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Insights Into The Non-Osmoregulatory Function Of A Pollen-Specific Mechanosensitive Ion Channel, Kari Miller

Arts & Sciences Electronic Theses and Dissertations

Pollen, the male gametophyte of flowering plants, delivers the sperm cells to the ovule to carry out sexual reproduction. During this process, the pollen grain undergoes dramatic physical changes. Survival requires careful control of cell mechanics, particularly the balance between protoplast expansion and cell wall resistance. One control mechanism is the use of a mechanosensitive (MS) ion channel, MscS-Like (MSL)8. This pollen-specific protein was previously shown to be essential for pollen survival during hydration and was proposed to function as a tension-gated osmoregulator. However, direct proof of osmoregulation during initial hydration has not yet been found. In fact, studies of …

Functional Analysis Of Recurrent Non-Coding Variants In Human Melanoma, Paula Maria Godoy

Arts & Sciences Electronic Theses and Dissertations

Worldwide incidence rates of cutaneous melanoma are increasing, and while survival rates for early stages of melanoma are high, rates drop precipitously for metastatic melanomas or those that are unable to be targeted by currently available treatments. As melanomas have a propensity to quickly metastasize, understanding the contributions of melanoma initiation remains critical for early intervention. Onset of melanoma is characterized most by mutations that stimulate mitogen-activated protein kinase (MAPK) signaling, disrupt DNA damage checkpoints, and trigger mechanisms to bypass senescence through elongation of telomeres. Additionally, in zebrafish melanoma models, the earliest cluster of melanoma-initiating cells activate expression of a …

Defining The Role Of Rare Genetic Variants That Drive Risk And Pathogenesis Of Alzheimer’S Disease, Matthew James Rosene

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is the leading cause of dementia and is pathologically defined by the aggregation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Rare heritable mutations within the genes for amyloid precursor protein (APP) and presenilin 1 (PSEN1), and presenilin 2 (PSEN2) cause early onset AD and account for approximately 1% of AD cases. While the majority of AD cases are late-onset (LOAD), which is defined by a markedly more complex genetic architecture that is comprised of many genetic risk factors that influence AD through multiple cellular pathways. The advent of deep sequencing analyses have allowed for the identification …

Control Of Intestinal Turnover And Cell Death Through Canonical Autophagy Pathways Within Mouse And Human Epithelia, John Steven Ekman

Arts & Sciences Electronic Theses and Dissertations

Regulation of epithelial turnover is essential for the maintenance of the structure and function of the intestine. The balance of intestinal epithelial turnover is known to be modulated by cell-extrinsic cytokines such as Tumor Necrosis Factor (TNF). Likewise, cell-intrinsic modulation of survival and death is afforded by a highly-conserved, multi-step pathway termed autophagy. In this body of work, I have characterized a specific and potent role for autophagy in protecting mouse intestinal epithelial cells (enterocytes) from TNF-triggered cell death. Specifically, I have found that the autophagy initiation factor Atg14 is central to mediating this protective role. Utilizing conditional loss of …

Molecular Characterization Of Integrase-Rna Interactions And Their Role In The Replication Of Hiv-1 And Other Retroviruses, Christian Shema Mugisha

Arts & Sciences Electronic Theses and Dissertations

HIV-1 integrase (IN) enzyme has an emerging non-catalytic role in particle maturation, whichinvolves its binding to the viral genome in virions. Allosteric integrase inhibitors (ALLINIs) and class II integrase substitutions inhibit the binding of IN to the viral genome and cause formation of eccentric non-infectious HIV-1 particles. These viruses are characterized by the mislocalization of the viral ribonucleoprotein complexes between the translucent conical CA lattice and the viral lipid envelope. We have previously demonstrated that IN binding to the viral genome is mediated by basic residues within the C-terminal domain of IN. In the first chapter, we show how basic …

Regulation And Function Of Integrin Β3 In Bone-Metastatic Breast Cancer Cells In The Therapeutic Setting, Gregory Chandler Fox

Arts & Sciences Electronic Theses and Dissertations

Breast cancer is the most common non-cutaneous malignancy in women, with over 250,000 patients diagnosed each year in the United States alone. The bone is the most common site of recurrence in breast cancer, affecting over two-thirds of patients with metastatic disease and presenting as the only evidence of distant spread in up to 30%. Clinically, breast cancer bone metastases manifest most often as profoundly osteolytic lesions that negatively impact survival and patient quality of life. Bone-targeted therapies such as bisphosphonates and the anti-RANKL monoclonal antibody denosumab have revolutionized the treatment of bone metastases through inhibition of osteoclast-mediated bone destruction; …

Dnmt3a Regulates Hematopoietic Stem Cells Via Dna Methylation-Independent Functions, Won Kyun Koh

Arts & Sciences Electronic Theses and Dissertations

Hematopoiesis is strictly regulated to sustain blood production throughout adult life. De novo DNA methyltransferase 3-alpha (DNMT3A) is one of the major epigenetic regulators found to have an essential role in hematopoietic stem cell (HSC) differentiation. DNMT3A mutations are prevalent in myeloid diseases and malignancies that include acute myeloid leukemia (AML; ~22%), myelodysplastic syndrome (MDS; ~10%), and myeloproliferative neoplasm (MPN; ~8%). Importantly, DNMT3A mutations are not only the founding events of HSC malignant transformation, but they are also occurring as pre-leukemic lesions. Therefore, it is necessary to evaluate the molecular changes that occur in DNMT3A mutant HSCs, and how those …

The Role Of Soxe Transcription Factors In Melanoma Initiation, Eva Tulchinsky Kramer

Arts & Sciences Electronic Theses and Dissertations

Cutaneous melanoma, a cancer of transformed melanocytes, has the highest mortality rate among skin cancers and remains difficult to treat once metastasized. Melanoma is characterized by high genetic heterogeneity, implicating epigenetic dysfunction as an additional regulator of oncogenesis. Indeed, an increasing number of epigenetic modifiers and modifications have been identified in melanoma linked to faster melanoma onset, and then targeted with therapeutics with success. Thus, identifying and mechanistically characterizing these epigenetic and transcriptional alterations in melanoma will further our understanding of their contributions to oncogenesis and enable more diverse therapeutic options.

To evaluate global epigenetic and transcriptional differences between melanocytes …