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Full-Text Articles in Cell Biology

The Role Of Calcineurin/Nfat Signaling In Fibroblast Homeostasis And Activation, Allyson Elizabeth Lieberman Jan 2019

The Role Of Calcineurin/Nfat Signaling In Fibroblast Homeostasis And Activation, Allyson Elizabeth Lieberman

Publicly Accessible Penn Dissertations

Fibroblast activation is a crucial step in tumor growth and metastatic progression; activated fibroblasts remodel extracellular matrix (ECM) in primary tumor and metastatic microenvironments, exerting both pro- and anti-tumorigenic effects. However, the intrinsic mechanisms that regulate the activation of fibroblasts are not well defined. The signaling axis comprising the calcium-activated Ser/Thr phosphatase calcineurin (CN), and its downstream target nuclear factor of activated T cells (NFAT), has been shown to play important roles in in endothelial and immune cell activation, but its role in fibroblasts is not known. We have shown that deletion of CN in fibroblasts in vitro results ...


Investigating The Role Of The Human Naip/Nlrc4 Inflammasome In Host Defense Against Gram-Negative Bacterial Infection, Valeria M. Reyes Ruiz Jan 2019

Investigating The Role Of The Human Naip/Nlrc4 Inflammasome In Host Defense Against Gram-Negative Bacterial Infection, Valeria M. Reyes Ruiz

Publicly Accessible Penn Dissertations

Inflammasomes are key multiprotein intracellular complexes that mediate host defense against pathogenic microorganisms by activating caspase-1-dependent cytokine secretion and cell death. In mice, specific nucleotide-binding domain, leucine-rich repeat-containing family, apoptosis inhibitory proteins (NAIPs) sense components of the type III secretion system (T3SS) and flagellar apparatus. Upon sensing of bacterial components, NAIPs recruit the nucleotide-binding domain, leucine-rich repeat-containing family, CARD domain-containing protein 4 (NLRC4). The resulting NAIP/NLRC4 inflammasome then recruits and activates caspase-1. Active caspase-1 mediates processing and secretion of IL-1 family cytokines and a proinflammatory cell death termed pyroptosis. In mice, bacterial ligands for four of seven distinct NAIPs ...


Cardiac Effects Of Huntington’S Disease In Murine Models, Daniel David Child Jan 2019

Cardiac Effects Of Huntington’S Disease In Murine Models, Daniel David Child

Publicly Accessible Penn Dissertations

Huntington’s disease (HD) is an autosomal dominant disease known for its severe neurologic phenotype. However, the causative protein in HD, mutant huntingtin (mHTT), is widely expressed across tissue types and may have profound consequences for peripheral organs. Notably, heart disease is the second leading cause of death in HD patients, but if or how cardiac mHTT expression causes pathology is still unknown. Here, I characterize the cardiac phenotype in two HD mouse models and show that dysregulated mTORC1 activity is a key underlying mechanism. I show that normal heart growth is limited in HD mouse models, with mass regulated ...


Hypoxic Influences On Myeloid Cells During Inflammation And Inflammation-Associated Cancer, Nan Lin Jan 2018

Hypoxic Influences On Myeloid Cells During Inflammation And Inflammation-Associated Cancer, Nan Lin

Publicly Accessible Penn Dissertations

Hypoxia is a prominent characteristic of many acute or chronic inflammatory diseases, and exerts significant influence on their progression. Macrophages and neutrophils are major cellular components of innate immunity and contribute not only to O2 deprivation at the site of inflammation, but also alter many of their functions in response to hypoxia to either facilitate or suppress inflammation. Hypoxia stabilizes HIF-αs in macrophages and neutrophils, and these O2-sensitive transcription factors are key regulators of inflammatory responses in myeloid cells. This body of work investigates the role of myeloid HIF-αs in the settings of several acute and chronic inflammatory diseases.

First ...


Gene Therapy Approaches To Immune Tolerance Induction In Canine Hemophilia, Robert French Jan 2018

Gene Therapy Approaches To Immune Tolerance Induction In Canine Hemophilia, Robert French

Publicly Accessible Penn Dissertations

A key issue in gene therapy is the immune response to the therapeutic transgene. This is especially important in applications where current treatments often elicit an antibody response, like hemophilia, where protein replacement therapy results in neutralizing

antibodies (“inhibitors”) in ~25% of severe hemophilia A and 1-3% of severe hemophilia B patients. To test the ability of skeletal muscle-directed gene therapy to prevent an immune response, we used an inhibitor-prone dog model of severe hemophilia B to express a hyperactive factor IX (FIX) variant from skeletal muscle via adeno-associated viral (AAV) vector and observed curative levels of expression that lasted ...


