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Full-Text Articles in Molecular Biology

Investigating Molecular Mechanisms Underlying Mild Phenotype In Friedreich Ataxia Patients With G130v Missense Mutation, Elisia Clark Jan 2018

Investigating Molecular Mechanisms Underlying Mild Phenotype In Friedreich Ataxia Patients With G130v Missense Mutation, Elisia Clark

Publicly Accessible Penn Dissertations

Friedreich’s Ataxia (FRDA) is an incurable neurodegenerative disease caused by mutations in the frataxin (FXN) gene, resulting in decreased expression of the mitochondrial protein FXN. 2-3% of FRDA patients carry a GAA expansion on one FXN allele, and a missense mutation on the other. The mechanism behind the disease‐causing features remains elusive. The phenotype associated with patients carrying point mutations cannot be predicted with certainty; these patients can have a mild or severe clinical outcome, creating a unique platform to understand clinical heterogeneity. FXN is important for proper mitochondrial function, and is involved in Fe-S cluster biogenesis, metabolism ...


Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics, Kellie Ann Woll Jan 2017

Shedding Light On General Anesthesia: Uncovering The Molecular Mechanisms For Propofol And Volatile Anesthetics, Kellie Ann Woll

Publicly Accessible Penn Dissertations

General anesthetics have played a pivotal role in the history of medicine. Despite accounts of their use within the earliest of human records, our understanding of anesthetic mechanisms remains unclear. Understanding these molecular mechanisms would be a significant advance toward enhanced drug design and optimal the clinical use of these potentially hazardous agents. Recent advances in chemical and molecular biology, including photoaffinity labeling, have allowed enhanced appreciation of the complex interactions anesthetic’s have with their macromolecular substrates. This work is dedicated to further define the protein interactions of the frequently administered volatile anesthetics sevoflurane and isoflurane, as well as ...


Defining Sites Of Replication Fork Collapse Caused By Atr Inhibition, Nishita Kalpendu Shastri Jan 2017

Defining Sites Of Replication Fork Collapse Caused By Atr Inhibition, Nishita Kalpendu Shastri

Publicly Accessible Penn Dissertations

DEFINING SITES OF REPLICATION FORK COLLAPSE CAUSED BY ATR INHIBITION

Nishita K. Shastri

Eric J. Brown

Replication stress, characterized by stalling of DNA replication and the accumulation of abnormal replication intermediates, has been linked to the genomic instability observed in cancer. Previous studies have defined specific genomic sequences that are difficult to replicate to be more vulnerable to replication-associated breaks and rearrangements. However, many of these sequences have been identified through indirect and potentially biased approaches. To identify DNA sequences that contribute to replication-associated genomic instability, I will describe genome-wide screens I have performed to determine the location, sequence, and ...


Infusing Factor Viii-Expressing Platelets Or Megakaryocytes As A Novel Therapeutic Strategy For Hemophilia A, Randolph B. Lyde Jan 2017

Infusing Factor Viii-Expressing Platelets Or Megakaryocytes As A Novel Therapeutic Strategy For Hemophilia A, Randolph B. Lyde

Publicly Accessible Penn Dissertations

Approximately 1:5000 males have the most common inherited form of severe bleeding, hemophilia A, a deficiency of functional coagulation factor VIII. Patients with severe hemophilia A suffer from recurrent bleeding with significant morbidity and mortality with 20-30% of these patients developing antibodies to infused Factor (F) VIII therapy. One area of on-going research for treatments for these patients is ectopically expressing FVIII in megakaryocytes and platelets. This FVIII, termed pFVIII, is stored in alpha granules of platelets and is capable of restoring hemostasis in FVIIInull mice, even in the presence of circulating inhibitors. pFVIII has been proposed to be ...


Tamoxifen Mediated Metabolic Stress: Molecular Mechanism And Therapeutic Opportunities, Natalie Ann Daurio Jan 2016

Tamoxifen Mediated Metabolic Stress: Molecular Mechanism And Therapeutic Opportunities, Natalie Ann Daurio

Publicly Accessible Penn Dissertations

Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER) positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacological and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMPK signaling pathway in vitro and in vivo. We also show that tamoxifen-induced cytotoxicity is modulated by ...


Function Of Bromodomain And Extra-Terminal Motif Proteins (Bets) In Gata1-Mediated Transcription, Aaron James Stonestrom Jan 2015

Function Of Bromodomain And Extra-Terminal Motif Proteins (Bets) In Gata1-Mediated Transcription, Aaron James Stonestrom

Publicly Accessible Penn Dissertations

Bromodomain and Extra-Terminal motif proteins (BETs) associate with acetylated histones and transcription factors. While pharmacologic inhibition of this ubiquitous protein family is an emerging therapeutic approach for neoplastic and inflammatory disease, the mechanisms through which BETs act remain largely uncharacterized. Here we explore the role of BETs in the physiologically relevant context of erythropoiesis driven by the transcription factor GATA1. First, we characterize functions of the BET family as a whole using a pharmacologic approach. We find that BETs are broadly required for GATA1-mediated transcriptional activation, but that repression is largely BET-independent. BETs support activation by facilitating both GATA1 occupancy ...


Role Of Ceramide Kinase In Breast Cancer Progression, Ania Warczyk Payne Jan 2014

Role Of Ceramide Kinase In Breast Cancer Progression, Ania Warczyk Payne

Publicly Accessible Penn Dissertations

Recurrent breast cancer is typically an incurable disease and, as such, is disproportionately responsible for deaths from this disease. Recurrent breast cancers arise from the pool of disseminated tumor cells (DTCs) that survive adjuvant or neoadjuvant therapy, and patients with detectable DTCs following therapy are at substantially increased risk for recurrence. Consequently, the identification of pathways that contribute to the survival of breast cancer cells following therapy could aid in the development of more effective therapies that decrease the burden of residual disease and thereby reduce the risk of breast cancer recurrence. We now report that Ceramide Kinase (Cerk) is ...


The Regulation Of Gene Expression During Memory Consolidation In The Hippocampus, Shane Gary Poplawski Jan 2014

The Regulation Of Gene Expression During Memory Consolidation In The Hippocampus, Shane Gary Poplawski

Publicly Accessible Penn Dissertations

Memory consolidation is the process through which short-term memories are stabilized for long-term retention. New gene expression is required for this process to occur successfully. Although gene expression is a necessary component for memory consolidation, the targets and regulation of this gene expression are not well understood. The advent of next-generation sequencing technologies has provided a tremendous resource to probe important questions genome-wide in ways that were previously impossible. In this dissertation, I use next-generation sequencing to investigate the transcriptional targets of learning in the hippocampus. Chapter 1 reviews the previous research on the regulation of gene expression during memory ...


The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal Jan 2013

The Multifunctional Protein Daxx: Studies Of Its Biology And Regulation, And Discovery Of A Novel Function, Trisha Agrawal

Publicly Accessible Penn Dissertations

Daxx, a multifunctional protein with a diverse set of proposed functions, is ubiquitously expressed and highly conserved through evolution. A primarily nuclear protein, Daxx is able to regulate apoptosis, transcription, and cellular proliferation. Despite many studies into the function of Daxx, its precise role in the cell remains enigmatic. Herein, evidence is presented to expand upon the known anti-apoptotic function of Daxx, to establish Daxx as a novel molecular chaperone, and to further its repertoire of transcriptional targets. As an apoptotic inhibitor, Daxx is known to regulate p53 by stabilizing its main negative regulator, Mdm2, via formation of a ternary ...