Life Sciences Commons^™

The Effects Of Molecular Chaperone Modulation On Protein Folding, Prion Formation, And Prion Propagation In Saccharomyces Cerevisiae, Leeran Blythe Dublin Ryan

Arts & Sciences Electronic Theses and Dissertations

Proper and efficient protein folding is vital for cell survival. Many factors affect protein folding fidelity and prion formation, including molecular chaperone availability and activity. Research has shown that modulating chaperone availability and function can affect protein misfolding and aggregation, as well as de novo prion formation and propagation. However, the factors involved and underlying mechanisms influencing prion formation and protein folding are largely unknown. The following work aims to elucidate these areas. The Nascent Polypeptide-Associated Complex (NAC) is the first point of chaperone contact for nascent polypeptides. Previous work has shown that disruption of the NAC leads to improved …

Rna Polymerase Binding Protein A (Rbpa) Regulation Of Mycobacteria Transcription And Sensitivity To Fidaxomicin, Jerome Prusa

Arts & Sciences Electronic Theses and Dissertations

Mycobacterium tuberculosis is the causative agent of the disease tuberculosis (TB) and remains one of the deadliest microorganisms on the planet. The effort to eradicate M. tuberculosis would benefit from the development of novel therapeutics, which requires a detailed understanding of M. tuberculosis physiology. Like all living organisms, M. tuberculosis gene expression requires transcription. Transcription in the phylum Actinobacteria, which includes mycobacteria, is unique because it includes RNA Polymerase Binding Protein A (RbpA) that is essential in both M. tuberculosis and the nonpathogenic model organism Mycobacterium smegmatis. RbpA increases the housekeeping A and housekeeping like B interactions with the RNA …

The Role Of Cd53 In Hematopoietic Development, Stress, And Malignancy, Zev Joshua Greenberg

Arts & Sciences Electronic Theses and Dissertations

For a cell to function properly, it must be able to interact with and respond to environmental cues; however, expression of surface molecules, proteins, and receptors is not always sufficient to execute a cellular response. Proper organization of the plasma membrane is necessary to facilitate these highly regulated protein interactions, such that a cell can respond to stressors, growth factors, and other signaling molecules. Tetraspanins are a family of transmembrane proteins which help correctly orient surface molecules on the cell membrane, often through tetraspanin enriched microdomains, a membrane structure similar to lipid rafts. As a family, tetraspanins are known to …

The Role Of Subclonal Gene Mutations During Progression From Myelodysplastic Syndrome To Secondary Acute Myeloid Leukemia, Andrew John Menssen

Arts & Sciences Electronic Theses and Dissertations

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by ineffective hematopoiesis. Approximately 30% of MDS patients progress to secondary acute myeloid leukemia (AML). MDS is caused by somatic mutations in hematopoietic stem/progenitor cells and progression to secondary AML is associated with the acquisition and/or expansion of at least one subclone. We hypothesized that specific gene mutations would be enriched in subclones compared to founding clones, and that the order of mutation acquisition would be critical for clonal evolution and progression from MDS to secondary AML. Sequencing of paired MDS and secondary AML samples from 44 …

The Role Of Enampt-Mediated Systemic Nad+ Biosynthesis In Aging And Lifespan, Mitsukuni Yoshida

Arts & Sciences Electronic Theses and Dissertations

Aging is a systemic decline in tissue functions that occurs during the course of our life leading to the development of age-associated health deteriorations and ultimately to the expiration of life. Over the past few decades, population aging has become increasingly evident in many parts of the world, leading to increased prevalence of age-related disabilities and diseases. Because age is a major risk factor for many chronic diseases, extensive research effort has been spent to identify common age-associated molecular changes contributing to the pathogenesis and progression of these health issues. One such molecule identified to play a central role in …

Single-Cell Resolution Mechanistic Analyses Of Direct Lineage Reprogramming, Chuner Guo

Arts & Sciences Electronic Theses and Dissertations

End-stage organ failures remain a clinical challenge with an unmet need for medical therapies, with transplantation often being the only curative option. Despite advances in transplantation outcomes, organ shortage continues to limit the availability of cures to patients in need. The direct lineage reprogramming of one cell type to another is a promising avenue for therapy with the following advantages: (1) patient-specific cell sources, (2) direct conversion without reverting to pluripotency and the associated risk of teratoma formation, and (3) utilization of the cell type responsible for fibrotic scar formation for the engineering towards the desired cell fate. Nonetheless, many …

Etv2/Myct1 Axis In The Regulation Of Tumor Angiogenesis And Anti-Tumor Immunity, Ashraf Ul Kabir

Arts & Sciences Electronic Theses and Dissertations

Angiogenesis is a critical determinant of neoplastic growth and metastatic spread. As such, anti-angiogenic approaches have long been tried to throttle down tumor progression. However, current anti-angiogenic treatments so far have produced modest clinical benefits. Further in-depth research has provided rationales behind these disappointing and apparent perplexing clinical outcomes. It is now established that VEGF (vascular endothelial growth factor) and other prominent current angiogenic targets are neither specific to the vascular system nor the pathological conditions explaining the sub-optimal angiogenic control following the existing treatments. This suggests that anti-angiogenesis could still be a viable strategy for cancer patients should there …

