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Evaluation Of A Tiered Opioid Prescribing Guideline For Inpatient Colorectal Operations, David C. Meyer Apr 2020

Evaluation Of A Tiered Opioid Prescribing Guideline For Inpatient Colorectal Operations, David C. Meyer

GSBS Dissertations and Theses

Background:

In light of the opioid epidemic, reducing excess prescription quantities while tailoring to patient need is key. We previously created an opioid prescribing guideline using retrospective institutional data to satisfy the majority of patients’ opioid needs following inpatient colorectal surgery.

Objective:

This study sought to prospectively validate an institutional prescribing guideline based on previously-defined opioid consumption patterns following inpatient colorectal operations.

Methods:

We carried out a cohort study comparing opioid prescribing and consumption patterns before (7/18 – 1/19) and after (9/19 – 2/20) adoption of a tiered opioid prescribing guideline for inpatient elective colorectal operations (colectomies, proctectomies ...


Ventricular Arrhythmias Complicating Coronary Artery Disease: Recent Trends, Risk Associated With Serum Glucose Levels, And Psychological Impact, Hoang V. Tran Jun 2018

Ventricular Arrhythmias Complicating Coronary Artery Disease: Recent Trends, Risk Associated With Serum Glucose Levels, And Psychological Impact, Hoang V. Tran

GSBS Dissertations and Theses

Introduction: Ventricular arrhythmias (VAs) are common after an acute coronary syndrome (ACS) and are associated with worse clinical outcomes. However, little is known about recent trends in their occurrence, their association with serum glucose levels, and their psychological impact in ACS setting.

Methods: We examined 25-year (1986-2011) trends in the incidence rates (IRs) and hospital case-fatality rates (CFRs) of VAs, and the association between serum glucose levels and VAs in patients with an acute myocardial infarction (AMI) in the Worcester Heart Attack Study. Lastly, we examined the relationship between in-hospital occurrence of VAs and 12-month progression of depression and anxiety ...


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 ...


Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster Aug 2017

Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster

GSBS Dissertations and Theses

Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends ...


Inhibiting Axon Degeneration In A Mouse Model Of Acute Brain Injury Through Deletion Of Sarm1, Nils Henninger May 2017

Inhibiting Axon Degeneration In A Mouse Model Of Acute Brain Injury Through Deletion Of Sarm1, Nils Henninger

GSBS Dissertations and Theses

Traumatic brain injury (TBI) is a leading cause of disability worldwide. Annually, 150 to 200/1,000,000 people become disabled as a result of brain trauma. Axonal degeneration is a critical, early event following TBI of all severities but whether axon degeneration is a driver of TBI remains unclear. Molecular pathways underlying the pathology of TBI have not been defined and there is no efficacious treatment for TBI.

Despite this significant societal impact, surprisingly little is known about the molecular mechanisms that actively drive axon degeneration in any context and particularly following TBI. Although severe brain injury may cause ...


The Origin Of Human White, Brown, And Brite/Beige Adipocytes, So Yun Min Dec 2016

The Origin Of Human White, Brown, And Brite/Beige Adipocytes, So Yun Min

GSBS Dissertations and Theses

During embryonic development, adipocytes emerge from microvasculature. Lineage-­‐tracing studies in mice have shown that adipocyte progenitors reside in the adipose tissue capillaries. However, the direct evidence of an association between adipocyte progenitors and vasculature in humans is lacking. A specific class of adipocytes (brown and beige/brite) expresses the uncoupling protein 1 (UCP1), which consumes glucose and fatty acids to generate heat. The abundance of UCP1- containing adipocytes correlates with a lean metabolically healthy phenotype in human. However, a causal relationship between the presence of these cells and metabolic benefits in human is not clear.

In this thesis, I ...


Investigation Of Rna Binding Protein Pumilio As A Genetic Modifier Of Mutant Chmp2b In Frontotemporal Dementia (Ftd): A Masters Thesis, Xing Du Aug 2016

Investigation Of Rna Binding Protein Pumilio As A Genetic Modifier Of Mutant Chmp2b In Frontotemporal Dementia (Ftd): A Masters Thesis, Xing Du

GSBS Dissertations and Theses

Frontotemporal dementia (FTD) is the second most common early-onset dementia. A rare mutation in CHMP2B gene was found to be associated with FTD linked to chromosome 3. Previous studies have shown that mutant CHMP2B could lead to impaired autophagy pathway and altered RNA metabolism. However, it is still unknown what genes mediate the crosstalk between different pathways affected by mutant CHMP2B. Genetic screens designed to identify genes interacting with mutant CHMP2B represents a key approach in solving the puzzle. Expression of mutant CHMP2B (CHMP2Bintron5) in Drosophila eyes leads to a neurodegenerative phenotype including melanin deposition and disrupted internal structure of ...


A Walk On The Fine Line Between Reward And Risk: Aav-Ifnβ Gene Therapy For Glioblastoma: A Dissertation, Dwijit Guhasarkar Jul 2016

A Walk On The Fine Line Between Reward And Risk: Aav-Ifnβ Gene Therapy For Glioblastoma: A Dissertation, Dwijit Guhasarkar

GSBS Dissertations and Theses

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The current standard-of-care treatment including surgery, radiation and temozolomide (TMZ) chemotherapy does not prolong the survival satisfactorily. Here we have tested the feasibility, efficacy and safety of a potential gene therapy approach using AAV as gene delivery vehicle for treatment of GBM.

Interferon-beta (IFNβ) is a cytokine molecule also having pleiotropic anticancerous properties. Previously it has been shown by our group that AAV mediated local (intracranial) gene delivery of human IFNβ (hIFNβ) could be an effective treatment for non-invasive human glioblastoma (U87) in orthotopic xenograft mouse model.But ...


