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Characterization Of The Effects Of The Pyrazolopyrimidine Inhibitor Grassofermata (Nav-2729) In The Eukaryotic Pathogen Trypanosoma Brucei, Kristina Marie Parman
Characterization Of The Effects Of The Pyrazolopyrimidine Inhibitor Grassofermata (Nav-2729) In The Eukaryotic Pathogen Trypanosoma Brucei, Kristina Marie Parman
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The protozoan pathogen, Trypanosoma brucei, is the causative agent of sleeping sickness in humans and nagana in livestock in sub-Saharan Africa. T. brucei cycles between tsetse fly and mammalian hosts, and it is adapted to survive in diverse host tissues. Variant Surface Glycoprotein (VSG) plays a key role in immune evasion in the mammalian host. The VSG membrane anchor requires two myristates, 14-carbon saturated fatty acids (FAs) that are scarce in the host. T. brucei can synthesize FAs de novo, but also readily takes up exogenous FAs, despite lacking homologs to fatty acid uptake proteins found in other …
Fatty Acids And Parasitism: Towards A Better Understanding Of Lipid Metabolism In Trypanosoma Brucei, Joshua Saliutama
Fatty Acids And Parasitism: Towards A Better Understanding Of Lipid Metabolism In Trypanosoma Brucei, Joshua Saliutama
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Trypanosoma brucei is an extracellular eukaryotic parasite that causes sleeping sickness in humans and cattle. As an extracellular parasite, T. brucei relies on the host’s nutrients to satisfy its growth requirements. The parasite is unusual because it does not uptake most of the host’s lipid species. Instead, T. brucei prefers to perform de novo synthesis of most lipid species. One of the lipid species that T. brucei can both uptake and synthesize is fatty acids. In my thesis work, I investigated the dynamics of fatty acid uptake, metabolism, and utilization of T. brucei. My work starts by determining the …
Optimization Of Modular, Long-Range, Ultra-Fast Optical Tweezers With Fluorescence Capabilities For Single-Molecule And Single-Cell Based Biophysical Measurements, Subash C. Godar
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An Optical tweezer is a tightly focused laser beam that applies and senses precise and localized optical force to a dielectric microsphere and offers a unique and effective tool for manipulating the single cell or cell components, including nucleotides and dynein motor proteins. Here, I used highly stabilized optomechanical components and ultra-sensitive detection modules to significantly improve the measurement capabilities over a wide range of temporal and spatial scales. I combined the optical tweezer-based force spectroscopy technique with fluorescence microscopy to develop an integrated high-resolution force-fluorescence system capable of measuring displacements at sub-nanometer, forces at sub-piconewton over a temporal range …
Characterization Of A Potential Glucose Transporter In Trypanosoma Brucei, Matthew Morgan
Characterization Of A Potential Glucose Transporter In Trypanosoma Brucei, Matthew Morgan
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Trypanosoma brucei, the African trypanosome, is an organism heavily dependent on glucose for ATP production during the infectious stage of its life cycle. Here, we have explored the role of an uncharacterized protein designated “novel glucose transporter” (NGT) as a potential glucose transporter. Sequence analyses suggests that NGT shares similarities (either at the primary sequence level or structurally) with Trypanosome Hexose Transporters 1 (TbTHT1), and human GLUT3, both of which are membrane sugar transporters. NGT was localized by fluorescence microscopy to subcellular structures consistent with lysosomes. Silencing NGT expression with RNA interference in parasites resulted in a growth defect …
Glucose Adaptation And Glycosome Import Machinery Of Trypanosoma Brucei, Logan Phillip Crowe
Glucose Adaptation And Glycosome Import Machinery Of Trypanosoma Brucei, Logan Phillip Crowe
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Trypanosoma brucei is the protozoan parasite responsible for Human African Trypanosomiasis (HAT) and the cattle wasting disease Nagana endemic to sub-Saharan Africa. T. brucei and other kinetoplastids possess specialized peroxisomes called glycosomes that compartmentalize many processes including glycolysis and gluconeogesis. While most studies on T. brucei has been performed on lab-adapted 29-13 strain parasites, it has been observed that glucose is an important signaling cue for differentiation of AnTat1.1 cells. Currently, most parasites are maintained in the glucose-rich medium SDM-79, and studies using low glucose media have used either SDM-80 or SDM-79 in which glucose has been depleted by cell …
