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Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Mediated Rnai Approach For Autosomal Dominant C9orf72 Associated Als, Gabriela Toro Mar 2019

Gene Therapy For Amyotrophic Lateral Sclerosis: An Aav Mediated Rnai Approach For Autosomal Dominant C9orf72 Associated Als, Gabriela Toro

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease that affects motor neurons causing progressive muscle weakness and respiratory failure. In 2011, the presence of a hexanucleotide repeat expansion within chromosome 9 open reading frame 72(C9ORF72) was identified in ALS patient samples, becoming the major known genetic cause for ALS and frontotemporal dementia (FTD). Carriers of this mutation present reduced levels of C9ORF72 mRNA, RNA foci produced by the aggregating expansion and toxic dipeptides generated through repeat-associated non-ATG translation. These findings have led to multiple hypotheses on the pathogenesis of C9ORF72: 1) Haploinsufficiency, 2) RNA gain-of-function, 3) RAN Translation ...


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 ...


Glial Control Of Synapse Assembly At The Drosophila Neuromuscular Junction: A Dissertation, Kimberly S. Kerr Sep 2012

Glial Control Of Synapse Assembly At The Drosophila Neuromuscular Junction: A Dissertation, Kimberly S. Kerr

GSBS Dissertations and Theses

Emerging evidence in both vertebrates and invertebrates is redefining glia as active and mobile players in synapse formation, maturation and function. However, the molecular mechanisms through which neurons and glia interact with each other to regulate these processes is not well known. My thesis work begins to understand how glia use secreted factors to modulate synaptic function. We use Drosophila melanogaster, a simple and genetically tractable model system, to understand the molecular mechanisms by which glia communicate with neurons at glutamatergic neuromuscular junctions (NMJs). We previously showed that a specific subtype of glia, subperineurial peripheral glia cells (SPGs), establish dynamic ...


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 ...


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 ...


Microrna Markers Of Acetaminophen Toxicity: A Master's Thesis, Jeanine Ward Jul 2012

Microrna Markers Of Acetaminophen Toxicity: A Master's Thesis, Jeanine Ward

GSBS Dissertations and Theses

Background
To investigate plasma microRNA (miRNA) profiles indicative of hepatotoxicity in the setting of lethal acetaminophen (APAP) toxicity in mice.

Methods
Using plasma from APAP poisoned mice, either lethally (500 mg/kg) or sublethally (150 mg/kg) dosed, we screened commercially available murine microRNA libraries (SABiosciences, Qiagen Sciences, MD) to evaluate for unique miRNA profiles between these two dosing parameters.

Results
We distinguished numerous, unique plasma miRNAs both up- and down-regulated in lethally compared to sublethally dosed mice. Of note, many of the greatest up- and down-regulated miRNAs, included, but were not limited to, 574-5p, 466g, 466f-3p, 375, 29c, and ...


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 ...


A New Murine Model For Enterohemorrhagic Escherichia Coli Infection Reveals That Actin Pedestal Formation Facilitates Mucosal Colonization And Lethal Disease: A Dissertation, Emily M. Mallick Mar 2012

A New Murine Model For Enterohemorrhagic Escherichia Coli Infection Reveals That Actin Pedestal Formation Facilitates Mucosal Colonization And Lethal Disease: A Dissertation, Emily M. Mallick

GSBS Dissertations and Theses

Enterohemorrhagic Escherichia coli (EHEC) colonizes the intestine and produces the phage-encoded Shiga toxin (Stx) which is absorbed systemically and can lead to hemolytic uremic syndrome (HUS) characterized by hemolytic anemia, thrombocytopenia, and renal failure. EHEC, and two related pathogens, Enteropathogenic E. coli (EPEC), and the murine pathogen, Citrobacter rodentium, are attaching and effacing (AE) pathogens that intimately adhere to enterocytes and form actin “pedestals” beneath bound bacteria. The actin pedestal, because it is a unique characteristic of AE pathogens, has been the subject of intense study for over 20 years. Investigations into the mechanism of pedestal formation have revealed that ...


Role Of Glia In Sculpting Synaptic Connections At The Drosophila Neuromuscular Junction: A Dissertation, Yuly F. Fuentes Medel Jan 2012

Role Of Glia In Sculpting Synaptic Connections At The Drosophila Neuromuscular Junction: A Dissertation, Yuly F. Fuentes Medel

GSBS Dissertations and Theses

Emerging evidence in both vertebrates and invertebrates is redefining glia as active players in the development and integrity of the nervous system. The formation of functional neuronal circuits requires the precise addition of new synapses. Mounting evidence implicates glial function in synapse remodeling and formation. However, the precise molecular mechanisms governing these functions are poorly understood. My thesis work begins to define the molecular mechanisms by which glia communicate with neurons at the Drosophila neuromuscular junction (NMJ).

