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Engineered Exosomes For Delivery Of Therapeutic Sirnas To Neurons, Reka A. Haraszti May 2018

Engineered Exosomes For Delivery Of Therapeutic Sirnas To Neurons, Reka A. Haraszti

GSBS Dissertations and Theses

Extracellular vesicles (EVs), exosomes and microvesicles, transfer endogenous RNAs between neurons over short and long distances. We have explored EVs for siRNA delivery to brain. (1) We optimized siRNA chemical modifications and siRNA conjugation to lipids for EV-mediated delivery. (2) We developed a GMP-compatible, scalable method to manufacture active EVs in bulk. (3) We characterized lipid and protein content of EVs in detail. (4) We established how protein and lipid composition relates to siRNA delivering activity of EVs, and we reverse engineered natural exosomes (small EVs) into artificial exosomes based on these data.

We established that cholesterol-conjugated siRNAs passively associate ...


Therapeutic Antibody Against Neisseria Gonorrhoeae Lipooligosaccharide, A Phase-Variable Virulence Factor, Srinjoy Chakraborti May 2017

Therapeutic Antibody Against Neisseria Gonorrhoeae Lipooligosaccharide, A Phase-Variable Virulence Factor, Srinjoy Chakraborti

GSBS Dissertations and Theses

Neisseria gonorrhoeae (Ng) which causes gonorrhea has become multidrug-resistant, necessitating the development of novel therapeutics and vaccines. mAb 2C7 which targets an epitope within an important virulence factor, the lipooligosaccharide (LOS), is a candidate therapeutic mAb. Ninety-four percent of clinical isolates express the 2C7-epitope which is also a vaccine target.

Ng expresses multiple LOS(s) due to phase-variation (pv) of LOS glycosyltransferase (lgt) genes. mAb 2C7 reactivity requires a lactose extension from the LOS core Heptose (Hep) II (i.e. lgtG ‘ON’ [G+]). Pv results in HepI with: two (2-), three (3-), four (4-), or five (5-) hexoses (Hex). How ...


Structural Mechanisms Of The Sliding Clamp And Sliding Clamp Loader: Insights Into Disease And Function: A Dissertation, Caroline M. Duffy Jul 2016

Structural Mechanisms Of The Sliding Clamp And Sliding Clamp Loader: Insights Into Disease And Function: A Dissertation, Caroline M. Duffy

GSBS Dissertations and Theses

Chromosomal replication is an essential process in all life. This dissertation highlights regulatory roles for two critical protein complexes at the heart of the replication fork: 1) the sliding clamp, the major polymerase processivity factor, and 2) the sliding clamp loader, a spiral-shaped AAA+ ATPase, which loads the clamp onto DNA.

The clamp is a promiscuous binding protein that interacts with at least 100 binding partners to orchestrate many processes on DNA, but spatiotemporal regulation of these binding interactions is unknown. Remarkably, a recent disease-causing mutant of the sliding clamp showed specific defects in DNA repair pathways. We aimed to ...


Characterizing The Disorder In Tristetraprolin And Its Contribution To Post-Transcriptional Gene Regulation: A Dissertation, Laura M. Deveau May 2016

Characterizing The Disorder In Tristetraprolin And Its Contribution To Post-Transcriptional Gene Regulation: A Dissertation, Laura M. Deveau

GSBS Dissertations and Theses

RNA-binding proteins (RBPs) are important for a wide variety of biological processes involved in gene regulation. However, the structural and dynamic contributions to their biological activity are poorly understood. The tristetraprolin (TTP) family of RBPs, including TTP, TIS11b and TIS11d, regulate the stability of mRNA transcripts encoding for key cancer-related proteins, such as tumor necrosis factor- and vascular endothelial growth factor. Biophysical studies have shown that the RNA binding domain, consisting of two CCCH zinc fingers (ZFs), is folded in the absence of RNA in TIS11d and TIS11b. In TTP, however, only ZF1 adopts a stable fold, while RNA is ...


