuals with type 2 diabetes. As such, this is an important and clinically relevant area to study. I am a basic scientist that is interested in elucidating the mechanisms responsible for vascular dysfunction in the context of type 2 diabetes. This is challenging but has potential to provide insight concerning mechanisms that might lead to efficacious therapeutic intervention strategies to treat cardiovascular complications associated with type 2 diabetes.
My ADA grant in general is important because it allows funds for: supplies, experimental animals, equipment and a contribution toward salary support for laboratory personnel. The MUI in particular is important because it provides Ms Uzoigwe with a stipend to participate in diabetes related research. It is my hope that facilitating her exposure to biomedical research might foster her consideration of a career as an academic physician -- with an interest in diabetes related research.
I thank the ADA for supporting my research. These experiments would not be possible without the generous monetary support from the donors and the administrative support from the agency and their dedicated staff.
In what direction do you see the future of diabetes research going?
While diabetes affects many individuals worldwide, each case is nuanced. In this regard, I see an integration of research findings from molecular, organ, whole animal, and clinical systems to a degree whereby each treatment plan/intervention strategy might become more personalized/individualized in the future.
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