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Full-Text Articles in Cell Biology

Modulation Of Transcription In The Murine Gut Epithelium In Development, Differentiation, And Disease, Julia Elise Kieckhaefer Jan 2017

Modulation Of Transcription In The Murine Gut Epithelium In Development, Differentiation, And Disease, Julia Elise Kieckhaefer

Publicly Accessible Penn Dissertations

The intestinal epithelium is a continuously self-renewing tissue that must balance its function as the site of nutrient absorption with its role as a barrier between the body and the external environment. With its high cellular turnover and continual exposure to lumenal antigens, the intestinal epithelium is highly susceptible to developing diseases, such as inflammatory bowel disease (IBD) and cancer. Understanding the factors that control intestinal epithelial development are key to discovering disease etiology and to engineering new treatments. In mammals, studies have pointed to dysregulation of RNA Polymerase III as playing a role in oncogenic transformation. A deletion in ...


The Specification Of Hemogenic Endothelium During Embryogenesis And Beyond, Amanda Danielle Yzaguirre Jan 2017

The Specification Of Hemogenic Endothelium During Embryogenesis And Beyond, Amanda Danielle Yzaguirre

Publicly Accessible Penn Dissertations

The primary goal of regenerative medicine is the in vitro derivation of cells that are functional and safe for transplantation into patients. Although progress has been made towards this goal there are no clinical applications that utilize cells derived in vitro from pluripotent stem cells or reprogrammed primary cells. The foremost reason for this is an incomplete understanding of the development processes that regulate cell identity. In order to gain a better understanding of the specification of hematopoietic stem cells (HSC), I studied their de novo generation during embryogenesis.

Using confocal microscopy, I mapped out hematopoiesis during midgestation and discovered ...


Systems Biology Derived Mechanism Of Bmp Gradient Formation, Joseph M. Zinski Jan 2017

Systems Biology Derived Mechanism Of Bmp Gradient Formation, Joseph M. Zinski

Publicly Accessible Penn Dissertations

A morphogen gradient of Bone Morphogenetic Protein (BMP) signaling patterns the dorsoventral (DV) axis of all vertebrates. This gradient is established by the extracellular interaction of the asymmetric expression of the BMP ligand and its extracellular regulators. Though the basic agonism and antagonism of BMP by these regulators has been established over the last two decades, the mechanism by which they come together to form a robust BMP signaling gradient remains poorly understood. The prevailing view in vertebrates for BMP gradient formation is through a counter gradient of BMP antagonists, often along with ligand shuttling to generate peak signaling levels ...


Regulation Of The Human Vascular Smooth Muscle Cell Transcriptome By Extracellular Matrix Stiffness, Christopher Yu Jan 2017

Regulation Of The Human Vascular Smooth Muscle Cell Transcriptome By Extracellular Matrix Stiffness, Christopher Yu

Publicly Accessible Penn Dissertations

Arterial stiffness is a risk factor for several cardiometabolic diseases and is caused by pathological remodeling of the vascular extracellular matrix (ECM). Vascular smooth muscle cells (VSMCs) respond to ECM stiffness by proliferating, migrating, and further remodeling the vascular ECM, thus contributing to vascular disease like atherosclerosis and hypertension. VSMCs along the vasculature are highly diverse as they arise from different embryologic origins, reside in ECMs of diverse compositions, and are exposed to various mechanical forces. This dissertation aims to understand how ECM stiffness regulates the transcriptional response of VSMCs from different origins, namely aortic (Ao) and coronary (Co) VSMCs ...


Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response, James Knox Jan 2017

Characterization Of Human T-Bet-Expressing B Lymphocytes And Their Role In The Hiv Immune Response, James Knox

Publicly Accessible Penn Dissertations

Humoral immunity is critical for the prevention and control of viral infections, yet the specific B cells and mechanisms regulating antiviral responses in humans remain poorly defined. The Th1-associated transcription factor T-bet coordinates intracellular pathogen immune responses, and recent murine studies identified a T-bet-expressing B cell subset that mediates humoral antiviral immunity, but an analogous cell population has not been identified in humans. In this study, we sought to investigate the role of T-bet-expressing B cells during human viral infections. We identified T-bet expression within the memory B cell compartment of healthy individuals and described a relationship between the transcription ...


Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis, Diana Leigh Avery Jan 2017

Extracellular Matrix Regulates Fibroblast Heterogeneity And Tumorigenesis, Diana Leigh Avery

Publicly Accessible Penn Dissertations

Heterogeneous activated fibroblasts that deposit and remodel extracellular matrix (ECM) comprise desmoplasia, a key regulator of tumor development. The divergent outcomes in response to varied therapies targeting intratumoral desmoplasia underscore the pressing need to delineate the intricate role of a heterogeneous stroma in tumorigenesis. Fibroblast activation protein (FAP) and alpha-smooth muscle actin (αSMA) identify distinct, yet overlapping, activated fibroblast subsets in myriad tumor types, fibrosis, and wound healing. FAPHi reactive fibroblasts and αSMAHi myofibroblasts can exert divergent influences on tumor progression. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these distinct phenotypes are not ...


The Human Heterochromatin Landscape: Genomic Subtypes, Bound Proteins, And Contributions To Cell Identity, Justin S. Becker Jan 2017

The Human Heterochromatin Landscape: Genomic Subtypes, Bound Proteins, And Contributions To Cell Identity, Justin S. Becker

Publicly Accessible Penn Dissertations

Large portions of mammalian genomes are packaged into structurally compact heterochromatin, which protects genome integrity and suppresses transcription of lineage-inappropriate genes. Characterization of heterochromatic regions has relied on genomic mapping of associated histone modifications, such as H3K9me3 and H3K27me3, and purification of proteins interacting with these modifications. Heterochromatic regions marked by H3K9me3 have been shown to impede gene activation during reprogramming to pluripotency, and I find that H3K9me3 domains can similarly impede conversion of fibroblasts to hepatocytes. However, both H3K9me3 and H3K27me3 can be found in transcriptionally active chromatin, limiting the accuracy of histone marks alone for identifying heterochromatin domains ...


Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci Jan 2017

Tumor Interferon Signaling Initiates And Sustains A Multigenic Resistance Program To Immune Checkpoint Blockade, Joseph Lawrence Benci

Publicly Accessible Penn Dissertations

Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows ...


Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude, Ryan James Cedeno Jan 2017

Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude, Ryan James Cedeno

Publicly Accessible Penn Dissertations

Epigenetic factors guide chromatin remodeling during cell state transitions and confer resistance to genotoxic stressors that could induce deleterious transformations. A particularly peculiar component of the epigenome with emerging roles in fine-tuning cell identity and upholding genomic stability is the structural histone variant macroH2A. Relatively little is currently known about macroH2A’s influence on overall cell developmental potency and less still is known about macroH2A’s contributions to adult stem cell identity and function in vivo. In this work, we use induced pluripotent stem cell (iPSC) reprogramming and the murine intestinal stem cell (ISC) system to model macroH2A’s overall ...


Platelet Dense Granules Mature Within Late Stages Of Megakaryocyte Differentiation By Cargo Delivery, Hayley Hanby Jan 2017

Platelet Dense Granules Mature Within Late Stages Of Megakaryocyte Differentiation By Cargo Delivery, Hayley Hanby

Publicly Accessible Penn Dissertations

Platelet dense granules (DGs) are storage organelles for calcium ions, small organic molecules such as ADP and serotonin, and larger polyphosphates that are secreted upon platelet stimulation to enhance platelet activation, adhesion, and stabilization at sites of vascular damage. However, the precise timing of DG formation and maturation has not been definitively characterized, and how and when DG membrane contents are delivered is not at all known. In this thesis, I will discuss two important findings relevant to DG biology.

The first finding addresses the timing of maturation of DGs within differentiation of the platelet precursor cell, the megakaryocyte (MK ...


Hiv And Antiretrovirals In The Central Nervous System: Molecular Mechanisms Of Cognitive Impairment, Anna Louise Stern Jan 2017

Hiv And Antiretrovirals In The Central Nervous System: Molecular Mechanisms Of Cognitive Impairment, Anna Louise Stern

Publicly Accessible Penn Dissertations

HIV-associated neurocognitive disorder (HAND) describes a wide range of cognitive impairments experienced by up to 55% of HIV+ individuals despite viral suppression by combined antiretroviral therapy. Reasons for the persistence of this disease are unknown, but may be related to both the presence of HIV-infected macrophages in the central nervous system as well as neurotoxicity of antiretroviral drugs. In this thesis, we identified two independent mechanisms of HIV-associated and antiretroviral-associated toxicity that may each contribute distinctly to HAND neuropathogenesis. First, we showed that β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which may play a role in the onset and ...


