Publication Date

12-2021

Date of Final Oral Examination (Defense)

11-4-2021

Type of Culminating Activity

Dissertation

Degree Title

Doctor of Philosophy in Biomolecular Sciences

Department

Biology

Supervisory Committee Chair

Richard Beard Jr., Ph.D.

Supervisory Committee Member

Daniel Fologea, Ph.D.

Supervisory Committee Member

Lisa Warner, Ph.D.

Abstract

Dysfunction of the blood vessels that form the blood-brain barrier (BBB) is observed across various neurological disorders, including multiple sclerosis (MS). As barrier loss culminates in neuronal dysfunction and degeneration, a better understanding of the mechanisms underlying BBB dysfunction is needed.

Tight junctions are multiprotein complexes maintained by the endothelial cells lining the inner blood vessel wall to seal the intercellular space, and their disruption impairs BBB function. In my first chapter, I focus on how tight junctions are altered in CNS inflammatory demyelinating diseases (CNS-IDDs) like MS as BBB dysfunction is one of the earliest known stages in their disease progression. Literature searches were conducted for relevant studies involving three prominent tight junction protein families, namely the claudins, tight junction-associated MARVEL proteins (TAMPs), and angulins. As few studies analyzed patient tissues, additional literature searches were conducted for relevant cell culture and animal models. Particular attention is paid to studies involving pharmacological interventions or genetic manipulations as tight junctions are increasingly being recognized as possible therapeutic targets for preserving or restoring BBB function and, in turn, CNS homeostasis.

In my second chapter, I explore how the molecular composition of the vascular basement membrane (BM) can influence barrier function. Under healthy conditions, the vascular BM surrounding the endothelium fosters BBB function through cell-extracellular matrix (ECM) protein interactions that promote the tight junction protein claudin-5. During inflammation, however, the molecular composition of the BM is perturbed. Recently, the ECM proteins collagen type I and decorin, both of which are typically absent from the BM, were observed surrounding vessels in the lesions of MS patients. As their roles in inflammation are poorly understood, I investigated whether they can influence barrier function or claudin-5 expression. Using a mouse model of inflammatory encephalomyelitis, I found that decorin is present within the BM during early disease when the onset of BBB dysfunction occurs. In complement, I conducted cell culture studies with mouse BBB endothelial cells, overall finding an inverse relationship between decorin and barrier function or claudin-5. Similar cell culture studies using collagen type I revealed a similar inverse relationship between it and barrier function or claudin-5.

Overall, this work suggests that 1) tight junction proteins may be a viable therapeutic target in restoring BBB dysfunction and 2) inflammation-associated alterations to the vascular BM may contribute to BBB dysfunction by suppressing the tight junction protein claudin-5.

DOI

https://doi.org/10.18122/td/1903/boisestate

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