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Theses/Dissertations

2013

University of Massachusetts Medical School

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Full-Text Articles in Life Sciences

A Role For Neuronal Nicotinic Acetylcholine Receptors In Dopamine-Mediated Behaviors And The Hypnotic Response To Anesthetics: A Dissertation, Lindsey G. Soll Dec 2013

A Role For Neuronal Nicotinic Acetylcholine Receptors In Dopamine-Mediated Behaviors And The Hypnotic Response To Anesthetics: A Dissertation, Lindsey G. Soll

GSBS Dissertations and Theses

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels that most notably influence dopamine (DA) release. In this thesis, I examine the role of nAChRs in mediating DA-related behaviors such as movement and drug dependence. To accomplish this, I utilized a “gain-offunction” knock-in mouse (the Leu9’Ala line) containing agonist-hypersensitive α4* nAChRs (* indicates other nAChR subunits in addition to α4 are within the receptor complex) that renders receptors 50-fold more sensitive to nicotine and acetylcholine than wild-type (WT) receptors. I found that DHβE, a selective antagonist for α4β2* nAChRs, induced reversible and robust motor dysfunction characterized by hypolocomotion, akinesia, catalepsy ...


Tissue-Dependent T Cell Apoptosis And Transcriptional Regulation Of Memory Cd8+T Cell Differentiation During Viral Infections: A Dissertation, Varun N. Kapoor Dec 2013

Tissue-Dependent T Cell Apoptosis And Transcriptional Regulation Of Memory Cd8+T Cell Differentiation During Viral Infections: A Dissertation, Varun N. Kapoor

GSBS Dissertations and Theses

Activation and proliferation of antigen-specific T cells is the hallmark of an anti-viral immune response. Effector T cells generated during an immune response are heterogeneous in regards to their ability to populate the memory pool once the immune response has resolved. Initial T cell activation takes place in the lymphoid organs, after which T cells migrate into the non-lymphoid tissues. The presence of memory T cells at non-lymphoid tissue sites has been shown to be critical for protection against secondary virus challenge. Our lab has previously demonstrated that during and after the resolution of the immune response to Lymphocytic choriomeningitis ...


Understanding Regulation Of The Cytoskeleton During Cell Cycle Transitions Through Examination Of Crosstalk Between Homologous Fission Yeast Pathways, Septation Initiation Network And Morphogenesis Orb6 Network: A Dissertation, Sneha Gupta Dec 2013

Understanding Regulation Of The Cytoskeleton During Cell Cycle Transitions Through Examination Of Crosstalk Between Homologous Fission Yeast Pathways, Septation Initiation Network And Morphogenesis Orb6 Network: A Dissertation, Sneha Gupta

GSBS Dissertations and Theses

The fission yeast Schizosaccharomyces pombe has become a powerful model system for studying cytokinesis, a process of cytoplasmic division by which one cell divides into two identical daughter cells. Like mammalian cells, S. pombe divides through the use of an actomyosin contractile ring, which is composed of a set of highly conserved cytoskeletal proteins. Cytokinesis in S. pombe is primarily regulated by the SIN pathway, which is activated in late mitosis and is required for actomyosin contractile ring and septum assembly, and also plays a role in spindle checkpoint inactivation, and telophase nuclear positioning. The various functions of the SIN ...


Pirna Biogenesis And Transposon Silencing In Drosophila: A Dissertation, Zhao Zhang Nov 2013

Pirna Biogenesis And Transposon Silencing In Drosophila: A Dissertation, Zhao Zhang

GSBS Dissertations and Theses

piRNAs guide PIWI proteins to silence transposons in animal germ cells. In Drosophila, the heterochromatic piRNA clusters transcribe piRNA precursors to be transported into nuage, a perinuclear structure for piRNA production and transposon silencing. At nuage, reciprocal cycles of piRNA-directed RNA cleavage—catalyzed by the PIWI proteins Aubergine (Aub) and Argonaute3 (Ago3) in Drosophila—destroy the sense transposon mRNA and expand the population of antisense piRNAs in response to transposon expression, a process called the Ping-Pong cycle. Heterotypic Ping-Pong between Aub and Ago3 ensures that antisense piRNAs predominate.

My thesis research mainly focuses on two fundamental questions about the piRNA ...