Genome Editing Approach To Uncover Microtubule-Actin Crosslinking Factor (Macf1) Essential Domains In Establishing Oocyte Polarity And Nuclear Positioning, Matias Escobar Jan 2017

Genome Editing Approach To Uncover Microtubule-Actin Crosslinking Factor (Macf1) Essential Domains In Establishing Oocyte Polarity And Nuclear Positioning, Matias Escobar

Publicly Accessible Penn Dissertations

The totipotent egg of most vertebrates is polarized in a so called animal-vegetal (AV) axis that is crucial for early embryonic development. AV polarity is established during early oogenesis through the formation and disassembly of the Balbiani Body (Bb) at the vegetal pole. The Bb is a non-membrane bound large mRNP granule, conserved from insects to humans and composed of mitochondria, RNAs and proteins. The Bb components, which include germ cell determinants, anchor to the vegetal cortex upon Bb dissociation in late stage I oocytes. Importantly, Bb dissociation at the oocyte cortex defines the future vegetal pole of the egg ...


Increased Expression Of Frontotemporal Dementia Risk Factor Tmem106b Alters Lysosomal And Autophagosomal Pathways, Johanna Irene Busch Jan 2016

Increased Expression Of Frontotemporal Dementia Risk Factor Tmem106b Alters Lysosomal And Autophagosomal Pathways, Johanna Irene Busch

Publicly Accessible Penn Dissertations

Frontotemporal lobar degeneration (FTLD) is an important cause of dementia in individuals under age 65. Common variants in the TMEM106B gene were previously discovered by genome-wide association (GWAS) to confer genetic risk for FTLD-TDP, the largest neuropathological subset of FTLD (p=1x10-11, OR=1.6). Prior to its discovery in the GWAS, TMEM106B, or Transmembrane Protein 106B, was uncharacterized. To further understand the role of TMEM106B in disease pathogenesis, we used immortalized as well as primary neurons to assess the cell biological effects of disease-relevant levels of TMEM106B overexpression and the interaction of TMEM106B with additional disease-associated proteins. We also ...


Endocytic Regulation Of Notch Signaling In Drosophila Melanogaster Neural Progenitor Cells, Seth Andrew Johnson Jan 2016

Endocytic Regulation Of Notch Signaling In Drosophila Melanogaster Neural Progenitor Cells, Seth Andrew Johnson

Publicly Accessible Penn Dissertations

Notch signaling is a ubiquitously used signaling pathway that is highly conserved and used throughout metazoan development. Understanding the regulation of Notch signaling is becoming increasingly important in determining the mechanism and treatment for the myriad of human Notch-related diseases. In Drosophila. melanogaster, the development of external sensory organs provides a context in which Notch can be manipulated and phenotypes can be easily interpreted. Here, we expand upon the growing field of Notch regulation through endocytic trafficking by examining the role of Numb and Sara endosomes. Numb is a potent Notch inhibitor whose function is conserved in higher organisms, but ...


Epigenetic Regulation Of The Dlk1-Meg3 Imprinted Locus In Human Islets, Vasumathi Kameswaran Jan 2016

Epigenetic Regulation Of The Dlk1-Meg3 Imprinted Locus In Human Islets, Vasumathi Kameswaran

Publicly Accessible Penn Dissertations

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by inadequate insulin secretion by the pancreatic β-cell in response to increased blood glucose levels. Despite compelling evidence that T2DM has a high rate of familial aggregation, known genetic risk variants account for less than 10% of the observed heritability. Consequently, post-transcriptional regulators of gene expression, including microRNAs and other noncoding RNAs, have been implicated in the etiology of T2DM, in part due to their ability to simultaneously regulate the expression of hundreds of targets.

To determine if microRNAs are involved in the pathogenesis of human T2DM, I sequenced ...


Car Drivers And Fuel Sources: How Distinct Signaling Domains In Chimeric Antigen Receptors Reprogram T Cells, Omkar Uday Kawalekar Jan 2016

Car Drivers And Fuel Sources: How Distinct Signaling Domains In Chimeric Antigen Receptors Reprogram T Cells, Omkar Uday Kawalekar

Publicly Accessible Penn Dissertations

With breakthroughs in synthetic biology, improved cell culture techniques and advanced genetic engineering, it has now become possible to generate bi-specific primary human T cells with desired specificities. One mode of redirecting specificity is the modification of T cells to express chimeric antigen receptors (CARs). Recent studies indicate that natural T cells have distinct biochemical and metabolic features that endow them with short lived effector or long lived memory fates. The central objective of this thesis was to investigate whether the signaling endodomain of CARs could reprogram T cells with pre-specified effector and memory fates. This thesis describes a novel ...