During development glia play a critical role in remodeling neuronal circuits in the CNS. In order to understand how glia remodel synapses, I ...


Intestine Homeostasis And The Role Of Tumor Suppressor Gene 101 In Drosophila Melanogaster: A Dissertation, Madhurima Chatterjee Dec 2011

Intestine Homeostasis And The Role Of Tumor Suppressor Gene 101 In Drosophila Melanogaster: A Dissertation, Madhurima Chatterjee

GSBS Dissertations and Theses

Tissue homeostasis in the adult Drosophila melanogaster intestine is maintained by controlling the proper balance of stem cell self-renewal and differentiation. In the adult fly midgut, intestinal stem cells (ISCs) are the only dividing cells and their identity maintenance is crucial to the proper functioning of the fly gut. Various pathways such as Notch, JAK-STAT and Wingless are known to regulate ISC division and differentiation.

Here I used a pathogen feeding model to study conditions that accelerate ISC division and guide intestinal cell differentiation favoring enterocyte development. I also examined the role of Tumor Suppressor Gene 101 (TSG101) in ISC ...


Cellular And Molecular Mechanisms Driving Glial Engulfment Of Degenerating Axons: A Dissertation, Johnna E. Doherty Nov 2011

Cellular And Molecular Mechanisms Driving Glial Engulfment Of Degenerating Axons: A Dissertation, Johnna E. Doherty

GSBS Dissertations and Theses

The nervous system is made up of two major cell types, neurons and glia. The major distinguishing feature between neuronal cells and glial cells is that neurons are capable of transmitting action potentials while glial cells are electrically incompetent. For over a century glial cells were neglected and it was thought they existed merely to provide trophic and structural support to neurons. However, in the past few decades it has become increasingly clear that glial cell functions underlie almost all aspects of nervous system development, maintenance, and health. During development, glia act as permissive substrates for axons, provide guidance cues ...


Autoregulatory And Paracrine Control Of Synaptic And Behavioral Plasticity By Dual Modes Of Octopaminergic Signaling: A Dissertation, Alex C. Koon Oct 2011

Autoregulatory And Paracrine Control Of Synaptic And Behavioral Plasticity By Dual Modes Of Octopaminergic Signaling: A Dissertation, Alex C. Koon

GSBS Dissertations and Theses

Synaptic plasticity—the ability of a synapse to change—is fundamental to basic brain function and behavioral adaptation. Studying the mechanisms of synaptic plasticity benefits our understanding of the formation of neuronal connections and circuitry, which has great implications in the field of learning and memory and the studies of numerous human diseases.

The Drosophila larval neuromuscular junction (NMJ) system is a powerful system for studying synaptic plasticity. The NMJ consists of at least two different types of motorneurons innervating the body wall muscles. Type I motorneurons controls muscle contraction using glutamate as the neurotransmitter, while type II are modulatory ...


Neuronal Diversification In The Postembryonic Drosophila Brain: A Dissertation, Suewei Lin Aug 2011

Neuronal Diversification In The Postembryonic Drosophila Brain: A Dissertation, Suewei Lin

GSBS Dissertations and Theses

A functional central nervous system (CNS) is composed of numerous types of neurons. Neurons are derived from a limited number of multipotent neural stem cells. Previous studies have suggested three major strategies nature uses to diversify neurons: lineage identity specification that gives an individual neural stem cell distinct identity based on its position in the developing CNS; temporal identity specification that gives neurons derived from a neural stem cell distinct identities based on their birth-order within the lineage; and binary cell fate specification that gives different identities to the two sister postmitotic neurons derived from the terminal division of a ...


Two Distinct Modes Of Signaling By Vascular Endothelial Growth Factor C Guide Blood And Lymphatic Vessel Patterning In Zebrafish: A Dissertation, Jacques A. Villefranc Aug 2011

Two Distinct Modes Of Signaling By Vascular Endothelial Growth Factor C Guide Blood And Lymphatic Vessel Patterning In Zebrafish: A Dissertation, Jacques A. Villefranc

GSBS Dissertations and Theses

Vascular Endothelial Growth Factor Receptor-3 (VEGFR3/Flt4) and its ligand Vegfc are necessary for development of both blood and lymphatic vasculature in vertebrates. In zebrafish, Vegfc/Flt4 signaling is essential for formation of arteries, veins, and lymphatic vessels. Interestingly, Flt4 appears to utilize distinct signaling pathways during the development of each of these vessels. To identify components of this pathway, we performed a transgenic haploid genetic screen in zebrafish that express EGFP under the control of a blood vessel specific promoter. As a result, we indentified a mutant allele of vascular endothelial growth factor c (vegfc), vegfcum18. vegfcum18 ...