Hox Gene Regulation And Function During Zebrafish Embryogenesis: A Dissertation, Steven E. Weicksel Oct 2013

Hox Gene Regulation And Function During Zebrafish Embryogenesis: A Dissertation, Steven E. Weicksel

GSBS Dissertations and Theses

Hox genes encode a conserved family of homeodomain containing transcription factors essential for metazoan development. The establishment of overlapping Hox expression domains specifies tissue identities along the anterior-posterior axis during early embryogenesis and is regulated by chromatin architecture and retinoic acid (RA). Here we present the role nucleosome positioning plays in hox activation during embryogenesis. Using four stages of early embryo development, we map nucleosome positions at 37 zebrafish hox promoters. We find nucleosome arrangement to be progressive, taking place over several stages independent of RA. This progressive change in nucleosome arrangement on invariant sequence suggests that trans-factors play an ...


A Novel Autophagy Regulatory Mechanism That Functions During Programmed Cell Death: A Dissertation, Tsun-Kai Chang Sep 2013

A Novel Autophagy Regulatory Mechanism That Functions During Programmed Cell Death: A Dissertation, Tsun-Kai Chang

GSBS Dissertations and Theses

Autophagy is a cellular process that delivers cytoplasmic materials for degradation by the lysosomes. Autophagy-related (Atg) genes were identified in yeast genetic screens for vehicle formation under stress conditions, and Atg genes are conserved from yeast to human. When cells or animals are under stress, autophagy is induced and Atg8 (LC3 in mammal) is activated by E1 activating enzyme Atg7. Atg8-containing membranes form and surround cargos, close and mature to become the autophagosomes. Autophagosomes fuse with lysosomes, and cargos are degraded by lysosomal enzymes to sustain cell viability. Therefore, autophagy is most frequently considered to function in cell survival. Whether ...


Disparate Activation Of The Inflammasome By Chitin And Chitosan: A Dissertation, Chelsea L. Bueter Sep 2013

Disparate Activation Of The Inflammasome By Chitin And Chitosan: A Dissertation, Chelsea L. Bueter

GSBS Dissertations and Theses

Chitin is an abundant polysaccharide found in fungal cell walls, crustacean shells, and insect exoskeletons. The immunological properties of both chitin and its deacetylated derivative chitosan are of relevance due to frequent natural exposure and their increasing use in translational applications. Depending on the preparation studied and the endpoint measured, these compounds have been reported to induce allergic responses, inflammatory responses, or no response at all. Highly purified chitosan and chitin were prepared and the capacity of these glycans to stimulate the release of the inflammasomeassociated cytokine IL-1β was examined. Chitosan was shown to be a potent inflammasome activator in ...


Human Cytomegalovirus Reprograms The Expression Of Host Micro-Rnas Whose Target Networks Are Required For Viral Replication: A Dissertation, Alexander N. Lagadinos Aug 2013

Human Cytomegalovirus Reprograms The Expression Of Host Micro-Rnas Whose Target Networks Are Required For Viral Replication: A Dissertation, Alexander N. Lagadinos

GSBS Dissertations and Theses

The parasitic nature of viruses requires that they adapt to their host environment in order to persist. Herpesviruses are among the largest and most genetically complex human viruses and they have evolved mechanisms that manipulate a variety of cellular pathways and processes required to replicate and persist within their hosts. Human cytomegalovirus (HCMV), a member of the β- herpesvirus sub-family, has the capacity to influence the expression of many host genes in an effort to create an optimal environment for infection. One mechanism utilized by HCMV to alter gene expression is the host RNA interference (RNAi) pathway. This is evidenced ...


Hiv-1 And The Nucleolus: A Role For Nucleophosmin/Npm1 In Viral Replication: A Dissertation, Tracy E. Schmidt Aug 2013

Hiv-1 And The Nucleolus: A Role For Nucleophosmin/Npm1 In Viral Replication: A Dissertation, Tracy E. Schmidt

GSBS Dissertations and Theses

The nucleolus is a plurifunctional organelle with dynamic protein exchange involved in diverse aspects of cell biology. Additionally, the nucleolus has been shown to have a role in the replication of numerous viruses, which includes HIV-1. Several groups have reported HIV-1 vRNA localization within the nucleolus. Moreover, it has been demonstrated the HIV-1 Rev protein localizes to the nucleolus and interacts with nucleolar proteins, including NPM1. Despite evidence for a nucleolar involvement during replication, a functional link has not been demonstrated. I investigated whether introncontaining vRNAs have a Rev-mediated nucleolar localization step prior to export. Furthermore, I examined whether NPM1 ...