Single-Molecule Imaging Reveals That Argonaute Re-Shapes The Properties Of Its Nucleic Acid Guides: A Dissertation, William E. Salomon Dec 2015

Single-Molecule Imaging Reveals That Argonaute Re-Shapes The Properties Of Its Nucleic Acid Guides: A Dissertation, William E. Salomon

GSBS Dissertations and Theses

Small RNA silencing pathways regulate development, viral defense, and genomic integrity in all kingdoms of life. An Argonaute (Ago) protein, guided by a tightly bound, small RNA or DNA, lies at the core of these pathways. Argonaute uses its small RNA or DNA to find its target sequences, which it either cleaves or stably binds, acting as a binding scaffold for other proteins. We used Co-localization Single-Molecule Spectroscopy (CoSMoS) to analyze target binding and cleavage by Ago and its guide. We find that both eukaryotic and prokaryotic Argonaute proteins re-shape the fundamental properties of RNA:RNA, RNA:DNA, and DNA ...


A Feedback Loop Couples Musashi-1 Activity To Omega-9 Fatty Acid Biosynthesis: A Dissertation, Carina C. Clingman Sep 2014

A Feedback Loop Couples Musashi-1 Activity To Omega-9 Fatty Acid Biosynthesis: A Dissertation, Carina C. Clingman

GSBS Dissertations and Theses

All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and activate second-­‐messenger systems. In bacteria, metabolites also affect post-­‐transcriptional regulatory mechanisms, but there are only a few isolated examples of this regulation in eukaryotes. Here, I present evidence that RNA-­‐binding by the stem cell translation regulator Musashi-­‐1 (MSI1) is allosterically inhibited by 18-­‐22 carbon ω-­‐9 monounsaturated fatty acids. The fatty acid binds to the N-­‐terminal RNA Recognition Motif (RRM) and induces a conformational change that prevents RNA association. Musashi ...


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 ...


An Extra-Embryonic Wnt Signaling Event Controls Gastrulation In Mice: A Dissertation, Giovane G. Tortelote Nov 2012

An Extra-Embryonic Wnt Signaling Event Controls Gastrulation In Mice: A Dissertation, Giovane G. Tortelote

GSBS Dissertations and Theses

The formation of the anterior-posterior axis requires a symmetry-breaking event that starts gastrulation. Ultimately, the morphogenetic movements of gastrulation reshape the embryo to its final tri-dimensional form. In mouse embryos, the identity of the molecule that breaks the bilateral symmetry and sets in motion gastrulation remains elusive. The Wnt signaling pathway plays a pivotal role during axial specification and gastrulation in metazoans. Loss-of-function experiments have demonstrated a requirement of Wnt3 for gastrulation in mice. But because Wnt3 is expressed sequentially in two tissues, the visceral endoderm and the epiblast, its tissue specific requirements remain uncertain. Here, we report that embryos ...


Investigating The Roles Of Nedd4.2s And Nef In The Release And Replication Of Hiv-1: A Dissertation, Eric R. Weiss Sep 2012

Investigating The Roles Of Nedd4.2s And Nef In The Release And Replication Of Hiv-1: A Dissertation, Eric R. Weiss

GSBS Dissertations and Theses

Replication of HIV-1 requires the assembly and release of mature and infectious viral particles. In order to accomplish this goal, HIV-1 has evolved multiple methods to interact with the host cell. HIV-1 recruits the host cell ESCRT machinery to facilitate the release of nascent viral particles from the host cell membrane. Recruitment of these cellular factors is dependent on the presence of short motifs in Gag referred to as Late-domains. Deletion or mutation of these domains results in substantial decrease in the release of infectious virions. However, previously published work has indicated that over-expression of the E3 ubiquitin ligase, NEDD4 ...


Hepatitis C Virus Non-Structural Protein 3/4a: A Tale Of Two Domains: A Dissertation, Cihan Aydin Aug 2012

Hepatitis C Virus Non-Structural Protein 3/4a: A Tale Of Two Domains: A Dissertation, Cihan Aydin

GSBS Dissertations and Theses

Two decades after the discovery of the Hepatitis C Virus (HCV), Hepatitis C infection still persists to be a global health problem. With the recent approval of the first set of directly acting antivirals (DAAs), the rate of sustained viral response for HCV-infected patients increased significantly. However, a complete cure has not been found yet. Drug development efforts primarily target NS3/4A protease, bifunctional serine protease-RNA helicase of HCV. HCV NS3/4A is critical in viral function; protease domain processes the viral polyprotein and helicase domain aids replication of HCV genome by unwinding double stranded RNA transcripts produced by NS5B ...


