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Erythrokeratodermia Variabilis Et Progressiva (Ekvp) Linked Cx30.3 Mutants Can Be Selectively Rescued By Co-Expression Of Wildtype Keratinocyte Connexins, Rhett O. Figliuzzi

Electronic Thesis and Dissertation Repository

Connexin 30.3 (Cx30.3) is a β-connexin encoded by GJB4 that is key in epidermal homeostasis. Eleven mutations to the GJB4 are linked to an autosomal dominant skin disease called erythrokeratodermia variabilis et progressiva (EKVP). These mutations remain largely uncharacterized, limiting therapeutic options. In this study, we characterize the expression and functional status of three EKVP-linked Cx30.3 mutants, G12D, T85P and F189Y in rat epidermal keratinocytes. We found that EKVP-linked Cx30.3 mutants were not functional due to their retention in the endoplasmic reticulum (ER), but did not upregulate BiP, an indicator of ER stress. Sub-physiological incubation and chemical chaperones (such as …

Discovery Of Novel Mechanisms Regulating Cancer Extravasation In The Chorioallantoic Membrane Model, Yohan Kim

Electronic Thesis and Dissertation Repository

Cancer metastasis is a multistep process that begins with the invasion of tumour cells into the stroma and migration towards the blood vessels. Tumour cells that have entered the bloodstream must then survive and leave by a process known as extravasation. Finally, extravasated cells proliferate and establish the secondary site in the metastatic cascade. Although extravasation encompasses key events during cancer cell invasion to aid in the development of effective treatments, an in vivo model that rapidly, reproducibly and economically recapitulates cancer cell extravasation is needed. Therefore, the objectives of my research were to 1) establish and validate an in …

The Role Of The Tau N-Terminal Phosphatase-Activating Domain And Phosphorylation At Thr175 In The Formation Of Tau Cytoplasmic Inclusions, Matthew A. Hintermayer

Electronic Thesis and Dissertation Repository

Cytoplasmic inclusions and fibrils of the microtubule-associated protein tau (tau protein) are a key neuropathological hallmark in tauopathies, including Alzheimer’s disease, chronic traumatic encephalopathy, and amyotrophic lateral sclerosis with cognitive impairment. Previous research has demonstrated that the phosphorylation of tau protein at Thr¹⁷⁵ is sufficient for the initiation of fibril formation both in vitro and in vivo. Here we use mutated tau protein constructs to demonstrate that phosphorylation at Thr¹⁷⁵ results in the aberrant exposure of an N-terminal phosphatase-activating domain (PAD). The tau PAD interacts with protein phosphatase 1 (PP1) leading to the activation of glycogen synthase …

The Effects Of Acetylenic Tricyclic Bis-(Cyano Enone) On Cell Migration, Eddie Chan

Electronic Thesis and Dissertation Repository

Although cancer survival rates have significantly improved over the past few decades, the improvements are primarily due to early diagnosis and inhibiting cancer growth. Limited progress has been made in the treatment of cancer metastasis, which contributes to 90% of cancer related deaths, and therapeutic agents targeting the various aspects of metastasis are lacking. One potential approach is to utilize small pharmacological compounds to inhibit tumour cell motility, as a strategy against tumour cell migration, invasion, and metastasis. The acetylenic tricyclic bis-(cyano enone), TBE-31, has been shown to be a promising chemopreventative compound. However, its effects on cell migration are …

Influence Of Polycaprolactone And Basic Fibroblast Growth Factor On Gingival Fibroblasts, Sarah Michelsons

Electronic Thesis and Dissertation Repository

Guided tissue regeneration (GTR) to regenerate periodontal tissue involves placement of a cell-occlusive barrier membrane functionally excluding the gingiva and associated oral epithelium from the periodontal defect. Gingival connective tissue (CT) contains a rich vascular plexus and is a source of progenitor cells which could contribute to periodontal regeneration. We propose the use of a novel biodegradable and bioactive electrospun fibrous polycaprolactone (PCL) scaffold loaded with microspheres releasing basic fibroblast growth factor (bFGF) to promote gingival CT growth while maintaining a barrier to the oral epithelium. Scaffolds supported human gingival fibroblast proliferation and mesenchymal cell infiltration in a bFGF dose …

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …

The Role Of Non-Canonical Wnt/Planar Cell Polarity Signalling In Breast Cancer Progression, Connor D. Macmillan

Electronic Thesis and Dissertation Repository

The role of planar cell polarity (PCP) signalling in breast cancer is unclear, as evidence shows that activation of this pathway with WNT5A can either promote or inhibit progression. Using the 21T cells, which represent distinct stages of breast cancer progression when grown in a mouse xenograft model (21PT, atypical ductal hyperplasia; 21NT ductal carcinoma in situ; 21MT-1, invasive mammary carcinoma), I hypothesized that WNT5A will promote progression only when VANGL1, another component of PCP signalling, is elevated.

Each 21T cell line showed distinct stage-specific morphologies when grown in a Matrigel “on-top” assay. WNT5A overexpression promoted progression to an invasive …