A Novel Role Of Uap56 In Pirna Mediated Transposon Silencing: A Dissertation, Fan Zhang Aug 2013

A Novel Role Of Uap56 In Pirna Mediated Transposon Silencing: A Dissertation, Fan Zhang

GSBS Dissertations and Theses

Transposon silencing is required to maintain genome stability. The non-coding piRNAs effectively suppress of transposon activity during germline development. In the Drosophila female germline, long precursors of piRNAs are transcribed from discrete heterochromatic clusters and then processed into primary piRNAs in the perinuclear nuage. However, the detailed mechanism of piRNA biogenesis, specifically how the nuclear and cytoplasmic processes are connected, is not well understood. The nuclear DEAD box protein UAP56 has been previously implicated in protein-coding gene transcript splicing and export. I have identified a novel function of UAP56 in piRNA biogenesis. In Drosophila egg chambers, UAP56 co-localizes with the ...


The Role Of Heterologous Immunity In Viral Co-Infections And Neonatal Immunity: A Dissertation, Laurie L. Kenney Aug 2013

The Role Of Heterologous Immunity In Viral Co-Infections And Neonatal Immunity: A Dissertation, Laurie L. Kenney

GSBS Dissertations and Theses

The dynamics of T cell responses have been extensively studied during single virus infection of naïve mice. During a viral infection, viral antigen is presented in the context of MHC class I molecules on the surface of infected cells. Activated CD8 T cells that recognized viral antigens mediate clearance of virus through lysis of these infected cells. We hypothesize that the balance between the replicating speed of the virus and the efficiency at which the T cell response clears the virus is key in determining the disease outcome of the host. Lower T cell efficiency and delayed viral clearance can ...


Structure-Based Targeting Of Transcriptional Regulatory Complexes Implicated In Human Disease: A Dissertation, Brendan J. Hilbert Jul 2013

Structure-Based Targeting Of Transcriptional Regulatory Complexes Implicated In Human Disease: A Dissertation, Brendan J. Hilbert

GSBS Dissertations and Theses

Transcriptional regulatory complexes control gene expression patterns and permit cellular responses to stimuli. Deregulation of complex components upsets target gene expression and can lead to disease. This dissertation examines proteins involved in two distinct regulatory complexes: C-terminal binding protein (CtBP) 1 and 2, and Interferon Regulatory Factors (IRF) 3 and 5. Although critical in developmental processes and injury response, CtBP transcriptional repression of cell adhesion proteins, pro-apoptotic factors, and tumor suppressors has been linked to the pathogenesis of multiple forms of cancer. IRFs function in the immune system and have been implicated in autoimmune disorders.

Understanding IRF activation is critical ...


Itk Is A Dual Action Regulator Of Immunoreceptor Signaling In The Innate And Adaptive Immune System: A Dissertation, John W. Evans Iii Jul 2013

Itk Is A Dual Action Regulator Of Immunoreceptor Signaling In The Innate And Adaptive Immune System: A Dissertation, John W. Evans Iii

GSBS Dissertations and Theses

The cells and molecules that comprise the immune system are essential for mounting an effective response against microbes. A successful immune response limits pathology within the host while simultaneously eliminating the pathogen. The key to this delicate balance is the correct recognition of the pathogen and the appropriate response of immune cells. Cellular activation originates through receptors that relay information about the state of the microenvironment to different compartments within the cell. The rapid relay of information is called signal transduction and employs a network of signaling mediators such as kinases, phosphatases, adaptor molecules, and transcription factors. IL-2 inducible T ...


Morphogenetic Requirements For Embryo Patterning And The Generation Of Stem Cell-Derived Mice: A Dissertation, Yeonsoo Yoon Jul 2013

Morphogenetic Requirements For Embryo Patterning And The Generation Of Stem Cell-Derived Mice: A Dissertation, Yeonsoo Yoon

GSBS Dissertations and Theses

Cell proliferation and differentiation are tightly regulated processes required for the proper development of multi-cellular organisms. To understand the effects of cell proliferation on embryo patterning in mice, we inactivated Aurora A, a gene essential for completion of the cell cycle. We discovered that inhibiting cell proliferation leads to different outcomes depending on the tissue affected. If the epiblast, the embryonic component, is compromised, it leads to gastrulation failure. However, when Aurora A is inactivated in extra-embryonic tissues, mutant embryos fail to properly establish the anteroposterior axis. Ablation of Aurora A in the epiblast eventually leads to abnormal embryos composed ...


