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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 ...


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 ...


Molecular Studies Of T Cell Recognition And Cross-Reactivity: A Dissertation, Zu T. Shen Jul 2012

Molecular Studies Of T Cell Recognition And Cross-Reactivity: A Dissertation, Zu T. Shen

GSBS Dissertations and Theses

Intracellular pathogens are recognized by a specialized subset of lymphocytes known as CD8+ T cells. Pathogen recognition by CD8+ T cells occurs through binding of T cell receptors (TCR) to processed antigens in complex with major histocompatibility complex (MHC) class I proteins. TCR engagement of antigens in complex with MHC class I typically lead to cytotoxic CD8+ T cell responses, which result in pathogen clearance. Due to the large number of foreign antigens that might be encountered by any given host a diverse repertoire of TCRs must be available for immune recognition. The main source of TCR diversity is generated ...


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 ...


Therapeutic Silencing Of Mutant Huntingtin By Targeting Single Nucleotide Polymorphisms: A Dissertation, Edith L. Pfister Jul 2012

Therapeutic Silencing Of Mutant Huntingtin By Targeting Single Nucleotide Polymorphisms: A Dissertation, Edith L. Pfister

GSBS Dissertations and Theses

Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disorder. Invariably fatal, HD is caused by expansion of the CAG repeat region in exon 1 of the Huntingtin gene which creates a toxic protein with an extended polyglutamine tract 1. Silencing mutant Huntingtin messenger RNA (mRNA) is a promising therapeutic approach 2-6. The ideal silencing strategy would reduce mutant Huntingtin while leaving the wild-type mRNA intact. Unfortunately, targeting the disease causing CAG repeat expansion is difficult and risks targeting other CAG repeat containing genes.

We examined an alternative strategy, targeting single nucleotide polymorphisms (SNPs) in the Huntingtin mRNA. The ...


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 ...


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 ...


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 ...


Chromatin Dynamics In Pluripotency And Differentiation: A Dissertation, Ozlem Yildirim May 2012

Chromatin Dynamics In Pluripotency And Differentiation: A Dissertation, Ozlem Yildirim

GSBS Dissertations and Theses

Different cell types in multi-cellular organisms heritably maintain different gene expression patterns despite carrying the same genome; a phenomenon termed epigenetics. It is widely believed that the packaging state of the genome, known as chromatin structure, carries epigenetic information. How chromatin states are inherited and how chromatin structure changes during development, moreover how different epigenomes, such as chromatin and DNA modifications communicate with each other during these processes are important questions. Accordingly, understanding the mechanisms that govern pluripotency and differentiation requires details of chromatin dynamics. The major goal of my doctoral thesis was to understand the genome wide view of ...


The Role Of Adaptor Protein Complex-3 Delta-Mediated Hiv-1 Gag Trafficking In Hiv-1 Replication: A Dissertation, Adonia Lee Kim May 2012

The Role Of Adaptor Protein Complex-3 Delta-Mediated Hiv-1 Gag Trafficking In Hiv-1 Replication: A Dissertation, Adonia Lee Kim

GSBS Dissertations and Theses

The process of HIV-1 particle production is a multi-step process directed by the viral structural protein Gag. As Gag is the only viral protein required to form virus-like particles, it presents a viable target for anti-viral therapeutics of which there are currently none. Although the functions of Gag during the particle assembly process have been well characterized, one of the least known parts of the assembly process is how Gag is targeted to the site of virus assembly.

Two main virus assembly sites have been identified in cells that support HIV-1 replication: the plasma membrane or multivesicular bodies (MVBs). However ...


Hiv-1 R5 Tropism: Determinants, Macrophages, And Dendritic Cells: A Dissertation, Thomas A. Musich May 2012

Hiv-1 R5 Tropism: Determinants, Macrophages, And Dendritic Cells: A Dissertation, Thomas A. Musich

GSBS Dissertations and Theses

Around thirty years ago HIV-1 was identified, and from that point the known epidemic has grown to over 30 million infected individuals. Early on in the course of HIV-1 research, viruses were classified as either syncytia inducing, CXCR4-using, T-cell tropic or non-syncytia inducing, CCR5-using, macrophage tropic. Since that time, several groups have shown that this is an oversimplification. There is a great deal of diversity amongst CCR5-using HIV-1 variants. There remains a great deal to be discovered regarding HIV-1 CCR5-tropism and how this affects other aspects of HIV-1 infection.

The CD4 binding site (CD4bs) on the HIV-1 envelope plays a ...


