Tissue injury-induced autoimmunity and the pathogenesis of cardiovascular disease complications in diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes
Type of Grant: Clinical Translational Research
Project Start Date: July 1, 2011
Project End Date: June 30, 2014
Patients with type 1 diabetes (T1D) suffer dispropotionately from heart attacks (myocardial infarction) but the reasons for this are unclear. Although numerous factors related to diabetes have been implicated, none of these factors are unique to people with T1D. We have discovered that the experimental induction of myocardial infarction in non-obese diabetic mice -- a model for human T1D -- triggers the development of an irreversible post-infarction autoimmune (PIA) syndrome characterized by: (1) destructive immune infiltrates in the heart similar in composition to 'insulitis' lesions in the pancreas that cause T1D; (2) poor infarct healing; and 3) development of autoantibodies directed against heart muscle proteins. We subsequently developed blood tests for the detection of cardiac autoantibodies in patients and have found that 83% (15/18) post-infarcted T1D patients but only 15% (3/20) post-infarcted T2D patients test positive for autoantibodies. These studies suggest that a PIA syndrome also develops in humans with T1D.
We propose to: 1) Directly test whether myocardial infarction induces PIA in T1D patients by measuring the development of cardiac autoantibodies in samples collected before and after heart attacks from the Pittsburgh Epidemiology of Childhood-Onset Diabetes Complications study; 2) Determine in our PIA cohort at Joslin whether the presence of cardiac autoantibodies correlates with abnormal T-cell responses to cardiac proteins; and 3) Define the prevalence of PIA in T2D by screening larger number of T2D patients with and without heart attacks. These studies could open a new window into our understanding of the cause and treatment of heart disease in diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I've had a longstanding interest in diabetes research as a Pediatric Endocrinologist and Immunologist.
I am extremely grateful to the ADA for providing me with this Clinical/Translational Award. This award will provide my laboratory with critical 'bridging funds' and enable us to continue to make important new discoveries until NIH funding can be secured.
In what direction do you see the future of diabetes research going?
When I started my research career, it was hoped that research focused on
mouse models (notably NOD mice) would hold the key to discovering
therapies to prevent and treat human type 1 diabetes. Now, we realize
that human disease is far more complex than anticipated, and there has
been a swing in the opposite direction with an emphasis on purely human
clinical studies without 'proof-of-principle' in animal models. I
ultimately see both approaches being pursued simultaneously, since the
potential information to be gained from this translational approach is
so complementary and synergistic.
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