Serotonin-Expressing Cells In The Corpus Of The Stomach Originate From Bone Marrow: A Master’S Thesis, Brian T. Johnston Aug 2012

Serotonin-Expressing Cells In The Corpus Of The Stomach Originate From Bone Marrow: A Master’S Thesis, Brian T. Johnston

GSBS Dissertations and Theses

Neurogenin 3 and its downstream target NeuroD are basic helix-loop-helix transcription factors which promote endocrine differentiation in the gastrointestinal tract. However, mice lacking Ngn3 still produce several hormones in the stomach. Lineage tracing mouse models demonstrated that a majority of hormone cells in the corpus region of the stomach did not express Ngn3 or NeuroD during differentiation. Serotonin and histamine cells were entirely NeuroD-independently derived, and serotonin cells were additionally entirely Ngn3-independently derived. In this study, we isolated serotonin and histamine cells from the gastric corpus of transgenic mice expressing the fluorescent marker CFP. Serotonin cells expressed multiple mast cell ...


A Novel Communication Mechanism Between The Presynapse And Postsynapse Through Exosomes: A Dissertation, Ceren Korkut Aug 2012

A Novel Communication Mechanism Between The Presynapse And Postsynapse Through Exosomes: A Dissertation, Ceren Korkut

GSBS Dissertations and Theses

The minimal element of the nervous system, the synapse, is a plastic structure that has the ability to change in response to various internal and external factors. This property of the synapse underlies complex behaviors such as learning and memory. However, the exact molecular and cellular mechanisms involved in this process are not fully understood. To understand the mechanisms that regulate synapse development and plasticity I took advantage of a powerful model system, the Drosophila larval neuromuscular junction (NMJ). In this system, both anterograde and retrograde signaling pathways critical for coordinated synapse development and plasticity have been documented.

An anterograde ...


Sequence And Target Specificity Of The C. Elegans Cell Fate Specification Factor Pos-1: A Dissertation, Brian M. Farley Aug 2012

Sequence And Target Specificity Of The C. Elegans Cell Fate Specification Factor Pos-1: A Dissertation, Brian M. Farley

GSBS Dissertations and Theses

In most metazoans, early embryogenesis is controlled by the translational regulation of maternally supplied mRNA. Sequence-specific RNA-binding proteins play an important role in regulating early embryogenesis, yet their specificities and regulatory targets are largely unknown. To understand how these RNA-binding proteins select their targets, my research focused on the C. elegans CCCH-type tandem zinc finger protein POS-1. Embryos lacking maternally supplied POS-1 die prior to gastrulation, and exhibit defects in the specification of pharyngeal, intestinal, and germline precursor cells. To identify the regulatory targets that contribute to the POS-1 mutant phenotype, we set out to determine the sequence specificity of ...


The Role Of Itk In The Development Of Gamma Delta Nkt Cells: A Dissertation, Catherine C. Yin Aug 2012

The Role Of Itk In The Development Of Gamma Delta Nkt Cells: A Dissertation, Catherine C. Yin

GSBS Dissertations and Theses

The immune system is a complex network of interacting cells and tissues that is designed to protect the body from pathogens and other foreign substances. T cells are a major component of the immune system and consist of two distinct lineages distinguished by the expression of αβ or γδ T cell receptors (TCR). The Tec family kinase, Itk is an important mediator of signaling downstream of the TCR. Past studies on Itk has focused on how Itk regulates development, activation and differentiation of conventional αβ T cells and more recently how Itk regulates the development of innate-like αβ T cells ...


Studies On Cellular Host Factors Involved In The Hiv-1 Life Cycle: A Dissertation, Anna Kristina Serquiña Aug 2012

Studies On Cellular Host Factors Involved In The Hiv-1 Life Cycle: A Dissertation, Anna Kristina Serquiña

GSBS Dissertations and Theses

Human Immunodeficiency Virus Type 1 (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), currently the leading cause of death from infectious diseases. Since HIV-1 co-opts the host cellular machinery, the study of cellular factors involved is a rational approach in discovering novel therapeutic targets for AIDS drug development. In this thesis, we present studies on two such proteins. APOBEC3G is from the family of cytidine deaminases known to keep endogenous retroviruses and retrotransposons at bay to maintain stability of the human genome. APOBEC3G targets Vif-deficient HIV-1 particles and renders them noninfectious, partially through deaminase-dependent hypermutation of the provirus ...