Genetic Approaches To Study Transcriptional Activation And Tumor Suppression: A Dissertation, Ling Lin May 2012

Genetic Approaches To Study Transcriptional Activation And Tumor Suppression: A Dissertation, Ling Lin

GSBS Dissertations and Theses

The development of methods and techniques is the driving force of scientific research. In this work, we described two large-scale screens in studying transcriptional activation and tumor suppression.

In Part I, we studied transcriptional activation mechanisms by deriving and characterizing activation defective mutants. Promoter-specific transcriptional activators stimulate transcription through direct interactions with one or more components of the transcription machinery, termed the “target.” The identification of direct in vivo targets of activators has been a major challenge. We perform a large-scale genetic screen to derive and characterize tra1 alleles that are selectively defective for interaction with Gal4 in vivo. Utilizing ...


Getting A Tight Grip On Dna: Optimizing Zinc Fingers For Efficient Zfn-Mediated Gene Editing: A Dissertation, Ankit Gupta Apr 2012

Getting A Tight Grip On Dna: Optimizing Zinc Fingers For Efficient Zfn-Mediated Gene Editing: A Dissertation, Ankit Gupta

GSBS Dissertations and Theses

The utility of a model organism for studying biological processes is closely tied to its amenability to genome manipulation. Although tools for targeted genome engineering in mice have been available since 1987, most organisms including zebrafish have lacked efficient reverse genetic tools, which has stymied their broad implementation as a model system to study biological processes. The development of zinc finger nucleases (ZFNs) that can create double-strand breaks at desired sites in a genome has provided a universal platform for targeted genome modification. ZFNs are artificial restriction endonucleases that comprise of an array of 3- to 6-C2H2 ...


Gene Therapy For Very Long Chain Acyl-Coa Dehydrogenase Deficiency Using Adeno-Associated Virus Vectors: A Dissertation, Allison M. Keeler Apr 2012

Gene Therapy For Very Long Chain Acyl-Coa Dehydrogenase Deficiency Using Adeno-Associated Virus Vectors: A Dissertation, Allison M. Keeler

GSBS Dissertations and Theses

Very long chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD deficient mice and patients’ clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD deficient mice were treated systemically with 1x10 12 vector genomes of rAAV9-VLCAD. Expression was detected in the liver, heart and muscle. Also substantial expression of VLCAD was noted in the brain, where it was expressed across different sections of the brain and in different cell types with different morphologies. Biochemical correction was observed in vector-treated mice beginning two weeks post-injection, as characterized by a significant ...


Distinct Gene Circuits Control The Differentiation Of Innate Versus Adaptive Il-17 Producing T Cells: A Dissertation, Nidhi Malhotra Feb 2012

Distinct Gene Circuits Control The Differentiation Of Innate Versus Adaptive Il-17 Producing T Cells: A Dissertation, Nidhi Malhotra

GSBS Dissertations and Theses

T lymphocytes are distinguished by the expression of αβ TCR or γδ TCR on their cell surface. The kinetic differences in the effector functions classifies γδ T cells as innate-like lymphocytes and αβ T cells as adaptive lymphocytes. Although distinct, αβ and γδ T cell lineages produce a common array of cytokines to mount an effective immune response against a pathogen. The production of cytokine IL-17 is a shared characteristic between the γδ T (Tγδ17) cells and the CD4 T (Th17) cells. γδ T cells develop into Tγδ17 cells in the thymus whereas CD4 T cells differentiate into Th17 cells ...


Control Of Bovine Papillomavirus E2 Function By Acetylation And The Novel E2 Interacting Protein Rint1: A Dissertation, Edward J. Quinlan Jan 2012

Control Of Bovine Papillomavirus E2 Function By Acetylation And The Novel E2 Interacting Protein Rint1: A Dissertation, Edward J. Quinlan

GSBS Dissertations and Theses

Human papillomavirus infection is the cause of more than 99% of cervical cancer cases. The current vaccine is ineffective therapeutically; highlighting the need for continued papillomavirus research. One avenue that could be explored in this regard is the function of the papillomavirus E2 regulatory proteins. HPV E2 represses expression of the viral E6 and E7 oncoproteins. Reintroduction of E2 into cervical carcinoma cells results in growth arrest and cellular senescence. Understanding the mechanism of how E2 regulates the early promoter may be key to developing new therapeutic and prophylactic vaccines. Here, we describe regulation of E2 through acetylation and possibly ...