Nuclear Import Of Smad: A Dissertation, Xiaochu Chen Aug 2011

Nuclear Import Of Smad: A Dissertation, Xiaochu Chen

GSBS Dissertations and Theses

Signal transduction by transforming growth factor β (TGF-β) cytokines is mediated by an evolutionarily conserved mechanism that depends on the Smad proteins to transduce an extracellular stimulus into the nucleus. In the unstimulated state, Smads spontaneously shuttle across the nuclear envelope and distribute throughout the cell. Upon TGF-β or bone morphogenetic protein (BMP) stimulation, the receptor-activated Smads are phosphorylated, assemble into complexes with Smad4, and become mostly localized in the nucleus. Such signal-induced nuclear translocation of activated Smads is essential for TGF-β–dependent gene regulation that is critical for embryonic development and homeostasis. The molecular machinery responsible for this process ...


Digital And Analog Stat5 Signaling In Erythropoiesis: A Dissertation, Ermelinda Porpiglia Aug 2011

Digital And Analog Stat5 Signaling In Erythropoiesis: A Dissertation, Ermelinda Porpiglia

GSBS Dissertations and Theses

Erythropoietin (Epo) modulates red blood cell production (erythropoiesis) by binding to its receptor and activating STAT5, a Signal Transducer and Activator of Transcription (STAT) protein implicated in both basal and stress erythropoiesis. Epo concentration in serum changes over three orders of magnitude, as it regulates basal erythropoiesis and its acceleration during hypoxic stress. However, it is not known how STAT5 translates the changes in Epo concentration into the required erythropoietic rates. We addressed this question by studying STAT5 phosphorylation, at the single cell level, in developing erythroblasts.

We divided erythroid progenitors in tissue into several flow-cytometric subsets and found that ...


Tyraminergic G Protein-Coupled Receptors Modulate Locomotion And Navigational Behavior In C. Elegans: A Dissertation, Jamie L. Donnelly Aug 2011

Tyraminergic G Protein-Coupled Receptors Modulate Locomotion And Navigational Behavior In C. Elegans: A Dissertation, Jamie L. Donnelly

GSBS Dissertations and Theses

An animal’s ability to navigate through its natural environment is critical to its survival. Navigation can be slow and methodical such as an annual migration, or purely reactive such as an escape response. How sensory input is translated into a fast behavioral output to execute goal oriented locomotion remains elusive. In this dissertation, I aimed to investigate escape response behavior in the nematode C. elegans. It has been shown that the biogenic amine tyramine is essential for the escape response. A tyramine-gated chloride channel, LGC-55, has been revealed to modulate suppression of head oscillations and reversal behavior in response ...


Chromosome-Biased Binding And Function Of C. Elegans Drm Complex, And Its Role In Germline Sex-Silencing: A Dissertation, Tomoko M. Tabuchi Jul 2011

Chromosome-Biased Binding And Function Of C. Elegans Drm Complex, And Its Role In Germline Sex-Silencing: A Dissertation, Tomoko M. Tabuchi

GSBS Dissertations and Theses

DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in the cell cycle and cancer. Recent work has unveiled a new aspect of DRM function in regulating genes involved in development and differentiation. These studies, however, were performed with cultured cells and a genome-wide study involving intact organisms undergoing active proliferation and differentiation was lacking. Our goal was to extend the knowledge of the role of DRM in gene regulation through development and in multiple tissues. To accomplish this, we employed genomic approaches to determine genome-wide targets of DRM using ...


Dynamics Of Erythropoietic Survival Pathways In Vivo: A Dissertation, Miroslav Koulnis Jul 2011

Dynamics Of Erythropoietic Survival Pathways In Vivo: A Dissertation, Miroslav Koulnis

GSBS Dissertations and Theses

Erythropoiesis maintains stable tissue oxygenation in the basal state, while accelerating red cell production in anemia, blood loss or high altitude. The principal regulator of erythropoiesis is the hormone erythropoietin (Epo). In response to hypoxic stress, Epo can increase a 1000-fold, driving erythropoietic rate by up to 10-fold. It’s been suggested that survival pathways activated by the Epo receptor (EpoR) underlie its regulation of erythropoietic rate. A number of apparently redundant EpoR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo.