Maintaining The Balance: Coordinating Excitation And Inhibition In A Simple Motor Circuit: A Dissertation, Hilary A. Petrash Aug 2012

Maintaining The Balance: Coordinating Excitation And Inhibition In A Simple Motor Circuit: A Dissertation, Hilary A. Petrash

GSBS Dissertations and Theses

The generation of complex behaviors often requires the coordinated activity of diverse sets of neural circuits in the brain. Activation of neuronal circuits drives behavior. Inappropriate signaling can contribute to cognitive disorders such as epilepsy, Parkinson’s, and addiction (Nordberg et al., 1992; Quik and McIntosh, 2006; Steinlein et al., 2012). The molecular mechanisms by which the activity of neural circuits is coordinated remain unclear. What are the molecules that regulate the timing of neural circuit activation and how is signaling between various neural circuits achieved? While much work has attempted to address these points, answers to these questions have ...


Mechanical Activation Of Valvular Interstitial Cell Phenotype: A Dissertation, Angela M. Throm Quinlan Aug 2012

Mechanical Activation Of Valvular Interstitial Cell Phenotype: A Dissertation, Angela M. Throm Quinlan

GSBS Dissertations and Theses

During heart valve remodeling, and in many disease states, valvular interstitial cells (VICs) shift to an activated myofibroblast phenotype which is characterized by enhanced synthetic and contractile activity. Pronounced alpha smooth muscle actin (αSMA)-containing stress fibers, the hallmark of activated myofibroblasts, are also observed when VICs are placed under tension due to altered mechanical loading in vivo or during in vitro culture on stiff substrates or under high mechanical loads and in the presence of transforming growth factor-beta1 (TGF-β1). The work presented herein describes three distinct model systems for application of controlled mechanical environment to VICs cultured in vitro ...


Role Of Perivascular And Visceral Adipose Tissues In Murine Models Of Obesity And Atherosclerosis: A Dissertation, Timothy P. Fitzgibbons Jul 2012

Role Of Perivascular And Visceral Adipose Tissues In Murine Models Of Obesity And Atherosclerosis: A Dissertation, Timothy P. Fitzgibbons

GSBS Dissertations and Theses

Expansion of visceral adipose tissue correlates with the metabolic syndrome and increased cardiovascular risk. Hypertrophied visceral fat becomes inflamed, causing increased lipolysis, decreased triglyceride storage, and lipotoxicity in skeletal muscle and liver resulting in insulin resistance. Perivascular adipose tissue is a normal component of the adventitia of arteries in humans and animals. Whether or not perivascular adipose also becomes inflamed in obesity is an important question, as this may be an additional, direct mechanism by which obesity causes vascular inflammation and disease.

Thus, for the first part of my thesis, we asked the question: does perivascular adipose in mice become ...


Protein Ligand Interactions Probed By Nmr: A Dissertation, Jennifer M. Laine Jul 2012

Protein Ligand Interactions Probed By Nmr: A Dissertation, Jennifer M. Laine

GSBS Dissertations and Theses

Molecular recognition, defined as the specific interactions between two or more molecules, is at the center of many biological processes including catalysis, signal transduction, gene regulation and allostery. Allosteric regulation is the modification of function caused by an intermolecular interaction. Allosteric proteins modify their activity in response to a biological signal that is often transmitted through the interaction with a small effector molecule. Therefore, determination of the origins of intermolecular interactions involved in molecular recognition and allostery are essential for understanding biological processes. Classically, molecular recognition and allosteric regulation have been associated to structural changes of the system. NMR spectroscopic ...


Gene Expression And Profiling Of Human Islet Cell Subtypes: A Master’S Thesis, David M. Blodgett Jul 2012

Gene Expression And Profiling Of Human Islet Cell Subtypes: A Master’S Thesis, David M. Blodgett

GSBS Dissertations and Theses

Background: The endocrine pancreas contains multiple cell types co-localized into clusters called the Islets of Langerhans. The predominant cell types include alpha and beta cells, which produce glucagon and insulin, respectively. The regulated release of these hormones maintains whole body glucose homeostasis, essential for normal metabolism and to prevent diabetes and complications from the disease. Given the heterogeneous nature of islet composition and absence of unique surface markers, many previous studies have focused on the whole islet. Sorting islet cells by intracellular hormone expression overcomes this limitation and provides pure populations of individual islet cell subsets, specifically alpha and beta ...