Studies On The Regulation Of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation, Chien-Ling Lin Jan 2012

Studies On The Regulation Of Cytoplasmic Polyadenylation Element-Binding Protein: A Dissertation, Chien-Ling Lin

GSBS Dissertations and Theses

Post-transcriptional regulation of gene expression sits at the core of proteomic complexity; trans-acting factors that regulate RNA localization and translation capacity are thus indispensible. In this thesis, I present studies of the cytoplasmic polyadenylation element binding protein (CPEB), a sequence specific RNA-binding protein important for cell cycle progression and neural synaptic plasticity. I focus on CPEB because the activity of RNA-binding proteins affects the destiny of their mRNA substrates. As presented in Chapter II, CPEB, though mostly cytoplasmic at steady state, shuttles between the nucleus and the cytoplasm. Surprisingly, the RNA recognition motifs are essential for the nuclear localization ...


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 ...


Support Of Mitochondrial Dna Replication By Human Rad51: A Dissertation, Jay M. Sage Dec 2011

Support Of Mitochondrial Dna Replication By Human Rad51: A Dissertation, Jay M. Sage

GSBS Dissertations and Theses

The function of homologous DNA recombination in human mitochondria has been a topic of ongoing debate for many years, with implications for fields ranging from DNA repair and mitochondrial disease to population genetics. While genetic and biochemical evidence supports the presence of a mitochondrial recombination activity, the purpose for this activity and the proteins involved have remained elusive. The work presented in this thesis was designed to evaluate the mitochondrial localization of the major recombinase protein in human cells, Rad51, as well as determine what function it plays in the maintenance of mitochondrial DNA (mtDNA) copy number that is critical ...


Telomere Length Dynamics In Human T Cells: A Dissertation, Joel M. O'Bryan Oct 2011

Telomere Length Dynamics In Human T Cells: A Dissertation, Joel M. O'Bryan

GSBS Dissertations and Theses

Telomere length has been shown to be a critical determinant of T cell replicative capacity and in vivo persistence in humans. We evaluated telomere lengths in virus-specific T cells to understand how they may both shape and be changed by the maintenance of memory T cells during a subsequent virus re-infection or reactivation. We used longitudinal peripheral blood samples from healthy donors and samples from a long-term HCV clinical interferon therapy trial to test our hypotheses.

To assess T cell telomere lengths, I developed novel modifications to the flow cytometry fluorescence in situ hybridization (flowFISH) assay. These flowFISH modifications were ...


Treating Gm1 Gangliosidosis With Ex Vivo Hematopoietic Stem Cell Gene Therapy Without Using Total Body Irradiation: A Masters Thesis, Michael Whalen Aug 2011

Treating Gm1 Gangliosidosis With Ex Vivo Hematopoietic Stem Cell Gene Therapy Without Using Total Body Irradiation: A Masters Thesis, Michael Whalen

GSBS Dissertations and Theses

GM1 gangliosidosis is an autosomal recessive lysosomal storage disease, caused by a deficiency in the enzyme β-galactosidase. The disease affects the CNS, liver, kidney, heart and skeletal system, leading to severe neurodegeneration and death. We propose to treat this disorder using ex vivo hematopoietic stem cell therapy. The effectiveness of this therapy requires the recruitment of transduced donor cells to the CNS. This is only found to occur after mice are conditioned with total body irradiation, due to the increase in CNS cytokine production and blood brain barrier permeability that occurs. As the use of total body irradiation in pediatric ...


Structural Studies Of The Anti-Hiv Human Protein Apobec3g Catalytic Domain: A Dissertation, Shivender Shandilya Aug 2011

Structural Studies Of The Anti-Hiv Human Protein Apobec3g Catalytic Domain: A Dissertation, Shivender Shandilya

GSBS Dissertations and Theses

HIV/AIDS is a disease of grave global importance with over 33 million people infected world-wide and nearly 2 million deaths each year. The rapid emergence of drug resistance, due to viral mutation, renders anti-retroviral drug candidates ineffective with alarming speed and regularity. Instead of targeting mutation prone viral proteins, an alternative approach is to target host proteins that interact with viral proteins and are critical for the HIV life-cycle. APOBEC3G is a host anti-HIV restriction factor that can exert tremendous negative pressure by hypermutating the viral genome and has the potential to be a promising candidate for anti-retroviral therapeutic ...


Cooperativity In Mammalian Rna Silencing: A Dissertation, Jennifer A. Broderick Jul 2011

Cooperativity In Mammalian Rna Silencing: A Dissertation, Jennifer A. Broderick

GSBS Dissertations and Theses

Argonaute proteins are the core component of an RNA silencing complex. The human genome encodes four Argonaute paralogs –Ago1, Ago2, Ago3 and Ago4– proteins that are guided to target mRNAs by microRNAs. More than 500 miRNAs are conserved between mammals, and each microRNA can repress hundreds of genes, regulating almost every cellular process. We still do not fully understand the molecular mechanisms by which miRNAs regulate gene expression. Although we understand many aspects of microRNA biogenesis and formation of the RNA-induced silencing complex, much less is known about the subsequent steps leading to target mRNA regulation.