Wnt5a Signaling Induced Phosphorylation Increases Acyl Protein Thioesterase Activity And Promotes Melanoma Metastatic Behavior, Rochelle Shirin Sadeghi Jan 2018

Wnt5a Signaling Induced Phosphorylation Increases Acyl Protein Thioesterase Activity And Promotes Melanoma Metastatic Behavior, Rochelle Shirin Sadeghi

Publicly Accessible Penn Dissertations

Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of pro-metastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remains unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization ...


Deregulation Of The Hippo Pathway Suppresses Differentiation And Promotes Sarcomagenesis, Adrian Rivera Reyes Jan 2018

Deregulation Of The Hippo Pathway Suppresses Differentiation And Promotes Sarcomagenesis, Adrian Rivera Reyes

Publicly Accessible Penn Dissertations

Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most aggressive and lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal ...


Intrathecal Aav9.Trastuzumab Tumor Prophylaxis And Treatment In A Murine Xenograft Model Of Her2+ Breast Cancer Brain Metastases, William Thomas Rothwell Jan 2017

Intrathecal Aav9.Trastuzumab Tumor Prophylaxis And Treatment In A Murine Xenograft Model Of Her2+ Breast Cancer Brain Metastases, William Thomas Rothwell

Publicly Accessible Penn Dissertations

Breast cancer brain metastases (BCBM) are a deadly sequela of breast tumors that overexpress human epidermal growth factor receptor 2 (HER2). HER2+ BCBM affects approximately 17,000 women in the US every year. Median survival is 10-13 months from the time of diagnosis of central nervous system (CNS) disease. Current therapeutic interventions are invasive, toxic, and largely ineffective, leaving a clear, unmet need for targeted HER2+ BCBM treatments. Trastuzumab(Herceptin®) is a monoclonal antibody used to treat HER2+ breast cancer successfully, but systemic trastuzumab cannot bypass the blood-brain barrier (BBB). To solve this problem, we have developed an adeno-associated virus ...


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 ...


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 ...


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 ...


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 ...


Estrogens Impair Antitumor Immunity By Promoting The Accumulation Of Myeloid-Derived Suppressor Cells, Nikolaos Svoronos Jan 2016

Estrogens Impair Antitumor Immunity By Promoting The Accumulation Of Myeloid-Derived Suppressor Cells, Nikolaos Svoronos

Publicly Accessible Penn Dissertations

Estrogens are pleiotropic steroid hormones with pro- and anti-inflammatory effects that influence autoimmune disease and pregnancy. Both autoimmunity and pregnancy are similar to cancer with regard to the immune system. In established tumors, as is the case in autoimmune disease and pregnancy, the host is exposed to self or allogeneic antigens, which are capable of eliciting immune responses. However, for pregnancies to remain viable, autoimmune disease patients survive, and tumors to persist, the immune system must be at least partially tolerized to these challenges. Therefore, I hypothesize that, just as they appear to influence pregnancy and autoimmunity, estrogens’ ability to ...


Coming Full Circle: Epithelial Plasticity And The Natural History Of Metastasis, Nicole Aiello Jan 2016

Coming Full Circle: Epithelial Plasticity And The Natural History Of Metastasis, Nicole Aiello

Publicly Accessible Penn Dissertations

The primary cause of cancer-related deaths is metastasis— the spread of cancer cells to distant organs— and yet the mechanisms underlying this process remain elusive due to the difficulty in detecting early metastatic events, which are rare, stochastic and microscopic. To investigate the cellular and molecular mechanisms of metastasis, I utilized an autochthonous mouse model of pancreatic cancer (KPCY) in which all tumor cells are genetically labeled with yellow fluorescent protein (YFP). The YFP lineage label allows for the detection and isolation of disseminated tumor cells as they delaminate from epithelial structures within the primary tumor, invade into the stroma ...