Understanding Small Rna Formation In Drosophila Melanogaster: A Dissertation, Elif Sarinay Cenik Jul 2012

Understanding Small Rna Formation In Drosophila Melanogaster: A Dissertation, Elif Sarinay Cenik

GSBS Dissertations and Theses

Drosophila Dicer-2 generates small interfering RNAs (siRNAs) from long double-stranded RNA (dsRNA), whereas Dicer-1 produces microRNAs from premicroRNA. My thesis focuses on the functional characteristics of two Drosophila Dicers that makes them specific for their biological substrates. We found that RNA binding protein partners of Dicers and two small molecules, ATP and phosphate are key in regulating Drosophila Dicers’ specificity. Without any additional factor, recombinant Dicer-2 cleaves pre-miRNA, but its product is shorter than the authentic miRNA. However, the protein R2D2 and inorganic phosphate block pre-miRNA processing by Dicer-2. In contrast, Dicer-1 is inherently capable of processing the substrates of ...


Mdm2-P53 Signaling In Tissue Homeostasis And The Dna Damage Response: A Dissertation, Hugh S. Gannon Jun 2012

Mdm2-P53 Signaling In Tissue Homeostasis And The Dna Damage Response: A Dissertation, Hugh S. Gannon

GSBS Dissertations and Theses

The p53 transcription factor responds to various cellular stressors by regulating the expression of numerous target genes involved in cellular processes such as cell cycle arrest, apoptosis, and senescence. As these downstream pathways are harmful to the growth and development of normal cells when prolonged or deregulated, p53 activity needs to be under tight regulatory control. The Mdm2 oncoprotein is the chief negative regulator of p53, and many mouse models have demonstrated that absence of Mdm2 expression leads to constitutive p53 activation in a variety of cell types. While unregulated p53 can be deleterious to cells, functional p53 is essential ...


Innate Signaling Pathways In The Maintenance Of Serological Memory: A Dissertation, Forum M. Raval Jun 2012

Innate Signaling Pathways In The Maintenance Of Serological Memory: A Dissertation, Forum M. Raval

GSBS Dissertations and Theses

Long-term antiviral antibody responses provide protection from re-infection and recurrence of persistent viruses. Using a polyomavirus (PyV) mouse model, our lab has shown that MyD88-deficient mice generate low levels of virus-specific IgG after the acute phase of infection and that these IgG responses have a skewed isotype distribution with low levels of IgG2a/c. Moreover MyD88-deficient mice have reduced numbers of long-lived plasma cells in the bone marrow. These studies suggest an important role of MyD88-mediated signaling in long-term antiviral responses. Our lab has shown that T cell-deficient mice can also maintain long-term virus-specific IgG responses following PyV infection. The ...


A Role For C-Jun Kinase (Jnk) Signaling In Glial Engulfment Of Degenerating Axons: A Dissertation, Jennifer M. Macdonald Jun 2012

A Role For C-Jun Kinase (Jnk) Signaling In Glial Engulfment Of Degenerating Axons: A Dissertation, Jennifer M. Macdonald

GSBS Dissertations and Theses

The central nervous system (CNS) is composed of two types of cells: neurons that send electrical signals to transmit information throughout the animal and glial cells. Glial cells were long thought to be merely support cells for the neurons; however, recent work has identified many critical roles for these cells during development and in the mature animal. In the CNS, glial cells act as the resident immune cell and they are responsible for the clearance of dead or dying material. After neuronal injury or death, glial cells become reactive, exhibiting dramatic changes in morphology and patterns of gene expression and ...


Transposition Driven Genomic Heterogeneity In The Drosophila Brain: A Dissertation, Paola N. Perrat Jun 2012

Transposition Driven Genomic Heterogeneity In The Drosophila Brain: A Dissertation, Paola N. Perrat

GSBS Dissertations and Theses

In the Drosophila brain, memories are processed and stored in two mirrorsymmetrical structures composed of approximately 5,000 neurons called Mushroom Bodies (MB). Depending on their axonal extensions, neurons in the MB can be further classified into three different subgroups: αβ, α’β’ and γ. In addition to the morphological differences between these groups of neurons, there is evidence of functional differences too. For example, it has been previously shown that while neurotransmission from α’β’ neurons is required for consolidation of olfactory memory, output from αβ neurons is required for its later retrieval. To gain insight into the functional ...