Modulating Influenza And Heparin Binding Viruses’ Pathogenesis With Extrinsic Receptor Decoy Liposomes: A Dissertation, Gabriel L. Hendricks Jun 2013

Modulating Influenza And Heparin Binding Viruses’ Pathogenesis With Extrinsic Receptor Decoy Liposomes: A Dissertation, Gabriel L. Hendricks

GSBS Dissertations and Theses

Influenza is a severe disease in humans and animals, causing upwards of 40,000 deaths every year in America alone. Influenza A virus (IAV) also causes periodic pandemics every 10 to 50 years, killing millions of people. Despite this, very few effective therapies are available. All strains of IAV are prone to developing resistance to antibodies due to the high mutation rate in the viral genome. Because of this mutation rate, a yearly vaccine must be generated before every flu season, and efficacy varies year to year. IAV has also mutated to escape several of the clinically-approved small molecule inhibitors ...


On Identifying Signatures Of Positive Selection In Human Populations: A Dissertation, Jessica L. Crisci Jun 2013

On Identifying Signatures Of Positive Selection In Human Populations: A Dissertation, Jessica L. Crisci

GSBS Dissertations and Theses

As sequencing technology continues to produce better quality genomes at decreasing costs, there has been a recent surge in the variety of data that we are now able to analyze. This is particularly true with regards to our understanding of the human genome—where the last decade has seen data advances in primate epigenomics, ancient hominid genomics, and a proliferation of human polymorphism data from multiple populations. In order to utilize such data however, it has become critical to develop increasingly sophisticated tools spanning both bioinformatics and statistical inference. In population genetics particularly, new statistical approaches for analyzing population data ...


Experimental Illumination Of Comprehensive Fitness Landscapes: A Dissertation, Ryan T. Hietpas Jun 2013

Experimental Illumination Of Comprehensive Fitness Landscapes: A Dissertation, Ryan T. Hietpas

GSBS Dissertations and Theses

Evolution is the single cohesive logical framework in which all biological processes may exist simultaneously. Incremental changes in phenotype over imperceptibly large timescales have given rise to the enormous diversity of life we witness on earth both presently and through the natural record. The basic unit of evolution is mutation, and by perturbing biological processes, mutations may alter the fitness of an individual. However, the fitness effect of a mutation is difficult to infer from historical record, and complex to obtain experimentally in an efficient and accurate manner.

We have recently developed a high throughput method to iteratively mutagenize regions ...


A Role For Intraflagellar Transport Proteins In Mitosis: A Dissertation, Alison R. Bright Jun 2013

A Role For Intraflagellar Transport Proteins In Mitosis: A Dissertation, Alison R. Bright

GSBS Dissertations and Theses

Disruption of cilia proteins results in a range of disorders called ciliopathies. However, the mechanism by which cilia dysfunction contributes to disease is not well understood. Intraflagellar transport (IFT) proteins are required for ciliogenesis. They carry ciliary cargo along the microtubule axoneme while riding microtubule motors. Interestingly, IFT proteins localize to spindle poles in non-ciliated, mitotic cells, suggesting a mitotic function for IFT proteins. Based on their role in cilia, we hypothesized that IFT proteins regulate microtubule-based transport during mitotic spindle assembly. Biochemical investigation revealed that in mitotic cells IFT88, IFT57, IFT52, and IFT20 interact with dynein1, a microtubule motor ...


Investigating Cancer Molecular Genetics Using Genome-Wide Rna Interference Screens: A Dissertation, Ryan W. Serra Jun 2013

Investigating Cancer Molecular Genetics Using Genome-Wide Rna Interference Screens: A Dissertation, Ryan W. Serra

GSBS Dissertations and Theses

The development of RNAi based technologies has given researchers the tools to interrogate processes as diverse as cancer biology, metabolism and organ development. Here I employ genome-wide shRNA screens to discover the genes involved in two different processes in carcinogenesis, oncogene-induced senescence [OIS] and epigenetic silencing of tumor suppressor genes [TSGs].

OIS is a poorly studied yet significant tumor suppressing mechanism in normal cells where they enter cell cycle arrest [senescence] or programmed cell death [apoptosis] in the presence of an activated oncogene. Here I employ a genomewide shRNA screen and identify a secreted protein, IGFBP7, that induces senescence and ...


Transcriptional And Translational Mechanisms Controlling Circadian Rhythms In Drosophila: A Dissertation, Jinli Ling Jun 2013

Transcriptional And Translational Mechanisms Controlling Circadian Rhythms In Drosophila: A Dissertation, Jinli Ling

GSBS Dissertations and Theses

Circadian rhythms are self-sustained 24-hour period oscillations present in most organisms, from bacteria to human. They can be synchronized to external cues, thus allowing organisms to anticipate environmental variations and optimize their performance in nature.

