Grants and Contracts Details
This proposed research will test the innovative hypothesis that the increased risk for cerebrovascular disease, including stroke, which are frequently seen in patients with metabolic disorders, may be caused, at least in part, by the cerebrovascular accumulation of amylin, a diabetogenic hormone secreted from the pancreas. This hypothesis is based on our recently published clinical study showing large deposits of amylin in brain blood vessel walls of aged individuals, preponderantly those who suffer from diabetes with cerebral amyloid angiopathy (CAA). In CAA patients, amylin formed both independent vascular amyloid and mixed amylin-Aâ deposits. Oligomerized amylin was previously shown to contribute to the development of type-2 diabetes, heart disease and kidney failure. We, therefore, hypothesize that i) vascular incorporation of oligomerized amylin causes CAA independently of Aâ pathology and ii) mitigating the vascular incorporation of amylin reduces the pathological progression of CAA. Because rodent amylin does not form amyloid, a diabetic rat model transgenic for human amylin will be used to determine functional effects of the cerebrovascular amylin deposition. To investigate amylin-mediated effects in the absence of diabetes, amylin knock-out mice will be intravenously infused with oligomerized human amylin or mouse amylin (controls). We will also test the progression of CAA in a CAA mouse model (APP/PS1 mouse) intravenously infused with oligomerized amylin. Animals will be tested for cerebrovascular amylin accumulation, cerebral blood flow, neurologic deficits and inflammation. The results of our studies will advance the fundamental understanding of the complex links between metabolism, pancreatic hormone amylin and cerebrovascular health. Therefore, this project is based on the importance of the pancreatic hormone amylin to metabolism and cerebrovascular disorders and current lack of understanding of mechanisms underlying the cerebrovascular accumulation of amylin and subsequent effects on the structure and function of brain blood vessels. We anticipate that the results of our proposed study will enrich our capabilities to adjust/reverse pathological changes of brain blood vessels in disease and ageing.
|Effective start/end date||7/1/16 → 12/31/18|
- American Heart Association Great Rivers Affiliate: $99,438.00
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