Exploring New Strategies To Overcome Resistance In Glioblastoma Multiforme: A Dissertation, Yulian P. Ellis Aug 2015

Exploring New Strategies To Overcome Resistance In Glioblastoma Multiforme: A Dissertation, Yulian P. Ellis

GSBS Dissertations and Theses

Glioblastoma multiforme (GBM) tumors are highly malignant in nature and despite an aggressive therapy regimen, long–term survival for glioma patients is uncommon as cells with intrinsic or acquired resistance to treatment repopulate the tumor. This creates the need to investigate new therapies for enhancing GBM treatment outside of the standard of care, which includes Temozolomide (TMZ). Our lab focused on two novel strategies to overcome resistance in GBMs. In our first approach, the cellular responses of GBM cell lines to two new TMZ analogues, DP68 and DP86, are reported. The efficacy of these compounds was independent of DNA repair ...


Causal Inference Methods For Assessing Neurodevelopment In Children Following Prenatal Exposure To Triptan Medications: A Dissertation, Mollie E. Wood Apr 2015

Causal Inference Methods For Assessing Neurodevelopment In Children Following Prenatal Exposure To Triptan Medications: A Dissertation, Mollie E. Wood

GSBS Dissertations and Theses

Background: Migraine headache is a chronic pain condition that affects 20% of women of reproductive age, and is often treated with triptans. Triptans are serotonin 1B, 1D, and 1F receptor agonists that act as vasoconstrictors and inhibitors of the trigeminal cervical complex as well as peripheral neurons; they cross the blood brain barrier and placenta, and as such are plausible neurodevelopmental teratogens. No studies have examined risk of neurodevelopmental problems in children with prenatal triptan exposure. This dissertation had three aims: (1) to examine risk of behavioral problems in children using in the presence of time-varying confounding by concomitant medication ...


The Three-Dimensional Structure Of The Cystic Fibrosis Locus: A Dissertation, Emily M. Smith Nov 2014

The Three-Dimensional Structure Of The Cystic Fibrosis Locus: A Dissertation, Emily M. Smith

GSBS Dissertations and Theses

The three dimensional structure of the human genome is known to play a critical role in gene function and expression. I used chromosome conformation capture (3C) and 3C-carbon copy (5C) techniques to investigate the three-dimensional structure of the cystic fibrosis transmembrane conductance regulator (CFTR) locus. This is an important disease gene that, when mutated, causes cystic fibrosis. 3C experiments identified four distinct looping elements that contact the CFTR gene promoter only in CFTR-expressing cells. Using 5C, I expanded the region of study to a 2.8 Mb region surrounding the CFTR gene. The 5C study shows 7 clear topologically associating ...


From Neurodegeneration To Infertility And Back - Exploring Functions Of Two Genes: Armc4 And Tardbp: A Dissertation, Wei Cheng Jan 2014

From Neurodegeneration To Infertility And Back - Exploring Functions Of Two Genes: Armc4 And Tardbp: A Dissertation, Wei Cheng

GSBS Dissertations and Theses

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset progressive neurodegenerative disease that causes degeneration in both upper and lower motor neurons. ALS progresses relentlessly after the onset of the disease, with most patients die within 3-5 years of diagnosis, largely due to respiratory failure. Since SOD1 became the first gene whose mutations were associated with ALS in 1993, more than 17 ALS causative genes have been identified. Among them, TAR DNA-binding protein (TARDBP) lies in the central of ALS pathology mechanism study, because TDP43 proteinopathy is observed not only in familial ALS cases carrying TARDBP mutations, but also in most of ...


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 ...


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 ...


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 ...


Eaters Of The Dead: How Glial Cells Respond To And Engulf Degenerating Axons In The Cns: A Dissertation, Jennifer S. Ziegenfuss Jun 2012

Eaters Of The Dead: How Glial Cells Respond To And Engulf Degenerating Axons In The Cns: A Dissertation, Jennifer S. Ziegenfuss

GSBS Dissertations and Theses

Glia, whose name derives from the original Greek word, meaning “glue,” have long been understood to be cells that play an important functional role in the nutritive and structural support of the central nervous system, yet their full involvement has been historically undervalued. Despite the strong evidence that glial reactions to cellular debris govern the health of the nervous system, the specific properties of damaged axonal debris and the mechanisms by which glia sense them, morphologically adapt to their presence, and initiate phagocytosis for clearance, have remained poorly understood. The work presented in this thesis was aimed at addressing this ...


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 ...


Inflammation Inhibits Osteoblast-Mediated Bone Formation In Rheumatoid Arthritis And Regulates The Wnt And Bmp Signaling Pathways: A Dissertation, Melissa M. Matzelle May 2012

Inflammation Inhibits Osteoblast-Mediated Bone Formation In Rheumatoid Arthritis And Regulates The Wnt And Bmp Signaling Pathways: A Dissertation, Melissa M. Matzelle

GSBS Dissertations and Theses

Osteoclast-mediated focal articular bone erosion is a hallmark of rheumatoid arthritis, a disease of inflammation-induced bone loss. Inflammation in the bone microenvironment enhances osteoclast differentiation leading to bone erosion. Simultaneously, inflammation also inhibits osteoblast-mediated bone formation, further contributing to the net loss of bone. Previous studies have shown a paucity of mature osteoblasts at eroded bone surfaces correlating with suppression of bone formation and upregulation of antagonists of the Wnt pathway, a signaling cascade essential for osteoblast lineage commitment. Despite these observations, the exact pathogenesis of impaired bone formation in the setting of inflammation is not clearly understood.

This dissertation ...


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 ...