In Drosophila, the molecular pacemaker consists of two interlocked transcriptional feedback loops. CLOCK/CYCLE (CLK/CYC) sits in the center and drives rhythmic transcription of period (per), timeless (tim), vrille (vri) and PAR domain protein 1 (Pdp1). PER and TIM negatively feedback on CLK/CYC transcriptional activity, forming one loop, while VRI and PDP1 form the other by regulating Clk transcription negatively and positively, respectively ...


Dynamic Regulation At The Neuronal Plasma Membrane: Novel Endocytic Mechanisms Control Anesthetic-Activated Potassium Channels And Amphetamine-Sensitive Dopamine Transporters: A Dissertation, Luke R. Gabriel Jun 2013

Dynamic Regulation At The Neuronal Plasma Membrane: Novel Endocytic Mechanisms Control Anesthetic-Activated Potassium Channels And Amphetamine-Sensitive Dopamine Transporters: A Dissertation, Luke R. Gabriel

GSBS Dissertations and Theses

Endocytic trafficking dynamically regulates neuronal plasma membrane protein presentation and activity, and plays a central role in excitability and plasticity. Over the course of my dissertation research I investigated endocytic mechanisms regulating two neuronal membrane proteins: the anesthetic-activated potassium leak channel, KCNK3, as well as the psychostimulant-sensitive dopamine transporter (DAT). My results indicate that KCNK3 internalizes in response to Protein Kinase C (PKC) activation, using a novel pathway that requires the phosphoserine binding protein, 14-3-3β, and demonstrates for the first time regulated KCNK3 channel trafficking in neurons. Additionally, PKC-mediated KCNK3 trafficking requires a non-canonical endocytic motif, which is shared exclusively ...


Dsarm/Sarm1 Governs A Conserved Axon Death Program: A Dissertation, Jeannette M. Osterloh Jun 2013

Dsarm/Sarm1 Governs A Conserved Axon Death Program: A Dissertation, Jeannette M. Osterloh

GSBS Dissertations and Theses

Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Using a forward genetic screen in Drosophila, we identified that loss of the Toll receptor adaptor dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is ...


Investigation Of Multiple Concerted Mechanisms Underlying Stimulus-Induced G1 Arrest In Yeast: A Dissertation, Patricia A. Pope Jun 2013

Investigation Of Multiple Concerted Mechanisms Underlying Stimulus-Induced G1 Arrest In Yeast: A Dissertation, Patricia A. Pope

GSBS Dissertations and Theses

Progression through the cell cycle is tightly controlled, and the decision whether or not to enter a new cell cycle can be influenced by both internal and external cues. For budding yeast one such external cue is pheromone treatment, which can induce G1 arrest. Two distinct mechanisms are known to be involved in this arrest, one dependent on the arrest protein Far1 and one independent of Far1, but the exact mechanisms have remained enigmatic. The studies presented here further elucidate both of these mechanisms.

We looked at two distinct aspects of the Far1-independent arrest mechanism. First, we studied the role ...


Rna Interference By The Numbers: Explaining Biology Through Enzymology: A Dissertation, Liang Meng Wee Jun 2013

Rna Interference By The Numbers: Explaining Biology Through Enzymology: A Dissertation, Liang Meng Wee

GSBS Dissertations and Theses

Small silencing RNAs function in almost every aspect of cellular biology. Argonaute proteins bind small RNA and execute gene silencing. The number of Argonaute paralogs range from 5 in Drosophila melanogaster , 8 in Homo sapiens to an astounding 27 in Caenorhabditis elegans. This begs several questions: Do Argonaute proteins have different small RNA repertoires? Do Argonaute proteins behave differently? And if so, how are they functionally and mechanistically distinct?

To address these questions, we examined the thermodynamic, kinetic and functional properties of fly Argonaute1 (dAgo1), fly Argonaute2 (dAgo2) and mouse Argonaute2 (mAGO2). Our studies reveal that in fly, small RNA ...


Structure And Dynamics Of Viral Substrate Recognition And Drug Resistance: A Dissertation, Aysegul Ozen May 2013

Structure And Dynamics Of Viral Substrate Recognition And Drug Resistance: A Dissertation, Aysegul Ozen

GSBS Dissertations and Theses

Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles ...