Antagonistic Pleiotropy: The Role Of Smurf2 In Cancer And Aging: A Dissertation, Charusheila Ramkumar Jun 2012

Antagonistic Pleiotropy: The Role Of Smurf2 In Cancer And Aging: A Dissertation, Charusheila Ramkumar

GSBS Dissertations and Theses

In response to telomere shortening, oxidative stress, DNA damage or aberrant activation of oncogenes, normal somatic cells exit the cell cycle and enter an irreversible growth arrest termed senescence. The limited proliferative capacity imposed by senescence on cells impedes the accumulation of mutations necessary for tumorigenesis and prevents proliferation of cells at risk of neoplastic transformation. Opposite to the tumor suppressor function, accumulation of senescent cells in adult organisms is thought to contribute to aging by depleting the renewal capacity of tissues and stem/progenitor cells, and by interfering with tissue homeostasis and functions. The Antagonistic Pleiotropy Theory of senescence ...


Mechanisms Of Kras-Mediated Pancreatic Tumor Formation And Progression: A Dissertation, Victoria A. Appleman May 2012

Mechanisms Of Kras-Mediated Pancreatic Tumor Formation And Progression: A Dissertation, Victoria A. Appleman

GSBS Dissertations and Theses

Pancreatic cancer is the 4th leading cause of cancer related death in the United States with a median survival time of less than 6 months. Pancreatic ductal adenocarcinoma (PDAC) accounts for greater than 85% of all pancreatic cancers, and is marked by early and frequent mutation of the KRAS oncogene, with activating KRAS mutations present in over 90% of PDAC. To date, though, targeting activated KRAS for cancer treatment has been very difficult, and targeted therapies are currently being sought for the downstream effectors of activated KRAS. Activation of KRAS stimulates multiple signaling pathways, including the MEK-ERK and PI3K-AKT signaling ...


Small Molecule Investigation Of Kcnq Potassium Channels: A Dissertation, Karen Mruk May 2012

Small Molecule Investigation Of Kcnq Potassium Channels: A Dissertation, Karen Mruk

GSBS Dissertations and Theses

Voltage-gated K+ channels associate with multiple regulatory proteins to form complexes with diverse gating properties and pharmacological sensitivities. Small molecules which activate or inhibit channel function are valuable tools for dissecting the assembly and function of these macromolecular complexes. My thesis focuses on the discovery and use of small molecules to probe the structure and function of the KCNQ family of voltage-gated K+ channels.

One protein that obligatorily assembles with KCNQ channels to mediate proper assembly, trafficking, and gating is the calcium sensor, calmodulin. Although resolution of the crystal structures of calmodulin associated with isolated peptide fragments from other ion ...


Transcriptional Regulation Of The Interleukin-8 Promoter By Multiple Dengue Viral Proteins: A Dissertation, Jacob M. Collins May 2012

Transcriptional Regulation Of The Interleukin-8 Promoter By Multiple Dengue Viral Proteins: A Dissertation, Jacob M. Collins

GSBS Dissertations and Theses

Dengue virus (DENV) causes over 500,000 infections annually with a spectrum of clinical diseases ranging from subclinical infection to dengue, a mild febrile illness, to life-threatening severe dengue. Vascular leakage without endothelial cell damage is the hallmark symptom of severe dengue illness and is proposed to be directly mediated by soluble inflammatory mediators IL-8 and TNFα. IL-8 production occurs in response to DENV infection, is elevated during severe dengue, is proposed to inhibit interferon, and could potentially recruit target cells to sites of infection. We previously showed that expression of DENV NS5 activates the IL-8 promoter, induces IL-8 transcription ...


Runx1 C-Terminal Domains During Hematopoietic Development And Leukemogenesis: A Dissertation, Christopher R. Dowdy May 2012

Runx1 C-Terminal Domains During Hematopoietic Development And Leukemogenesis: A Dissertation, Christopher R. Dowdy

GSBS Dissertations and Theses

Runx1 is a master regulator of hematopoiesis, required for the initiation of definitive hematopoiesis in the embryo and essential for appropriate differentiation of many hematopoietic lineages in the adult. The roles of Runx1 in normal hematopoiesis are juxtaposed with the high frequency of Runx1 mutations and translocations in leukemia. Leukemia associated Runx1 mutations that retain DNA-binding ability have truncations or frame shifts that lose C-terminal domains. These domains are important for subnuclear localization of Runx1 and protein interactions with co-factors. The majority of leukemia associated Runx1 translocations also replace the C-terminus of Runx1 with chimeric fusion proteins. The common loss ...