Differential Domain Architecture Directs Nedd4 Family E3 Ligase Function., Christopher Riling Jan 2015

Differential Domain Architecture Directs Nedd4 Family E3 Ligase Function., Christopher Riling

Publicly Accessible Penn Dissertations

Nedd4-family E3 ubiquitin ligases regulate signaling in intracellular pathways that control cancer, blood pressure, iron metabolism, and inflammation. These E3 ligases are catalytically active, and share a highly conserved, modular architecture. How Nedd4 family members are differentially regulated, despite their high degree of homology, is unclear. A regulatory mechanism that maintains an inactive state, common to Nedd4 family members, is autoinhibition. The majority of Nedd4 family members are autoinhibited by an intramolecular interaction between the N terminal C2 domain and the HECT domain. One subfamily of Nedd4 family members that includes the E3 ligase Itch does not appear to be ...


Immunosenescence In B Cells: A Study On Changes In Immunoregulator Expression And Metabolism With Age, Senthil Kannan Jan 2015

Immunosenescence In B Cells: A Study On Changes In Immunoregulator Expression And Metabolism With Age, Senthil Kannan

Publicly Accessible Penn Dissertations

There is a vital need for better vaccines for the aging population, and especially better vaccines to influenza viruses. To address this, I studied immunosenescence in B cells and antibody secreting cells (ASCs) in mice and humans. In humans, I measured humoral immune responses to the trivalent inactivated influenza vaccine (TIV) during the 2011-12 and 2012-13 influenza seasons. ASCs in the aged were observed to have decreased expression of the defining markers CD27 and CD38. Aged ASCs also expressed lower levels of B and T Lymphocyte attenuator (BTLA) on their surface. Expression of BTLA inversely correlated with age and appeared ...


Frβ-Directed Car T Cells For Immunotherapy Of Cancer, Rachel Christina Lynn Jan 2015

Frβ-Directed Car T Cells For Immunotherapy Of Cancer, Rachel Christina Lynn

Publicly Accessible Penn Dissertations

T-cells expressing chimeric antigen receptors (CARs) can elicit dramatic clinical responses in CD19+ malignancies; however, therapeutic options for acute myeloid leukemia (AML) and solid tumors remain limited. Folate receptor beta (FRβ) is a myeloid-lineage antigen expressed in 70% of AML. Here, we tested the hypothesis that FRβ could be an effective new CAR T-cell target in AML. Low affinity FRβ CAR T-cells displayed specific reactivity for FRβ+ cells in vitro and delayed human AML outgrowth in mice but were unable to completely eliminate the tumor. An optimized higher affinity CAR exhibited drastically increased anti-leukemic activity in vitro and in vivo ...


Context- Dependent Gene Expression Programs Promote Lymphocyte Development And Function And Suppress Transformation, Amy Demicco Jan 2015

Context- Dependent Gene Expression Programs Promote Lymphocyte Development And Function And Suppress Transformation, Amy Demicco

Publicly Accessible Penn Dissertations

Coordinated orchestration of gene expression programs at the transcriptional, post-transcriptional, and post-translational levels is essential for development and function of all cells, including lymphocytes. Normal tissue function also demands that the genome be faithfully passed from mother to daughter cell during the many rounds of cell division required to generate a mammalian organism. Genome integrity is maintained in part by integration of DNA damage signaling with cell cycle control. These mechanisms are especially critical for lymphocytes following V(D)J recombination, since V(D)J recombination involves genetic cutting and pasting of germline gene segments to form antigen receptors (AgRs ...


The Role Of Αv Integrins In Human Skin Tissue Homeostasis, Wound Healing And Squamous Cell Carcinoma, Elizabeth Kennedy Duperret Jan 2015

The Role Of Αv Integrins In Human Skin Tissue Homeostasis, Wound Healing And Squamous Cell Carcinoma, Elizabeth Kennedy Duperret

Publicly Accessible Penn Dissertations

Integrins play crucial roles in epithelial adhesion, proliferation, wound healing and cancer. In the epidermis, the roles of many integrin subunits are incompletely defined and mechanistic details regarding their functions are lacking. We performed a multiplexed shRNA screen to define roles for each subunit in human organotypic skin. This screen identified the integrin αv class of heterodimers as essential for generation of human skin tissue. We demonstrate that integrin αv loss drives a keratinocyte G1-S cell cycle checkpoint block. Surprisingly, αv integrins are not localized within keratinocyte focal adhesions and instead maintain proliferation by controlling c-myc translation through FAK, p38 ...


