Vascular cognitive impairment in diabetes: mechanisms and intervention
Description: Vascular contributions to cognitive impairment and dementia (VCID) spectrum disorders are the second leading cause of all dementias. Cerebrovascular dysfunction contributes to neuronal inflammation and white matter degeneration in VCID. Diabetes is a major risk factor for vascular dysfunction and VCID. Yet, mechanisms that disrupt neurovascular crosstalk and promote development of VCID are not well understood. The goal of this application is to start addressing this gap by defining mechanisms contributing to the disruption of communication within the neurovascular unit (NVU) using a microemboli-based model of VCID and diabetic animals that develop early cerebrovascular dysfunction and cerebral hypoperfusion. To achieve this goal, two aims will test the central hypothesis that cerebrovascular dysfunction in diabetes facilitates entrapment of microemboli and amplifies senescence associated vascular inflammation leading to disruption of trophic coupling within the NVU and development of cognitive decline. AIM 1 will determine whether a) diabetic animals develop amplified and sustained endothelial senescent-associated secretory phenotype (SASP) after microemboli injection that leads to demyelination and accelerated cognitive decline using a battery of behavioral tests and ultra-sensitive molecular magnetic resonance imaging (mMRI) in control and diabetic rats, and b) treatment with vasodilator cilostazol prevents endothelial SASP and VCID. AIM 2 will test the working hypothesis that diabetes-mediated endothelial senescence or associated increase in IL-1ß decreases endothelial trophic coupling and propagates OPC senescence and how cilostazol prevents this harmful outcome. Better understanding of the mechanisms by which cerebrovascular dysfunction mediates the development of neurovascular senescent-linked inflammation has the potential to identify novel preventive/therapeutic targets for VCID.
Funder: American Heart Association
Amount: $144,700
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2021-04-01
End date: 2022-03-05
Investigators: Raghavendar Chandran, Raghavendar Chandran
Institution: Medical University of South Carolina
Funded outputs count: 1
Funder award ID: 831316
OpenAlex ID: G3359468960