Author ORCID Identifier

https://orcid.org/0000-0002-8263-9662

Semester

Fall

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

A. Courtney DeVries-Nelson

Committee Co-Chair

Paul D. Chantler

Committee Member

James W. Simpkins

Committee Member

Candice M. Brown

Committee Member

I. Mark Olfert

Abstract

Despite decades of research psychological stress remains a prevalent problem in society, often diminishing quality of life and increasing the risk of developing dementia. The brain plays a central role in the response to stress and as it is unable to store energy substrates, the brain relies heavily on dynamically regulated blood flow. Therefore, it is important that there is a tight coupling between neural activity and cerebral blood flow to meet metabolic demands and maintain critical brain function. It has been established that chronic psychological stress has detrimental effects on cerebrovascular function, potentially through increased superoxide anion production through the xanthine oxidase (XO) pathway. While the alterations to cerebrovascular function and increased oxidative stress have been well-defined, there is no evidence of a mechanism behind such alterations. Therefore, there is a critical need to identify the mechanism linking chronic stress and cerebrovascular dysfunction as well as the potential role of the XO pathway.

The projects specific aims are:

  1. Specific Aim 1: To test the hypothesis that the xanthine oxidase pathway mediates the cerebrovascular dysfunction associated with chronic stress.
    1. Determine the impact of complete inhibition of the XO pathway by means of a novel drug, febuxostat, on cerebrovascular function in a model of chronic stress.
    2. Examine the impact of pharmacological manipulation of the xanthine oxidase pathway through a sodium nitrite supplementation on cerebrovascular function in a model of chronic stress.
  1. Specific Aim 2: To test the hypothesis that toll-like receptor 4 activation plays a central role in exacerbating the cerebrovascular dysfunction with chronic stress.
  1. 3. Specific Aim 3: To test the hypothesis that chronic stress accelerates Alzheimer’s disease-related cerebrovascular dysfunction in a triple transgenic mouse model.

The results of these studies have helped to gain an understanding of the mechanisms driving cerebrovascular dysfunction with chronic stress. By thoroughly interrogating these mechanisms and applying them to a model of Alzheimer’s disease, this dissertation hopes to lay the groundwork for assessing the impact of chronic stress on accelerating the pathology of Alzheimer’s disease and elucidating a potential mechanism behind this pathology.

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