Ubiquitylation Regulates Cd4+ T Cell Activation And Effector Differentiation To Shape The Immune Response, Claire Elizabeth O'Leary Jan 2015

Ubiquitylation Regulates Cd4+ T Cell Activation And Effector Differentiation To Shape The Immune Response, Claire Elizabeth O'Leary

Publicly Accessible Penn Dissertations

Ubiquitylation of cellular proteins alters protein function and half-life to impact cell signaling and fate decisions. In T cells, ubiquitylation events, mediated by substrate-specific E3 ubiquitin ligases and deubiquitylating enzymes, can promote or limit T cell activation and alter function. For example, the catalytic E3 ligase Nedd4 is required for robust T cell activation, while a related Nedd4 family member, Itch, negatively regulates T cell signaling. Several Nedd4 family ligases are activated by binding Nedd4 family interacting protein 1 (Ndfip1) and/or Ndfip2. I have determined that ligase activity depends non-redundantly on both Ndfip1 and Ndfip2. Unlike Ndfip1, Ndfip2 is ...


T Cell Immunosurveillance In Pancreatic Ductal Adenocarcinoma, Rebecca A. Evans Jan 2015

T Cell Immunosurveillance In Pancreatic Ductal Adenocarcinoma, Rebecca A. Evans

Publicly Accessible Penn Dissertations

ABSTRACT

T CELL IMMUNOSURVEILLANCE IN PANCREATIC DUCTAL ADENOCARCINOMA

Rebecca A. Evans

Robert H. Vonderheide

The prevailing theory of cancer immune surveillance, as understood from carcinogen-driven mouse models of highly mutated tumors, states that T cell-mediated immune pressure drives a continuum of tumor elimination, equilibrium, and escape. This “Triple E Hypothesis” reflects host-tumor interactions in a subset of human cancers that have responded well to cancer immunotherapy, including melanoma, small cell lung carcinoma, and bladder carcinoma; yet, many tumors remain refractory to such interventions. These clinical failures suggest that immunosurveillance in other cancers manifests with a fundamentally different biology than previously ...


Targeting Stress Response Pathways In Soft Tissue Sarcoma: The Role Of Hypoxia And Autophagy In Tumor Survival, Michael Nakazawa Jan 2015

Targeting Stress Response Pathways In Soft Tissue Sarcoma: The Role Of Hypoxia And Autophagy In Tumor Survival, Michael Nakazawa

Publicly Accessible Penn Dissertations

Soft tissue sarcomas (STS) are a group of malignancies that arise from mesenchymal tissue, consisting of over 50 distinct histiologic subtypes. Unfortunately, the five-year survival rate of sarcoma patients has remained relatively unchanged, and due to the rarity of the disease, research and development of adequate therapeutics for STS lags behind other cancers. Therefore, understanding the molecular drivers of STS is important in developing new therapeutics, as well as discovering druggable processes that occur across multiple subtypes. One feature common to STS is hypoxia, or low O2 conditions. Using molecular biology, biochemical approaches, genetically engineered mouse models, as well as ...


Ex Vivo Gene Therapy For Lysosomal Storage Disease Using Ipsc-Derived Neural Stem Cells, Tagan Aaron Griffin Jan 2015

Ex Vivo Gene Therapy For Lysosomal Storage Disease Using Ipsc-Derived Neural Stem Cells, Tagan Aaron Griffin

Publicly Accessible Penn Dissertations

Diseases affecting the central nervous system (CNS) pose a formidable obstacle to the delivery of effective therapeutics. A tight-knit collection of cells and macromolecules known as the blood-brain-barrier (BBB) prevents most substances from entering the brain. One intriguing approach to overcoming this obstacle involves transplanting neural stem cells (NSCs), the precursor cells to neurons and glia in the brain, as vehicles for the delivery of therapeutic proteins in their native environment. Notably, this strategy has already been successfully applied to several lysosomal storage diseases caused by genetic deficiencies in one of the many lysosomal hydrolases expressed throughout the body. A ...