Novel Methods For Monitoring Glucose Metabolism In Trypanosoma Brucei Using Fluorescent Biosensors, Charles Voyton
Novel Methods For Monitoring Glucose Metabolism In Trypanosoma Brucei Using Fluorescent Biosensors, Charles Voyton
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Members of the class Kinetoplastea including Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. cause diseases endemic in rural regions of South America, Sub‐Saharan African and the Eastern Asian continent, effecting hundreds of millions of people and livestock. Existing treatments are associated with high toxicity and rates of resistance, are expensive to produce, and are difficult to administer in rural areas. To develop additional treatment strategies, we must better illuminate the pathways amenable for anti kinetoplastid treatments. One pathway susceptible to drug intervention is glucose metabolism, which in kinetoplasts takes place in glycosomes that are specialized organelles related to mammalian peroxisomes. …
Glucose Sensing In Trypanosoma Brucei, Yijian Qiu
Glucose Sensing In Trypanosoma Brucei, Yijian Qiu
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Trypanosoma brucei is the protozoan parasite that causes human African trypanosomiasis (HAT, also known as sleeping sickness) and nagana disease in livestock. During its life cycle, trypanosomes occupy niches with very different nutrient contents and immune features. They use glucose solely for ATP production in the mammalian bloodstream while switching to amino acid metabolism in the midgut of the tsetse fly vector. A fast and accurate coordination of gene expression with environment alteration is critical for the successful parasitization of the two hosts. My study focuses on the signaling role of glucose in the development and adaptation of T. brucei. …
Lipid Metabolism In Trypanosoma Brucei: Molecular Characterization Of Fatty Acid Synthesis And Uptake, Patrick Vigueira
Lipid Metabolism In Trypanosoma Brucei: Molecular Characterization Of Fatty Acid Synthesis And Uptake, Patrick Vigueira
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My doctoral studies focused on the fatty acid metabolism of the deadly protozoan parasite, Trypanosoma brucei. Fatty acid metabolism in T. brucei can be broadly divided into two pathways, synthesis and uptake. In Chapters 2-4 I describe experiments investigating the parasite's fatty acid synthesis pathway. Chapter 2 contains the initial characterization of acetyl-CoA carboxylase (ACC) in T. brucei. Knockdown of TbACC by RNA interference (RNAi) reduced parasite virulence in a mouse model, suggesting that TbACC has the potential to be utilized as a drug target. Chapters 3 and 4 explore the effects of two known ACC inhibitors, the …
Regulation Of Trypanosoma Brucei Hexokinase 1 And 2 On Multiple Levels: Transcript Abundance, Protein Expression And Enzyme Activity, Heidi Dodson
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Trypanosoma brucei, a unicellular eukaryotic parasite, is the causative agent of African sleeping sickness in sub-Saharan Africa. The parasite encounters two main environments as it progresses through its life cycle: the tsetse fly and the mammalian
bloodstream. Nutrient availability is distinct in the two environments, requiring the parasite to utilize diverse metabolic pathways to efficiently produce ATP for survival. Bloodstream form parasites (BSF), residing in a glucose rich environment, rely solely on
glycolysis for energy, while procyclic form (PF) parasites metabolize readily available proline and threonine in addition to glucose.
T. brucei expresses two hexokinases, the first enzyme in the …
Exploring T. Brucei Hexokinase Biology: Localization And Inhibition Studies, Todd Lyda
Exploring T. Brucei Hexokinase Biology: Localization And Inhibition Studies, Todd Lyda
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Trypanosoma brucei, the causative agent of the disease African sleeping sickness
in humans and nagana in animals, is a scourge of sub-Saharan Africa. There is a
desperate need for more efficacious therapies for the disease; here we describe research
validating T. brucei hexokinase 1 (TbHK1) as a drug therapeutic target for T. brucei
infection and the identification and characterization of novel inhibitors of the enzyme by
both low throughput and high throughput means. Additionally this thesis introduces
efforts at characterizing a second T. brucei hexokinase, focusing mostly on cell biology
and the determination of localization.
The small molecule quercetin (QCN) …