An Olfactory Cilia Pattern In The Mammalian Nose Ensures High Sensitivity To Odors, Rosemary Challis Jan 2016

An Olfactory Cilia Pattern In The Mammalian Nose Ensures High Sensitivity To Odors, Rosemary Challis

Publicly Accessible Penn Dissertations

In many sensory organs, specialized receptors are strategically arranged to enhance detection sensitivity and acuity. It is unclear whether the olfactory system utilizes a similar organizational scheme to facilitate odor detection. Curiously, olfactory sensory neurons (OSNs) in the mouse nose are differentially stimulated depending on the cell location. We therefore asked whether OSNs in different locations evolve unique structural and/or functional features to optimize odor detection and discrimination. Using immunohistochemistry, computational fluid dynamics modeling, and patch clamp recording, we discovered that OSNs situated in highly stimulated regions have much longer cilia and are more sensitive to odorants than those ...


Haloferax Volcanii Strategies To Regulate Type Iv Pilus Dependent Adhesion And Microcolony Formation, Rianne Nicole Esquivel Jan 2016

Haloferax Volcanii Strategies To Regulate Type Iv Pilus Dependent Adhesion And Microcolony Formation, Rianne Nicole Esquivel

Publicly Accessible Penn Dissertations

Microorganisms can utilize type IV pili to initiate and maintain biofilms - microbial communities that provide protection against stressful conditions. Because environmental conditions change suddenly, microorganisms have evolved multiple mechanisms to rapidly transition from a planktonic to sessile cell state. Despite the presence of archaea alongside bacteria throughout the environment, including the human microbiome, little is known about how these organisms form and maintain biofilms. Here we use genetic, microscopic and biochemical techniques to investigate multiple strategies the model archaeon Haloferax volcanii employs to permit effective adhesion and microcolony formation, early steps in biofilm formation and maturation, as well as eventual ...


Adventures With Rna Fish For Diagnosing Viral Infections And Exploring Single-Cell Heterogeneity In Cancer, Sydney Shaffe Shaffer Jan 2016

Adventures With Rna Fish For Diagnosing Viral Infections And Exploring Single-Cell Heterogeneity In Cancer, Sydney Shaffe Shaffer

Publicly Accessible Penn Dissertations

Single-molecule RNA FISH is a robust method for visualizing individual molecules of RNA within intact cells that has been used extensively for describing single-cell hetero- geneity in gene expression. In this thesis, we leverage RNA FISH-based technologies for two major problems in biology and medicine: rapid detection of viral infections and understanding mechanisms of resistance to targeted therapy in cancer. Until recently, RNA FISH was not a viable technology for rapid diagnostics, as the hybridization process required a minimum of 6 hours. We start by presenting a modification to the RNA FISH protocol developed by Raj et al. 2008, that ...


Uncovering Bunyavirus-Host Interactions, Mary Jane Drake Jan 2016

Uncovering Bunyavirus-Host Interactions, Mary Jane Drake

Publicly Accessible Penn Dissertations

Bunyaviruses are a large family of enveloped RNA viruses that are distributed globally and include many important human and agricultural pathogens. Compared with other pathogenic viruses, bunyaviruses are relatively understudied. Currently, there are no licensed vaccines or antivirals to treat bunyavirus infections in the United States. To better understand bunyavirus interactions with their mammalian hosts in the hopes of uncovering novel therapeutic targets, we utilized a forward genetic screening approach in a human haploid cell line (HAP1). We performed insertional mutagenesis of the HAP1 cells with a retroviral gene-trap vector and subsequently challenged the cells with recombinant vesicular stomatitis viruses ...


