The influence of "a5ß1" integrin inhibition in a clinically relevant model of vascular dementia
Description: Approximately 34 million people live in the USA with type-2 diabetes mellitus, a known risk factor for vascular dementia (VaD). VaD currently lacks effective therapy. In 2016 alone, it cost $950 billion to care for VaD patients across the world. The burden of VaD is projected to rise as the global aging population and prevalence of type-2 diabetes increases. Although, it is now established that midlife diagnosis of these diseases is associated with cognitive decrements and considerably worsens the progression of VaD, scientific studies primarily use healthy young adult rodents without clinically relevant factors for VaD. Hence, there is a critical translational need to characterize type-2 diabetes in middle-age rodents in the context of VaD. Bilateral carotid artery stenosis (BCAS), which results in shortage of blood to the brain is used to model VaD, causes cognitive impairment due to white matter injury and blood-brain barrier (BBB) disruption. My preliminary data suggests that measures of brain injury are worsened in middle age and with type-2 diabetes in mice. Also, I demonstrate that BCAS increases the expression of brain a5ß1 integrin and that inhibition with the peptide ATN-161, which can be safely administered to humans, improves BBB stability and attenuates working memory impairment following 14 days BCAS in mice. The next logical step is to understand the impact of BCAS in middle-age mice, with or without type-2 diabetes, and to test the ameliorative effect of ATN-161 during BCAS. Therefore, I hypothesize that type-2 diabetes and middle age will intensify post-BCAS effects and cognitive decline and that inhibition of a5ß1 integrin with ATN-161 (1 mg/kg, i.p., immediately after BCAS and on alternate days) would stabilize the BBB and attenuate brain-vascular pathology. BCAS or sham surgery will be performed in young or middle-aged diabetic and genotype control mice. I will utilize a battery of cognitive functional assays and neuro-histological panels to characterize vascular pathology following at 15 days post-BCAS. I expect to demonstrate that inhibition of a5ß1 with ATN-161 will improve outcome measures following BCAS in middle aged and diabetic mice. The findings of this study will advance the mission of AHA as this project will characterize VaD in middle age with or without type-2 diabetes as well as investigating the potential therapeutic benefit ATN-161 may provide. This fellowship will support my development as an independent investigator.
Funder: American Heart Association
Amount: $133,500
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2021-04-01
End date: 2023-03-31
Investigators: Ifechukwude Biose, Ifechukwude Biose
Institution: Tulane University Health Sciences Center
Funded outputs count: 1
Funder award ID: 831577
OpenAlex ID: G2919475424