Despa, Florin , PhD
Epoxide hydrolyse, a new therapeutic target for cardioprotection in insulin resistance and diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications, Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes, Integrated Physiology\Insulin Resistance
Type of Grant: Innovation
Project Start Date: January 1, 2013
Project End Date: December 31, 2014
We will test the hypothesis that limiting cardiac accumulation of oligomeric amylin, an amyloidogenic hormone that is elevated in the blood of patients with obesity and type 2 diabetes, delays the development of diabetic heart failure. In particular, we are trying to elucidate whether endogenous molecules with anti-aggregation effects may limit amylin oligomerization and target amylin oligomers for removal from the circulation. At the same time, we are testing methods to increase the concentration of anti-aggregation molecules in the blood, so that we can effectively reduce accumulation of oligomeric amylin in the heart.
Our data show that epoxyeicosatrienoic acids, pro-fibrinolytic molecules contained in human blood and tissues, block amylin oligomerization and attachment of oligomeric amylin to the myocyte sarcolemma and improve cardiac myocyte function. We now work with rats that express amyloidogenic human amylin and accumulate oligomeric amylin in the heart to test whether increasing the availability of epoxyeicosatrienoic acids limits cardiac amylin deposition and its deleterious effects.
Our long term goal is to understand how amylin oligomers accumulate in the heart, how they affect cardiac function, and how amylin deposition could be prevented/ limited in patients with obesity and type 2 diabetes.
This study will demonstrate whether endogenous pro-fibrinolytic epoxyeicosatrienoic acids are involved in removal of amylin oligomers from the circulation, thus limiting their deposition in the heart. If our hypothesis that limiting amylin oligomer deposition in the heart improves cardiac function is proven, then this study will be a basis for designing future therapeutic strategies for treating diabetic heart disease.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and curing diabetes?
Our research focuses on cardiovascular complications of pre-diabetes. Specifically, this research project will test the hypothesis that limiting cardiac accumulation of oligomerized amylin, an amyloidogenic hormone that is elevated in the blood of patients with obesity and insulin resistance, prevents/ delays the development of diabetic heart failure. If successful, this innovative project will lead to new treatment strategies for patients with pre-diabetes and diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Accumulation of oligomerized amylin in the cardiovascular system is toxic and increases the risk for heart failure. This proof of concept will test whether modulating the endogenous levels of molecules with anti-aggregation effects can disrupt oligomeric amylin circulating in the blood. At the same time, we are testing methods to increase the concentration of anti-aggregation molecules in the blood, so that we can effectively reduce accumulation of oligomeric amylin in the heart and thus, prevent/ reduce heart injury.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Diabetes has reached epidemic proportions in the US. As a scientist and a member of our community, it is part of my responsibility to help increase our understanding of the disease and advance the research for a cure. The award will help my lab to continue our innovative project on deciphering the early molecular links of pancreatic dysfunction with cardiovascular disease. This award provides recognition to our work and will also seed other successful research grant applications.
In what direction do you see the future of diabetes research going?
Prevention of diabetes and diabetes complications should be an important focus of our research.
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