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Articles 1 - 30 of 188

Full-Text Articles in Cell Biology

Multiple Feedback Mechanisms Fine-Tune Rho Signaling To Regulate Morphogenetic Outcomes, Katy Lauren Ong Jan 2019

Multiple Feedback Mechanisms Fine-Tune Rho Signaling To Regulate Morphogenetic Outcomes, Katy Lauren Ong

Publicly Accessible Penn Dissertations

Rho signaling is a conserved mechanism for generating forces through activation of contractile actomyosin. How this pathway is tuned to produce different morphologies of cells and tissues is poorly understood. In the Drosophila embryonic epithelium, I investigated how Rho signaling controls force asymmetries to drive morphogenesis. Specifically, I studied a distinctive morphogenetic process termed “alignment”. This process of coordinated cell shape changes results in a unique cell geometry of rectilinear cells connected by aligned cell-cell contacts. I found that this rearrangement is initialized by contractility of actomyosin cables that elevate the local tension along aligning interfaces. Curiously, I find that ...


Role Of The Nuclear Receptor Pparγ In Clear Cell Renal And Bladder Urotheial Carcinoma, Danielle Sanchez Jan 2019

Role Of The Nuclear Receptor Pparγ In Clear Cell Renal And Bladder Urotheial Carcinoma, Danielle Sanchez

Publicly Accessible Penn Dissertations

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has a well-characterized role in the developmental process of adipogenesis and transcriptional regulation of lipid metabolism. However, its expression patterns and functions in various cancer subtypes are less understood. My studies investigate the role of PPARγ in two distinct cancers of the urinary tract: clear cell renal cell carcinoma (ccRCC) and bladder urothelial carcinoma (UC). In ccRCC, I hypothesized that PPARγ activity contributes to the aberrant lipid accumulation phenotype characteristic of this disease, thereby promoting tumor progression. Through ChIP-seq, I demonstrated that PPARγ and its heterodimeric DNA binding partner retinoid X receptor ...


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 ...


Unraveling The Beta Cell Translatome: Elucidation Of An Erk/Hnrnpk/Jund Axis, Austin Lewis Good Jan 2019

Unraveling The Beta Cell Translatome: Elucidation Of An Erk/Hnrnpk/Jund Axis, Austin Lewis Good

Publicly Accessible Penn Dissertations

In type 2 diabetes, oxidative stress contributes to the dysfunction and loss of pancreatic β cells. A highly conserved feature of the cellular response to stress is the regulation of mRNA translation, however, the mechanisms underlying this process in β cells are not fully understood. Here we use TRAP-seq to examine changes in the ribosome occupancy of mRNAs during conditions associated with β cell dysfunction, leading us to identify a cohort of translationally regulated genes with 3’UTR enrichment of a cytosine-rich motif. Of particular interest was the gene encoding JUND, a transcription factor with anti-oxidant functions in other cell ...


The Role Of P120catenin In The Initiation And Dissemination Of Pancreatic Cancer, Basil Bakir Jan 2019

The Role Of P120catenin In The Initiation And Dissemination Of Pancreatic Cancer, Basil Bakir

Publicly Accessible Penn Dissertations

Pancreatic cancer is the third leading cause of cancer mortality, the overwhelming majority of which is due to metastasis. The mechanisms of dissemination have been intensively studied, but questions remain as to how epithelial properties are regulated between the primary tumor site and destination as well as to how organotropic patterns of metastasis are determined. We demonstrate, using multiple complementary mouse models, that liver and lung metastatic organotropism in pancreatic cancer is dependent on p120catenin (p120ctn)-mediated epithelial identity. Monoallelic p120ctn loss accelerates KrasG12D-driven PanIN/PDAC formation and metastasis to the liver as well as being sufficient for E-CADHERIN-mediated cell ...


Roles Of Euchromatin And Heterochromatin In Hepatocyte Maturation And Liver Fibrosis, Jessica Mae Grindheim Jan 2019

Roles Of Euchromatin And Heterochromatin In Hepatocyte Maturation And Liver Fibrosis, Jessica Mae Grindheim

Publicly Accessible Penn Dissertations

Liver transplantation is the main treatment for acute liver failure patients; however, there is an insufficient supply of donor livers. Since transplanting hepatocytes, the main liver cell type, provides therapeutic effect and can be a bridge to transplant or recovery, scientists are working on generating replacement hepatocytes from stem cells and other cell types through reprogramming protocols. Currently, replacement hepatocytes recapitulate a subset of natural hepatocyte features, yet are still in an immature state, as they have not silenced all immature hepatocyte genes and activated all mature hepatocyte genes. Consequently, replacement hepatocytes do not perform as well as natural hepatocytes ...


