Skin and Connective Tissue Diseases Commons^™

Kindlin-1 Is Involved In Spreading, Migration, And Protein Regulation In Epidermal Scc-13 Cells, Naomi Mishan

Electronic Thesis and Dissertation Repository

Kindlin-1 is a scaffold protein linking the cytoskeleton to the extracellular matrix. Loss of function mutations in the FERMT1 gene (encoding Kindlin-1) cause gastrointestinal and skin defects associated with increased susceptibility to aggressive epidermal squamous cell carcinoma (SCC). This study investigated the consequences of targeted FERMT1 inactivation in the SCC-13 cell line of epidermal SCC. My studies demonstrate Kindlin-1 is not essential for SCC-13 proliferation or clonogenic potential in culture. Kindlin-1 was required for cell spreading on collagen I, but not on laminin-332, and its absence enhanced SCC-13 directional migration. Finally, I identified several proteins involved in tumor formation and …

The Regulation Of Pannexin1 And Pannexin2 In The Skin In Health And Disease, Rafael E. Sanchez Pupo

Electronic Thesis and Dissertation Repository

Pannexins (PANX1, 2, 3) are a family of channel-forming glycoproteins that mediate intracellular and paracrine signaling. In contrast to PANX2, PANX1 has been extensively investigated in the skin, modulating cell differentiation, wound healing, and melanoma development. PANX1 and PANX2 can co-exist in the same cell and form mixed channels where their glycosylation seems to regulate their intermixing. N-glycosylation and caspase cleavage have been proposed as modulators of the function of PANX1, but their effects on PANX2 are unknown. We explored the PANX2 expression in mouse skin and showed that a Panx2 splice variant (PANX2-202) is continuously expressed throughout aging skin. …

Yap-Mediated Mechanotransduction Promotes Fibrotic Activity, Michael Racanelli

Electronic Thesis and Dissertation Repository

Fibrosis, a phenotype associated with mortality for a multitude of diseases, has no disease-modifying treatment. We examine if Verteporfin (VP), an inhibitor of the YAP-TEAD complex, currently in wide clinical use for macular degeneration, can inhibit pro-fibrotic gene expression in human dermal fibroblasts. Also, an in vivo approach was taken using a Pten-deficient mouse of progressive skin fibrosis for examining effects on melanoma metastasis. We found that treatment with VP reduced basal expression of a variety of profibrotic genes and prevented a myofibroblast-like phenotype in response to TGFβ1. Indeed, genome-wide expression analysis suggested that VP inhibited a cluster of …

The Effect Of Function-Blocking Rhamm Peptides In A Mouse Model Of Bleomycin-Induced Systemic Sclerosis, Kitty Y. Wu

Electronic Thesis and Dissertation Repository

Systemic sclerosis is a chronic, fibrotic disorder associated with high disease-specific mortality and morbidity. Cutaneous manifestations include dermal thickening and obliteration of dermal adipose tissue. The efficacy of function-blocking Rhamm peptides, NPI-110 and NPI-106, were tested in reducing skin fibrosis and promoting adipogenesis in a bleomycin-induced mouse model of systemic sclerosis. NPI-110 reduced both visible measures of fibrosis (dermal thickness, collagen density, and fibril bundling) and mRNA expression of pro-fibrotic genes (Tgfb1, c-Myc, Col1a1, Col3a1). While there was no measurable change in dermal adipose thickness, NPI-110 treatment upregulated Perilipin mRNA and Adiponectin protein expression and is therefore hypothesized to …

Methotrexate And Cardiovascular Events, Alpesh Shah

Electronic Thesis and Dissertation Repository

We conducted a systematic review and meta-analysis to assess the association of MTX with cardiovascular morbidity, cardiovascular mortality and all-cause mortality in patients with autoimmune disease. Our primary outcome was incident cardiovascular events. After screening 13,479 citations, we identified a total of 30 eligible studies. We synthesized adjusted risk estimates using a random effects model. MTX was significantly associated with a 25% reduction in cardiovascular events (pooled RR: 0.75, 95% CI: 0.65, 0.86, I²: 11%), a 55% reduction in cardiovascular mortality (0.45, 95% CI: 0.26, 0.80, I²: 33%) and a 40% reduction in all-cause mortality (0.60, …

Investigation Of Β-Catenin-Mediated Regulation Of Igfbp-6 And The Roles Of Igfbp-6 And Igf-Ii In Dupuytren's Disease, Christina N. Raykha

Electronic Thesis and Dissertation Repository

Dupuytren’s Disease (DD) is a benign and heritable connective tissue fibrosis that affects the palmar fascia and typically results in permanent finger contracture(s). Similar to other fibroses, DD is characterized by increased fibroblast proliferation, myofibroblast differentiation and excess collagen deposition. Currently, there are no truly effective treatment options for connective tissue fibroses.

Increased levels of β-catenin, an intracellular trans-regulator of gene transcription, have been previously reported in DD. Genes that are associated with, and therefore potentially transcriptionally regulated by, β-catenin during DD development were identified in this thesis. One of these gene targets, IGFBP6, was shown to consistently be …

Evaluation Of Matricellular Proteins As Potential Therapeutics For The Treatment Of Human Chronic Skin Wounds, Christopher G. Elliott

Electronic Thesis and Dissertation Repository

There is currently an unmet need for treatments to enhance healing of human chronic skin wounds. Previously, therapy development has focused on growth factors and physical matrices, often resulting in disappointing clinical outcomes. In this thesis, we approached chronic skin wound treatment with a focus on fibrosis and matricellular proteins. Fibrosis is a pathological condition where tissue repair continues, unchecked, resulting in excess contraction, matrix accumulation and fibrogenic growth factor activity; features critically reduced in chronic skin wounds. Identifying factors that promote fibrosis may offer new therapeutic targets for use in chronic skin wounds. Two such factors are the matricellular …

Mutant Cx43 In Skin Differentiation And Disease, Jared M. Churko

Electronic Thesis and Dissertation Repository

Connexin43 (Cx43) is expressed within keratinocytes, dermal fibroblasts, and the hair follicle epithelium. Since Cx43 is so widely expressed in resident cells of the skin, we speculated that this connexin would play an essential role in skin homeostasis, hair growth and wound healing. Mutations in the gene which encodes Cx43 lead to a disease called oculodentodigital dysplasia (ODDD) and patients expressing the frame-shift mutants (fs230 or fs260) develop a skin disease called palmar plantar hyperkeratosis. In addition, patients with ODDD often develop hair which is dry, sparse, and slow growing. To study skin abnormalities associated with ODDD, hair growth and …