The Role Of Cytosolic Access In Streptococcus Pneumoniae Nasopharyngeal Colonization, Jamie Lemon Jan 2015

The Role Of Cytosolic Access In Streptococcus Pneumoniae Nasopharyngeal Colonization, Jamie Lemon

Publicly Accessible Penn Dissertations

Cytosolic detection of pathogen associated molecular patterns is a key event in host discrimination between commensal and pathogenic microbes. While cytosolic access is critical for the pathogenesis of intracellular bacteria, access to the cytosolic compartment by extracellular bacteria is less well understood. The leading extracellular pathogen Streptococcus pneumoniae (the pneumococcus) activates intracellular innate immune responses, but unlike intracellular bacterial pathogens, S. pneumoniae is killed and degraded upon uptake by phagocytic cells. The pneumococcus serially colonizes the human upper respiratory tract and is eventually cleared over a period of weeks by the host immune response. Previous studies have defined a critical ...


Roles Of Dendritic Cells In Immunity To Toxoplasma Gondii, Christopher David Dupont Jan 2014

Roles Of Dendritic Cells In Immunity To Toxoplasma Gondii, Christopher David Dupont

Publicly Accessible Penn Dissertations

Toxoplasma gondii is an intracellular protozoan parasite that actively invades host cells. During toxoplasmosis, dendritic cells (DCs) promote CD4+ and CD8+ T cell responses, which are critical for long-term immunity. Despite this critical role of DCs, questions remain regarding how this population is regulated during infection, and the specific types of interactions (phagocytosis or active invasion) between parasites and DCs that are necessary to induce T cell responses.

Previous studies have observed an infection-induced expansion of DC populations during toxoplasmosis, but the factors that regulate this expansion are currently unknown. Mice deficient in the cytokine Flt3L, which promotes the proliferation ...


Effect Of Cyclosporin A On The Tumor Microenvironment, Yao Zhou Jan 2014

Effect Of Cyclosporin A On The Tumor Microenvironment, Yao Zhou

Publicly Accessible Penn Dissertations

Tumor angiogenesis is a hallmark of cancer, and plays a critical role in tumor growth, expansion, and metastasis. Both physiological and pathological angiogenesis is assumed to be regulated by the balance between pro and anti-angiogenic factors. One of the best characterized and most potent pro-angiogenic regulators is vascular endothelial growth factor, or VEGF. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by increased expression of its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis. However, a potent pharmacological calcineurin inhibitor, the commonly used immunosuppressant cyclosporin A (CsA), significantly ...


Ebna1-Specific T Cell Responses During Persistent Rhesus Lcv Infection And The Development Of A Novel Therapeutic Prototype Vaccine For Ebv-Associated Diseases, Rachel Mandy Leskowitz Jan 2014

Ebna1-Specific T Cell Responses During Persistent Rhesus Lcv Infection And The Development Of A Novel Therapeutic Prototype Vaccine For Ebv-Associated Diseases, Rachel Mandy Leskowitz

Publicly Accessible Penn Dissertations

The impact of EBV on human health is substantial, but vaccines that prevent primary EBV infections or treat EBV-associated diseases are not yet available. The Epstein-Barr nuclear antigen 1 (EBNA1) is an important target for vaccination because it is the only protein expressed in all forms of latency and in all EBV-associated malignancies. The overarching goal throughout this dissertation was to determine if EBNA1 is a suitable target for vaccine development. This was addressed in two ways. First, because an improved understanding of EBNA1-specific T cell responses benefits EBV vaccine development, we characterized responses against EBNA1 of the EBV-homologous rhesus ...


Opposing Actin Networks Modulate The Mechano-Activation Of The Integrin Lfa-1 During Immunological Synapse Formation, William Andrew Comrie Jan 2014

Opposing Actin Networks Modulate The Mechano-Activation Of The Integrin Lfa-1 During Immunological Synapse Formation, William Andrew Comrie

Publicly Accessible Penn Dissertations

Formation of a functional immune response requires the regulated transfer of information between T cells, and APCs, which leads to a variety of functional outcomes. In many cases this information transfer occurs at a regulated area of cell - cell contact termed the immunological synapse (IS). In T cells responding to APCs there is a robust accumulation of F-actin on the T cell side of the synapse. This F-actin response is characterized by robust polymerization at the periphery of the contact site followed by centripetal flow of the network towards the center of the IS. While it is well known that ...