The Mitotic Genome: Accessibility And Transcriptional Control, Chris Hsiung Jan 2016

The Mitotic Genome: Accessibility And Transcriptional Control, Chris Hsiung

Publicly Accessible Penn Dissertations

Mitosis entails dramatic global alterations to genome structure and regulation, including

chromosome condensation, dissociation of the transcriptional machinery from chromosomes, and transcriptional silencing. Here I report studies that address the macromolecular accessibility of the mitotic genome and the control of transcriptional reactivation upon mitotic exit in a mammalian cell line. The results obtained from measuring the sensitivity of chromatin to DNase I cleavage by sequencing (DNase-seq) in pure mitotic cell populations demonstrate that macromolecular accessibility of the mitotic genome is widely preserved. Thus, steric hindrance from chromatin condensation is insufficient for explaining the eviction of transcription factors from mitotic chromatin ...


Molecular Mechanisms Of Oncogenesis & Precision Medicine Approaches For Pediatric Low-Grade Gliomas, Payal Jain Jan 2016

Molecular Mechanisms Of Oncogenesis & Precision Medicine Approaches For Pediatric Low-Grade Gliomas, Payal Jain

Publicly Accessible Penn Dissertations

Pediatric low-grade gliomas (PLGGs) are a heterogeneous group of tumors that collectively represent the most common childhood brain cancer. Despite favorable outcomes with surgical and adjuvant therapies, majority of patients suffer from long-term treatment-related morbidities and recurrent/inoperable disease. This necessitates a deeper understanding of PLGG biology to aid development of molecular diagnostics and low-toxicity targeted therapeutics.

Hitherto, PLGGs have been defined by activating mutations that dysregulate the MAPK signaling pathway, leading to clinical testing of RAF/MAPK inhibitors for PLGGs. Interestingly, recent large-scale sequencing efforts discovered novel gene fusions in PLGGs and we identified the unique recurrent association of ...


Treating Cancer With Engineered T Cell Therapies: Murine And Canine Models Of Safety And Efficacy, Jenessa Barbara Smith Jan 2016

Treating Cancer With Engineered T Cell Therapies: Murine And Canine Models Of Safety And Efficacy, Jenessa Barbara Smith

Publicly Accessible Penn Dissertations

Redirecting a patient’s T-cells against cancer shows tremendous clinical responses in certain tumor types, but potent therapies for ovarian cancer remain limited. Here we describe the preclinical development of three novel cancer immunotherapy platforms. We first isolated an ErbB2(369-377)-specific T-cell receptor (TCR) from a patient who was previously vaccinated against ErbB2, a protein ubiquitously overexpressed in ovarian cancer. We hypothesized that an ErbB2(369-377)-specific TCR can recognize endogenously processed ErbB2 protein in human cancer. This strategy re-directed human T-cells against ErbB2(369-377), conferring recognition of ErbB2(+) HLA-A2(+) tumor cell lines in vitro and in vivo. Together ...


A Study Of The Role Of Gata6 In Definitive Endoderm Specification And Β-Cell Functionality By Genome Engineering Of Pluripotent Stem Cells, Amita Tiyaboonchai Jan 2016

A Study Of The Role Of Gata6 In Definitive Endoderm Specification And Β-Cell Functionality By Genome Engineering Of Pluripotent Stem Cells, Amita Tiyaboonchai

Publicly Accessible Penn Dissertations

Human pluripotent stem cells (PSCs) provide a powerful model system for the study of early human development, disease modeling and physiology. We chose to focus our studies on monogenic diabetes using this model system. Within the pancreas, β cells are one of the most critical endocrine cells as loss of this cell type disrupts blood glucose homeostasis, leading to diabetes. Due to the limited availability of primary human cells it is difficult to study them in vitro, especially in the context of genetic disease where patient material is even more difficult to obtain. Here, we characterize endodermal progenitor (EP) derived ...


Investigation Of The Spatiotemporal Dynamics Of Camp And Pka Signaling And The Role Of Hcn4 Subunits In Anxiety-Related Behavior And Memory, Vincent Gerard Luczak Jan 2016

Investigation Of The Spatiotemporal Dynamics Of Camp And Pka Signaling And The Role Of Hcn4 Subunits In Anxiety-Related Behavior And Memory, Vincent Gerard Luczak

Publicly Accessible Penn Dissertations

In the hippocampus, long-term memory and synaptic plasticity occur through a series of coordinated intracellular signaling cascades that strengthen and stabilize subsets of synaptic connections while leaving thousands of others unaltered. Therefore, understanding how molecular signals are accurately transmitted is critical to understanding how hippocampal neurons store information. Molecules like cAMP and protein kinase A are critical components of memory and plasticity, but it is unclear how these diffusible signals are dynamically regulated to achieve the spatial and temporal specificity that underlies pathway-specific plasticity. Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are ion channels that are modulated by cAMP and are ...