Mammalian microRNAs rarely have ...


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 ...


Global Dna Demethylation During Erythropoiesis: A Dissertation, Jeffrey R. Shearstone Jul 2011

Global Dna Demethylation During Erythropoiesis: A Dissertation, Jeffrey R. Shearstone

GSBS Dissertations and Theses

In the mammalian genome, 5‟-CpG-3‟ dinucleotides are frequently methylated, correlating with transcriptional silencing. Genome-wide waves of demethylation are thought to occur only twice during development, in primordial germ cells and in the pre-implantation embryo. They are followed by de novo methylation, setting up a pattern that is inherited throughout development. No global methylation changes are thought to occur during further somatic development, although methylation does alter at gene-specific loci, contributing to tissue-specific patterns of gene expression. Here we studied DNA methylation in differentiating mouse erythroblasts in vivo using several approaches including genomic-scale, reduced representation bisulfite sequencing (RRBS). Surprisingly, demethylation ...


Regulation Of Runx Proteins In Human Cancers: A Dissertation, Sandhya Pande Jul 2011

Regulation Of Runx Proteins In Human Cancers: A Dissertation, Sandhya Pande

GSBS Dissertations and Theses

Runt related transcription factors (Runx) play an important role in mammalian development by regulating the expression of key genes involved in cell proliferation, differentiation and growth. The work described in this thesis details the mechanisms by which the activity of two members of this family are regulated in human cells. Chapter One provides a brief introduction of Runx transcription factors.

Chapter Two describes the regulation of Runx2 protein by the PI3 kinase/Akt pathway in human breast cancer cells. The PI3 kinase/Akt pathway is one of the major signal transduction pathways through which growth factors influence cell proliferation and ...


Investigation Of The C-Terminal Helix Of Hiv-1 Matrix: A Region Essential For Multiple Functions In The Viral Life Cycle: A Dissertation, Laura A. Brandano Jul 2011

Investigation Of The C-Terminal Helix Of Hiv-1 Matrix: A Region Essential For Multiple Functions In The Viral Life Cycle: A Dissertation, Laura A. Brandano

GSBS Dissertations and Theses

Since the first cases were reported over thirty years ago, great strides have been made to control disease progression in people living with HIV/AIDS. However, current estimates report that there are about 34 million individuals infected with HIV worldwide. Critical in the ongoing fight against this pandemic is the continuing development of highly active anti-retroviral therapies, ideally those with novel mechanisms of action. Currently, there are no medications approved for use that exploit the HIV-1 MA protein, despite its central role in multiple stages of the virus life cycle.

This thesis sought to examine whether a highly conserved glutamate ...


The Role Of Pc4 In Oxidative Stress: A Dissertation, Lijian Yu Jun 2011

The Role Of Pc4 In Oxidative Stress: A Dissertation, Lijian Yu

GSBS Dissertations and Theses

Oxidative stress is a cellular condition where cells are challenged by elevated levels of reactive oxygen species (ROS) that are produced endogenously or exogenously. ROS can damage vital cellular components, including lipid, protein, DNA and RNA. Oxidative damage to DNA often leads to cell death or mutagenesis, the underlying cause of various human disease states. Previously our laboratory discovered that human PC4 gene can prevent oxidative mutagenesis in the bacterium Escherichia coli and that the yeast homolog SUB1 has a conserved function in oxidation protection. In this thesis I examined the underlying mechanisms of PC4’s oxidation protection function. My ...


Investigating Age-Dependent Arthropathy In A Circadian Mutant Mouse Model: A Dissertation, Elizabeth A. Yu Jun 2011

Investigating Age-Dependent Arthropathy In A Circadian Mutant Mouse Model: A Dissertation, Elizabeth A. Yu

GSBS Dissertations and Theses

Ectopic calcification can cause pain and limit mobility. Studies suggest that circadian genes may play a role in the calcification process. Core circadian genes Clock, Npas2, and Bmal1 are transcription factors that form CLOCK:BMAL1 or NPAS2:BMAL1 transactivator complexes that drive the rhythmic expression of circadian oscillator genes and output genes. Circadian oscillator genes Period1-3 and Cryptochrome1-2 encode proteins that form transcription repressor complexes that feedback to inhibit CLOCK/NPAS2:BMAL1 activity, thus completing the feedback loop that is the basis of the molecular circadian clockwork. Arrhythmic Bmal1-/- mice exhibit site-specific, age-dependent arthropathy. While studying the circadian phenotype of ...