Here I assessed the roles of three survival pathways activated by EpoR ...


Identification Of A Command Neuron Directing The Expression Of Feeding Behavior In Drosophila Melanogaster: A Dissertation, Thomas F. Flood May 2011

Identification Of A Command Neuron Directing The Expression Of Feeding Behavior In Drosophila Melanogaster: A Dissertation, Thomas F. Flood

GSBS Dissertations and Theses

Feeding is one of the most important behaviors for an animal’s survival. At a gross level, it is known that the nervous system plays a major role in the expression of this complex behavior, yet a detailed understanding of the neural circuits directing feeding behavior remains unknown. Here we identify a command neuron in Drosophila melanogaster whose artificial activation, using dTrpA1, a heat-activated cation channel, induces the appearance of complete feeding behavior. We use behavioral, genetic, cellular and optical imaging techniques to show that the induced behavior is composed of multiple motor programs and can function to uptake exogenous ...


Molecular Mechanisms Of Pirna Biogenesis And Function In Drosophila: A Dissertation, Chengjian Li Apr 2011

Molecular Mechanisms Of Pirna Biogenesis And Function In Drosophila: A Dissertation, Chengjian Li

GSBS Dissertations and Theses

In the Drosophila germ line, PIWI-interacting RNAs (piRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences.

We examined the genetic requirements for the biogenesis and function of piRNAs in both female and male germ line. We found that piRNAs function through the PIWI, rather than the AGO, family Argonaute proteins, and the production of piRNAs requires neither microRNA (miRNA) nor small interfering RNA (siRNA) pathway machinery. These findings allowed the discovery of the third conserved small RNA silencing pathway, which is distinct from both the miRNA and RNAi pathways in its mechanisms of ...


Immunity, Pathogenesis, And Prevention Of Poxvirus Infections: A Dissertation, Mina O. Seedhom Dec 2010

Immunity, Pathogenesis, And Prevention Of Poxvirus Infections: A Dissertation, Mina O. Seedhom

GSBS Dissertations and Theses

Vaccinia virus (VAC) is the prototypical member of the orthopoxvirus genus of the poxvirus family and the virus used for smallpox vaccinations. The following describes the testing of VAC variants designed to have similar immuno-protective profiles with decreased pathogenicity, examines the immune response to VAC after lethal infection in wild type and lupus-prone mice, and describes a method that allows for the enumeration of VAC-specific CD8+ T in naïve and VAC-immune mice.

The first part describes work examining VAC Wyeth (VAC-Wy) variants engineered to be less pathogenic in vivo. VAC-Wy variants included genes that code for three immunomodulatory proteins, an ...


Axon Death Prevented: WldS And Other Neuroprotective Molecules: A Dissertation, Michelle A. Avery Dec 2010

Axon Death Prevented: WldS And Other Neuroprotective Molecules: A Dissertation, Michelle A. Avery

GSBS Dissertations and Theses

A common feature of many neuropathies is axon degeneration. While the reasons for degeneration differ greatly, the process of degeneration itself is similar in most cases. Axon degeneration after axotomy is termed ‘Wallerian degeneration,’ whereby injured axons rapidly fragment and disappear after a short period of latency (Waller, 1850). Wallerian degeneration was thought to be a passive process until the discovery of the Wallerian degeneration slow (Wlds) mouse mutant. In these mice, axons survive and function for weeks after nerve transection. Furthermore, when the full-length protein is inserted into mouse models of disease with an axon degeneration phenotype (such ...


Converging Pathways In The Regulation Of Longevity And Metabolism In Caenorhabditis Elegans: A Dissertation, Sri Devi Narasimhan Nov 2010

Converging Pathways In The Regulation Of Longevity And Metabolism In Caenorhabditis Elegans: A Dissertation, Sri Devi Narasimhan

GSBS Dissertations and Theses

The lifespan of an organism is determined by a complex array of genetic, environmental and nutritional factors. Yet single gene manipulations have been shown to significantly extend lifespan in several model organisms. Of all the genes that have been studied thus far, components of the insulin/IGF-1 signaling (IIS) pathway have emerged as the most robust regulators of longevity. In addition, IIS also regulates development, energy metabolism and the response to stress in a conserved manner. In Caenorhabditis elegans, signaling through this pathway is initiated by activation of the insulin/IGF-1 receptor tyrosine kinase DAF-2, which then activates a PI3-kinase ...