Akt Controls Adipocyte Function And Systemic Metabolism, Abigail Shearin Jan 2016

Akt Controls Adipocyte Function And Systemic Metabolism, Abigail Shearin

Publicly Accessible Penn Dissertations

ABSTRACT

AKT CONTROLS ADIPOCYTE FUNCTION AND SYSTEMIC METABOLISM

Abigail L. Shearin

Morris J. Birnbaum

Adipose tissue is a key regulator of energy homeostasis. Diseases with an increase or decrease in adiposity result in perturbations of systemic metabolism. The insulin signaling and insulin-like growth factor 1 (IGF-1) cascades are vital to the function of many tissues during development and in the mature organism. AKT, a Ser/Thr kinase, is a central node in the insulin and IGF-1 pathways. In the liver, much is known about the consequences when insulin-AKT signaling is lost, but adipose tissue has presented a unique challenge to ...


Molecular And Cellular Approaches Toward Understanding Dynein-Driven Motility, Swathi Ayloo Jan 2016

Molecular And Cellular Approaches Toward Understanding Dynein-Driven Motility, Swathi Ayloo

Publicly Accessible Penn Dissertations

Active transport is integral to organelle localization and their distribution within the cell. Kinesins, myosins and dynein are the molecular motors that drive this long range transport on the actin and microtubule cytoskeleton. Although several families of kinesins and myosins have evolved, there is only one form of cytoplasmic dynein driving active retrograde transport in cells. While dynactin is an essential co-factor for most cellular functions of dynein, the mechanistic basis for this evolutionarily well conserved interaction remains unclear. Here, I use single molecule approaches with purified dynein to reconstitute processes in vitro, and implement an optogenetic tool in neurons ...


Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza Jan 2016

Modulation Of Antitumor Immunity By The Mek Inhibitor Trametinib: Implications For Targeted Therapy Of Cancer, Michael J. Allegrezza

Publicly Accessible Penn Dissertations

Through rational drug design, much progress has been made to develop small molecules that specifically inhibit the oncogenic signaling pathways driving malignant growth. However, the normal function of immune cells depends upon many of the same pathways inhibited by such targeted cancer therapies. Because the immune system can influence the growth of many cancers, I hypothesized that most small molecule inhibitors would have activity on leukocytes relevant in cancer, and this activity would contribute to their antitumor mechanisms. In order to test this hypothesis, I first screened a panel of over 40 small molecule inhibitors for their activity on proliferating ...


Genetic Requirement For The Rna Helicase Mov10l1 In Pirna Biogenesis, Qi Fu Jan 2016

Genetic Requirement For The Rna Helicase Mov10l1 In Pirna Biogenesis, Qi Fu

Publicly Accessible Penn Dissertations

GENETIC REQUIREMENT FOR THE RNA HELICASE MOV10L1 IN PIRNA BIOGENESIS

Qi Fu

P. Jeremy Wang

Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs required for transposon silencing, germ cell development, and fertility in many eukaryotic species. However, many of the mechanisms underlying piRNA biogenesis have not been elucidated. Studies of MOV10L1 support its function as an RNA helicase in the processing of piRNA precursors. In this study, we elucidate the requirement for MOV10L1 RNA helicase activity in piRNA biogenesis.

To determine the requirement for MOV10L1 RNA helicase activity in piRNA biogenesis in vivo, we generated two knock-in mouse ...


Coordination Of Vibrio Cholerae Early Colonization Phenotypes In Response To Host Intestinal Factors, Amanda J. Hay Jan 2016

Coordination Of Vibrio Cholerae Early Colonization Phenotypes In Response To Host Intestinal Factors, Amanda J. Hay

Publicly Accessible Penn Dissertations

Vibrio cholerae causes human infection through ingestion of contaminated food and water, leading to the diarrheal disease, cholera. In aquatic environments this bacterium displays an expression profile that is distinct from that observed during infection. It can also form matrix-encased aggregates known as biofilms, typically on chitinous surfaces, which can be important for transmission and infectivity. Upon entry into the host, a tightly regulated circuit coordinates induction of two major virulence factors: cholera toxin (CT) and a toxin co-regulated pilus (TCP). This study finds that bile components present in the host intestine can affect both of these processes. Certain bile ...