Mechanisms Of Natural Killer Cell Anti-Tumor Function And Homeostasis, Julia Alexandra Wagner

Arts & Sciences Electronic Theses and Dissertations

Natural killer (NK) cells are innate lymphoid cells (ILCs) that mediate anti-tumor and anti-viral immune responses. They do so via two primary effector functions: cytokine production and direct cytotoxicity. Unlike adaptive T and B lymphocytes, NK cells do not rearrange their DNA to express a predominant antigen-specific receptor, and instead express a variety of stochastically-expressed, germline DNA-encoded activating and inhibitory receptors whose signals integrate to govern their functional responses. What results is a diverse repertoire of NK cells capable of recognizing a variety of malignantly-transformed or virally-infected cells. Studies from several groups have established the anti-tumor potential of NK cells, …

The Role Of Mature Secretory Cells In Gastrointestinal Regeneration, Megan Deanna Radyk

Arts & Sciences Electronic Theses and Dissertations

Differentiated cells exhibit the ability to adjust their cell fate and become more progenitor-like after wide-scale tissue injury. This inherent cell plasticity is shown across many tissues and organisms and is a conserved behavior that ensures organ function even in a chronic injury setting. At the tissue level, the change in cell fate from a differentiated cell to one with more progenitor properties can be identified as metaplasia. Importantly, metaplasias, like Spasmolytic Polypeptide-Expressing Metaplasia (SPEM) in the stomach and Acinar-to-Ductal Metaplasia (ADM) in the pancreas, are risk factors for the development of adenocarcinoma. Thus, understanding the cellular and molecular mechanisms …

Targeting The Phgdh-Mtor Metabolic Axis In Osteosarcoma, Richa Rathore

Arts & Sciences Electronic Theses and Dissertations

Altering cellular energy metabolism has been highlighted as one of the emerging hallmarks of cancer. The reprogramming of bioenergetic pathways towards enhanced glycolysis, rather than the mitochondrial oxidative phosphorylation indicative of normal cells, results in increased biomass production and is associated with the activation of various oncogenes. The increased or decreased expression of key metabolic enzymes has been identified as a potential family of biomarkers that could serve as the targets for novel metabolic-based therapies in cancer.

The serine, glycine, and one-carbon (SGOC) metabolism pathway consists of a series of enzymes and metabolites that drive protein and lipid production, enhanced …

Protein Synthesis Adaptation To The Au-Rich Transcriptome Of Plasmodium Falciparum, Jessey Lee Erath

Arts & Sciences Electronic Theses and Dissertations

The process of protein synthesis whereby a messenger RNA is decoded into an amino acid chainis conserved among the domains. Fastidious protein synthesis is necessary for organism survival. However, exceptions negatively affecting the mRNA translation cycle – inadvertently or by design – may occur. Polyadenosine tracts are one such motif causing ribosomal stalling and frameshifting in almost all organisms tested thus far; save Plasmodium spp. Thus, with ~60% of their protein-coding genome harboring polyadenosine tracts, the elucidation of such paradigm-breaking adaptations enabling Plasmodium spp. to translate this typically problematic motif without issue is salient from both basic science and clinical …

Homeostatic T Cell Receptor Interactions With Self-Peptide Tune Cd4+ T Cell Function, Juliet Marie Bartleson

Arts & Sciences Electronic Theses and Dissertations

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function

by

Juliet Marie Bartleson

Doctor of Philosophy in Biology and Biomedical Sciences

Immunology

Washington University in St. Louis, 2021

Professor Paul M. Allen, Chair

Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions …

Understanding The Molecular Mechanisms Of Photoferrotrophy And Phototrophic Extracellular Electron Uptake, Dinesh Gupta

Arts & Sciences Electronic Theses and Dissertations

Several anoxygenic phototrophs grow by utilizing soluble iron or insoluble mixed-valence iron minerals (such as rust) as electron donors to fix carbon dioxide using light energy, a process called photoferrotrophy. Photoferrotrophs can also use electron donors such as poised electrodes that serve as proxies for rust via phototrophic extracellular electron uptake (EEU). Despite the recognition that these two related microbial processes contribute to various biogeochemical cycles such as iron and carbon, the electron uptake mechanisms underlying photoferrotrophy and phototrophic EEU are poorly understood. To address the key knowledge gaps in our understanding of these microbial metabolisms, here we characterized Rhodopseudomonas …

Measuring And Manipulating Tension-Dependent Behavior Of Mechanosensitive Ion Channels, Angela M. Schlegel

Arts & Sciences Electronic Theses and Dissertations

Mechanical forces play critical roles throughout the lives of all organisms and, as such, diverse arrays of mechanotransduction systems have evolved to detect and initiate responses to force. Many mechanotransduction systems consist of mechanosensitive (MS) ion channels, membrane pores that open in response to sufficient mechanical force. My dissertation focuses on both the study and application of force-dependent conformational changes of MS channels. I tested whether charged pore-lining residues R326 and D327 of the Arabidopsis thaliana mitochondrial MS channel MSL1 function in inward rectification or gating kinetics. Mutating these residues showed no effect on MSL1 rectification; however, these residues are …