The Regulation Of Egfr Signaling And Kras Tumorigenesis By Receptor Palmitoylation, Akriti Kharbanda Jan 2019

The Regulation Of Egfr Signaling And Kras Tumorigenesis By Receptor Palmitoylation, Akriti Kharbanda

Publicly Accessible Penn Dissertations

Non-Small Cell Lung Cancer (NSCLC) is often characterized by mutually exclusive mutations in epidermal growth factor receptor (EGFR) or KRAS. The mutual exclusivity of these mutations is due to synthetic lethality, revealing a potential therapeutic vulnerability if possible to selectively activate EGFR in KRAS mutant cells. This thesis work demonstrates a previously unidentified mechanism of EGFR signal regulation through palmitoylation, the addition of the 16-carbon palmitate. The palmitoyltransferase, DHHC20, catalyzes this palmitoylation to Cys1025, Cys1122 and Cys1034 on the C-terminal tail of EGFR. Loss of EGFR palmitoylation leads to hyperactivation of the receptor, but decreased cell growth of KRAS mutant ...


Little Elongation Complex (Lec) And Super Elongation Complex (Sec) As Regulators Of Tdp-43-Associated Neurodegeneration, Chia-Yu Chung Jan 2018

Little Elongation Complex (Lec) And Super Elongation Complex (Sec) As Regulators Of Tdp-43-Associated Neurodegeneration, Chia-Yu Chung

Publicly Accessible Penn Dissertations

TDP-43 aggregation is the pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). To define pathways important in TDP-43 proteinopathy, a genetic screen for modifiers of TDP-43-mediated eye degeneration was conducted in the fruit fly (Drosophila melanogaster). This approach and the following studies in the fly identified transcriptional elongation factor Ell as a potent dose-dependent modifier. Ell is a shared component of little elongation complex (LEC) and super elongation complex (SEC). Our studies show that downregulation of additional components in LEC or SEC partially but consistently ameliorates TDP-43-associated eye degeneration, implicating both Ell-associated complexes ...


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 ...


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 ...


Extracellular Cues In The Regulation Of Tube Shape During Organogenesis, Jeffrey Bryan Rosa Jan 2018

Extracellular Cues In The Regulation Of Tube Shape During Organogenesis, Jeffrey Bryan Rosa

Publicly Accessible Penn Dissertations

Biological tubes adopt a variety of shapes to carry out their functions. In addition to multicellular tubes, single epithelial or endothelial cells build unicellular lumens lined by an apical membrane devoid of cell junctions, or seams. Such seamless tubes are highly conserved from invertebrates to vertebrate organs, but the factors regulating their formation and maintenance remain poorly understood in any system. Using a forward genetic approach in the Drosophila tracheal (respiratory) system, we have characterized a mutant called ichor, which compromises the integrity and shape of seamless tubes in tracheal terminal cells. We demonstrate that Ichor promotes seamless tube integrity ...


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 ...


Cargo Specific Regulation Of Cytoplasmic Dynein By Effector Proteins, Mara Olenick Jan 2018

Cargo Specific Regulation Of Cytoplasmic Dynein By Effector Proteins, Mara Olenick

Publicly Accessible Penn Dissertations

Axonal transport is vital for the development and survival of neurons. The transport of cargo and organelles from the axon to the cell body is driven almost completely by the molecular motor, cytoplasmic dynein. Yet, it remains unclear how dynein is spatially and temporally regulated given the variety of cargo that must be properly localized to maintain cellular function. Previous work has suggested that adaptor proteins provide a mechanism for cargo-specific regulation of motors. During my thesis work, I have investigated the role of mammalian Hook proteins, Hook1 and Hook3, as potential motor adaptors. Using optogenetic and single molecule assays ...


The Role Of Molecular Motors In Peripheral Nerve Regeneration, Melissa D. Priest Jan 2018

The Role Of Molecular Motors In Peripheral Nerve Regeneration, Melissa D. Priest

Publicly Accessible Penn Dissertations

Following injury, axons of the peripheral nervous system have retained the capacity for regeneration. While it is well established that injury signals require molecular motors for their transport from the injury site to the nucleus, whether kinesin and dynein motors play additional roles in peripheral nerve regeneration is not well understood. Here we use genetic mutants of motor proteins in a zebrafish peripheral nerve regeneration model to visualize and define in vivo roles for kinesin and dynein. We find that both kinesin-1 and dynein are required for zebrafish peripheral nerve regeneration. While loss of kinesin-1 reduced the overall robustness of ...


