Date of Award

1-1-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Pharmaceutical Sciences

Specialization

Pharmacology and Toxicology

Department

Biomedical and Pharmaceutical Sciences

First Advisor

William E Van Nostrand

Abstract

Hypertension (HTN) and thrombotic events cause vascular compromise and are both related to pathology of cerebral amyloid angiopathy (CAA). Both HTN and CAA are cerebral small vessel diseases that cause many of the same pathologies, particularly thrombosis, intracerebral hemorrhage, and stroke. The purpose of this dissertation is to elucidate how introducing the common vascular comorbidity HTN (with two differing rat models) or the pharmacological targeting of thrombin by dabigatran etexilate, impacts pathology in the transgenic rTg-DI rat model of CAA to elucidate mechanisms of the disease with and without a comorbidity.

Cross breeding of rTg-DI with Spontaneously Hypertensive Stroke Prone (SHR-SP) and Spontaneously Hypertensive (SHR) rat lines established two novel rat lines exhibiting both CAA and HTN. Using these new lines of rats, experiments for blood pressure readings, behavioral testing, perfusions and subsequent specimen collection, enzyme-linked immunosorbent assay (ELISA), stereology by histochemical and immunohistochemical techniques, and proteomics by mass spectrometry were completed. It was found that cross breeding of the rTg-DI rat with SHR-SP and SHR rats produced moderate yet different changes in typical pathologies of the rTg-DI rat. The variety of pathologies and effects seen in these bigenic animals provide two novel and differing platforms for further studies of HTN and CAA.

Oral treatment of rTg-DI rats with the thrombin inhibitor dabigatran etexilate for one month followed by perfusion and subsequent specimen collection, ELISA, stereology by histochemical and immunohistochemical techniques, and proteomics by mass spectrometry were completed to understand the drug’s effects on already developed thrombotic pathologies of CAA in the rTg-DI rat. Administration of dabigatran etexilate rat showed no apparent changes of pathologies as identified by stereology but had effects on cerebral proteins implicated in CAA in the rTg-DI rat.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Figure S1 Decrease in HTRA1 protein Expression in Dabigatran Treated rTg-DI Rats.jpg (972 kB)
Figure S1: HTRA1 Protein Expression Graph

Table S1. Elevated Proteins in the SHRSP Cortex.xlsx (18 kB)
Table S1. Elevated Proteins in the SHRSP Cortex

Table S2. Elevated Proteins in the rTgDI Cortex.xlsx (29 kB)
Table S2. Elevated Proteins in the rTgDI Cortex

Table S3. Elevated Proteins in the rTgDI_SHRSP Cortex.xlsx (17 kB)
Table S3. Elevated Proteins in the rTgDI_SHRSP Cortex

Table S4. Decreased Proteins in the SHRSP Cortex.xlsx (12 kB)
Table S4. Decreased Proteins in the SHRSP Cortex

Table S5. Decreased Proteins in the rTgDI Cortex.xlsx (17 kB)
Table S5. Decreased Proteins in the rTgDI Cortex

Table S6. Decreased Proteins in the rTgDI_SHRSP Cortex.xlsx (22 kB)
Table S6Table S6. Decreased Proteins in the rTgDI_SHRSP Cortex

Table S7 Elevated and reduced proteins in dabigatran treated WT and rTg-DI rat brain.xlsx (15 kB)
Table S7 Elevated and reduced proteins in dabigatran treated WT and rTg-DI rat brain

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