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Description
The WNT signaling pathway plays numerous roles in development and maintenance of adult homeostasis. In concordance with it’s numerous roles, dysfunction of WNT signaling leads to a variety of human diseases ranging from developmental disorders to cancer. WNT signaling is composed of a family of 19 WNT soluble secreted glycoproteins, which are evolutionarily conserved across all phyla of the animal kingdom. WNT ligands interact most commonly with a family of receptors known as frizzled (FZ) receptors, composed of 10 independent genes. Specific interactions between WNT proteins and FZ receptors are not well characterized and are known to be promiscuous, Traditionally canonical WNT signaling is described as a binary system in which WNT signaling is either off or on. In the ‘off’ state, in the absence of a WNT ligand, cytoplasmic β-catenin is continuously degraded by the action of the APC/Axin/GSK-3β destruction complex. In the ‘on’ state, when WNT binds to its Frizzled (Fz) receptor and LRP coreceptor, this protein destruction complex is disrupted, allowing β-catenin to translocate into the nucleus where it interacts with the DNA-bound T cell factor/lymphoid factor (TCF/LEF) family of proteins to regulate target gene expression. However in a variety of systems in development and disease canonical WNT signaling acts in a gradient fashion, suggesting more complex regulation of β-catenin transcriptional activity. As such, the traditional ‘binary’ view of WNT signaling does not clearly explain how this graded signal is transmitted intracellularly to control concentration-dependent changes in gene expression and cell identity. I have developed an in vitro human pluripotent stem cell (hPSC)-based model that recapitulates the same in vivo developmental effects of the WNT signaling gradient on the anterior-posterior (A/P) patterning of the neural tube observed during early development. Using RNA-seq and ChIP-seq I have characterized β-catenin binding at different levels of WNT signaling and identified different classes of β-catenin peaks that bind cis-regulatory elements to influence neural cell fate. This work expands the traditional binary view of canonical WNT signaling and illuminates WNT/β-catenin activity in other developmental and diseased contexts.
ContributorsCutts, Joshua Patrick (Author) / Brafman, David A (Thesis advisor) / Stabenfeldt, Sarah (Committee member) / Nikkhah, Mehdi (Committee member) / Wang, Xiao (Committee member) / Plaisier, Christopher (Committee member) / Arizona State University (Publisher)
Created2019
Description
Malignant Pleural Mesothelioma (MPM) is an aggressive deadly tumor that has few therapeutic options. Immunotherapies have shown great potential in alleviating MPM patient symptoms. Using patient data from the Cancer Genome Atlas (TCGA) we sought to identify mutations, regulators, and immune factors driving immune cell migration. We explored computational methods to define regulatory causal flows in order to make biological predictions. These predictions were verified by cross-referencing peer-reviewed articles. A disease-relevant inference model was developed to examine the chemokine IL-18’s effect on natural killer cell (NK cell) migration.
ContributorsWipper, Gabrielle Frances (Author) / Plaisier, Christopher (Thesis director) / Plaisier, Seema (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Malignant Pleural Mesothelioma is a type of lung cancer usually discovered at an advanced stage at which point there is no cure. Six primary MPM cell lines were used to conduct in vitro research to make conclusions about specific gene mutations associated with Mesothelioma. DNA exome sequencing, a time efficient and inexpensive technique, was used for identifying specific DNA mutations. Computational analysis of exome sequencing data was used to make conclusions about copy number variation among common MPM genes. Results show a CDKN2A gene heterozygous deletion in Meso24 cell line. This data is validated by a previous CRISPR-Cas9 outgrowth screen for Meso24 where the knocked-out gene caused increased Meso24 growth.
ContributorsKrdi, Ghena (Author) / Plaisier, Christopher (Thesis director) / Wilson, Melissa (Committee member) / School of Life Sciences (Contributor) / Hugh Downs School of Human Communication (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Glioblastoma (GBM) is the most lethal primary brain tumor in adults with a less than 5% chance of survival beyond 5 years. With few effective therapies beyond the standard of care, there are often treatment resistant recurrences seen in most patients. STAT5 is a protein that has shown to be upregulated in highly invasive and treatment resistant GBM. Elucidating the role of STAT5 in GBM could reveal a node of therapeutic vulnerability in primary and recurrent GBM.
ContributorsInforzato, Hannah (Author) / Plaisier, Christopher (Thesis director) / Tran, Nhan (Committee member) / Blomquist, Mylan (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / Department of Psychology (Contributor)
Created2022-05
Description
An immune regulatory network was constructed for the purpose of identifying target regulators in malignant pleural mesothelioma for therapies. An identified causal flow linked a mutation of D-dopachrome tautomerase to a heightened expression of regulator ASH1L and consequent down regulation of chemokine CCL5 and invasion of CD8+ T cells. Experimental validation of this initial use case indicates mRNA expression of CCL5 within the tumor cells and subsequent protein expression and secretion. Further analyses will explore the migration of CD8+ T cells in response to the chemotactic CCL5.
ContributorsCook, Margaret (Author) / Plaisier, Christopher (Thesis director, Committee member) / Wilson, Melissa (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor) / School of Molecular Sciences (Contributor)
Created2022-05
Description
panCanSYGNAL is a web-application designed to allow cancer researchers to search the relationships between somatic mutations, regulators, and biclusters corresponding to many cancers using a Google-like searchable database.
ContributorsWatson, Jacob (Author) / Plaisier, Christopher (Thesis director) / Clough, Michael (Committee member) / Barrett, The Honors College (Contributor) / Computer Science and Engineering Program (Contributor)
Created2022-05