Discovering Novel Hearing Loss Genes: Roles For Esrp1 And Gas2 In Inner Ear Development And Auditory Function, Alex Martin Rohacek Jan 2018

Discovering Novel Hearing Loss Genes: Roles For Esrp1 And Gas2 In Inner Ear Development And Auditory Function, Alex Martin Rohacek

Publicly Accessible Penn Dissertations

Hearing loss is the most common form of congenital birth defect, affecting an estimated

35 million children worldwide. To date, nearly 100 genes have been identified which

contribute to a deafness phenotype in humans, however, many cases remain in which a

causative mutation has yet to be found. In addition, the exact mechanism by which

hearing loss occurs in the presence of many of these mutations is still not understood.

This is due, in part, to the complex nature of the development and function of the

cochlear duct, the organ of hearing. The cochlea undergoes an intricate morphogenetic

development and ...


Elucidation Of Histone Modifications And Nucleosomal Structure Using Novel Mass Spectrometry Approaches, Kelly Karch Jan 2018

Elucidation Of Histone Modifications And Nucleosomal Structure Using Novel Mass Spectrometry Approaches, Kelly Karch

Publicly Accessible Penn Dissertations

The fundamental repeating unit of chromatin is the nucleosome, composed of 147 base pairs of DNA wrapped around a histone protein octamer containing two copies of H2A, H2B, H3, and H4. Histone proteins are involved in many critical nuclear processes including transcription and maintenance of chromatin structure. Histone function is mediated by a dynamic and extensive array of post-translational modifications (PTMs). Mass spectrometry (MS) has emerged as a leading tool to study these complex histone PTM profiles. Generally, MS experiments utilize data dependent acquisition (DDA) methods on high-resolution MS instruments because they can more readily distinguish PTMs with small mass ...


Palmitoylation And Polarity: Regulation Of Asymmetric Partitioning Of Notch And Wnt Signaling By Reversible Lipid Modification In Dividing Cells, Ewa Stypulkowski Jan 2018

Palmitoylation And Polarity: Regulation Of Asymmetric Partitioning Of Notch And Wnt Signaling By Reversible Lipid Modification In Dividing Cells, Ewa Stypulkowski

Publicly Accessible Penn Dissertations

Protein palmitoylation is a reversible lipid modification that regulates protein-membrane interaction, activity, trafficking, and stability in a spatio-temporal manner similar to phosphorylation and ubiquitination. Asymmetric cell division results in two distinctly fated daughter cells, by unequally partitioning proteins known as cell fate determinants. I have characterized a mechanism for protein palmitoylation to asymmetrically partition cell fate determinants, e.g. Numb and β-catenin, through the activity of the depalmitoylating enzyme APT1. Using point mutations, I have found specific palmitoylated residues on Numb are required for its asymmetric localization in dividing cells. By live-cell imaging, I have also identified a reciprocal interaction ...


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 ...


Regulation Of Mitochondrial Dynamics And Quality Control In Mammalian Cells, Andrew Stephen Moore Jan 2018

Regulation Of Mitochondrial Dynamics And Quality Control In Mammalian Cells, Andrew Stephen Moore

Publicly Accessible Penn Dissertations

Mitochondria are conserved eukaryotic organelles that carry out myriad cellular functions including energy generation, reactive oxygen species signaling, and lipid synthesis. In metazoans, mitochondria form dense, reticular networks that must be maintained through rigorous quality control mechanisms. Here, we describe three distinct aspects of mitochondria network homeostasis. In chapter 3, we investigate the spatiotemporal dynamics of mitophagy, tracking the association of autophagy machinery with individual damaged mitochondria. Using a range of damage paradigms, we dissect the kinetics of mitochondrial turnover and demonstrate that ALS-linked mutations in the proteins Optineurin and TBK1 interfere with efficient mitophagy. In chapter 5, we characterize ...


Dissecting The Functions Of Atr In Replication Fork Stability, Theonie Anastassiadis Jan 2017

Dissecting The Functions Of Atr In Replication Fork Stability, Theonie Anastassiadis

Publicly Accessible Penn Dissertations

Genome maintenance is required for cellular viability, and failure to preserve genomic integrity is associated with an increased risk of diseases, such as cancer. To ensure genomic stability, cells have checkpoints that control cell cycle progression in the event of DNA damage or incomplete DNA replication. The DNA replication checkpoint is regulated by the ATR-CHK1 pathway that stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Two distinct models have been proposed to explain how ATR stabilizes stalled forks: 1) through local modulation of fork remodelers, such as SMARCAL1 inhibition, and 2) through inhibition of CDK-dependent ...


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 ...


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 ...


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 ...


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 ...


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 ...


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 ...


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 ...