Expanding The Known Dna-Binding Specificity Of Homeodomains For Utility In Customizable Sequence-Specific Nucleases: A Dissertation, Stephanie W. Chu May 2013

Expanding The Known Dna-Binding Specificity Of Homeodomains For Utility In Customizable Sequence-Specific Nucleases: A Dissertation, Stephanie W. Chu

GSBS Dissertations and Theses

Homeodomains (HDs) are a large family of DNA-binding domains contained in transcription factors that are most notable for regulating body development and patterning in metazoans. HDs consist of three alpha helices preceded by an N- terminal arm, where the third helix (the recognition helix) and the N-terminal arm are responsible for defining DNA-binding specificity. Here we attempted to engineer the HDs by fully randomizing positions in the recognition helix to specify each of the 64 possible 3’ triplet sites (i.e. TAANNN). We recovered HD variants that preferentially recognize or are compatible with 44 of the possible sites, a ...


The Study Of Two Strategies For Decreasing Mutant Huntingtin: Degradation By Puromycin Sensitive Aminopeptidase And Rna Interference: A Dissertation, Joanna Chaurette May 2013

The Study Of Two Strategies For Decreasing Mutant Huntingtin: Degradation By Puromycin Sensitive Aminopeptidase And Rna Interference: A Dissertation, Joanna Chaurette

GSBS Dissertations and Theses

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the huntingtin gene, resulting in an expanded polyglutamine (polyQ) repeat in the huntingtin protein. Patients receive symptomatic treatment for motor, emotional, and cognitive impairments; however, there is no treatment to slow the progression of the disease, with death occurring 15-20 years after diagnosis. Mutant huntingtin protein interferes with multiple cellular processes leading to cellular dysfunction and neuronal loss. Due to the complexity of mutant huntingtin toxicity, many approaches to treating each effect are being investigated. Unfortunately, addressing one cause of toxicity ...


The Role And Regulation Of Etv2 In Zebrafish Vascular Development: A Dissertation, John C. Moore May 2013

The Role And Regulation Of Etv2 In Zebrafish Vascular Development: A Dissertation, John C. Moore

GSBS Dissertations and Theses

Etv2 is an endothelial-specific ETS transcription factor that is essential for endothelial differentiation and vascular morphogenesis in vertebrates. However, etv2 expression dynamics during development and the mechanisms regulating it are poorly understood. I found that etv2 transcript and protein expression are highly transient during zebrafish vascular development, with both expressed early during development and then subsequently downregulated. Inducible knockdown of Etv2 in zebrafish embryos prior to mid-somitogenesis, but not later, causes severe vascular defects, suggesting a role for Etv2 in specifying angioblasts from the lateral mesoderm. I further demonstrate that the 3’UTR of etv2 is post-transcriptionally regulated in part ...


Elucidating The Molecular Mechanism Of Cyld-Mediated Necrosis: A Dissertation, David M. Moquin May 2013

Elucidating The Molecular Mechanism Of Cyld-Mediated Necrosis: A Dissertation, David M. Moquin

GSBS Dissertations and Theses

TNFα-induced programmed necrosis is a caspase-independent cell death program that is contingent upon the formation of a multiprotein complex termed the necrosome. The association of two of the components of the necrosome, receptor interacting protein 1 (RIP1) and RIP3, is a critical and signature molecular event during necrosis. Within this complex, both RIP1 and RIP3 are phosphorylated which are consequential for transmission of the pro-necrotic signal. Namely, it has been demonstrated that RIP3 phosphorylation is required for binding to downstream substrates. Nevertheless, the regulatory mechanisms governing necrosome activation remain unclear. Since necrosis is implicated in a variety of different diseases ...


Layered Reward Signalling Through Octopamine And Dopamine In Drosophila: A Dissertation, Christopher J. Burke May 2013

Layered Reward Signalling Through Octopamine And Dopamine In Drosophila: A Dissertation, Christopher J. Burke

GSBS Dissertations and Theses

Evaluating our environment by deciding what is beneficial or harmful, pleasant or punishing is a part of our daily lives. Seeking pleasure and avoiding pain is a common trait all mobile organisms exhibit and understanding how rewarding stimuli are represented in the brain remains a major goal of neuroscience. Studying reward learning in the fruit fly, Drosophila melanogaster has enabled us to better understand the complex neural circuit mechanisms involved in reward processing in the brain. By conditioning flies with sugars of differing nutritional properties, we determined that flies trained with sweet but non-nutritive sugars formed robust short-term memory (STM ...