Extracellular Vesicle-Mediated Nrf2 Protein Secretion and its Therapeutic Application in Cardiogenic Dementia

Grants and Contracts Details

Description

Cardiogenic dementia has been used to characterize patients suffering from cognitive decline after chronic heart diseases. Although the mechanism responsible for cognitive decline following cardiac injury is multifactorial, the mechanism by which cardiac injury contributes to cognitive deficits remain to be well elucidated. Oxidative stress and neuroinflammation are common features of virtually every neurological disease and are increasingly recognized as potential mediators of neurological dysfunction. Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a critical role in maintaining and improving cognitive function by upregulating the antioxidant genes to protect cells from oxidative stress and by attenuating inflammation via regulation of proinflammatory cytokine genes. Our previous studies showed the potential involvement of extracellular vesicles (EVs) in disrupting redox homeostasis by downregulating brain Nrf2 signaling following myocardial injury. More recently, we observed the uptake of cardiac EVs by brain glial cells, suggesting the involvement of cardiac EVs in neuroinflammation. Moreover, our novel preliminary data also suggest a potential secretory pathway of Nrf2 and its downstream targets by EVs. These findings have led to our central hypothesis that cardiac EVs dysregulate neuroinflammation and redox homeostasis, eventually resulting in cardiogenic dementia, and the engineering brain-targeted EVs abundant with Nrf2 will provide a promising therapeutic strategy for cardiogenic dementia. To test our hypothesis, we proposed two Specific Aims: 1) To determine the contributions of cardiac EVs to brain inflammation and oxidative stress, and evaluate the cognitive impairment following myocardial injury; 2) To investigate the secretory mechanism of Nrf2 once activation, and develop the engineering brain-targeted Nrf2-enriched EVs and determine if these EVs attenuate neuroinflammation, oxidative stress and improve cognitive impairment caused by cardiac injury. Collectively, the proposed study will provide a novel Heart-brain communication pathway contributing to cognitive impairment following cardiac injury, and also provide a novel therapeutic strategy by developing the engineering brain-targeted Nrf2-enriched EVs for neurological disorders.
StatusActive
Effective start/end date7/1/246/30/27

Funding

  • American Heart Association: $100,000.00

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