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Articles 31 - 60 of 161

Full-Text Articles in Molecular Biology

Biochemical And Functional Studies Of Histone Deacetylase 3 In Metabolic Tissues, Jarrett Renn Remsberg Jan 2017

Biochemical And Functional Studies Of Histone Deacetylase 3 In Metabolic Tissues, Jarrett Renn Remsberg

Publicly Accessible Penn Dissertations

Organismal physiology is built upon the foundation of molecular processes. A central axis to maintaining homeostasis in vivo is at the level of gene regulation. Tissue specific gene expression is created at the level of epigenetics, where proteins guided by tissue specific DNA binding proteins create a chromatin landscape for precise gene programs. Understanding these molecular processes is of vital importance to understand the underpinning pathologies, such as metabolic syndrome, which are a growing medical concern and require greater research efforts in order to tackle its challenges. A major epigenetic regulator is histone deacetylase 3 (HDAC3), which is a core ...


Engineered Cytoskeletal Arrays Reveal Mechanisms Of Membrane Transport And Tubulation, Betsy Buechler Mcintosh Jan 2017

Engineered Cytoskeletal Arrays Reveal Mechanisms Of Membrane Transport And Tubulation, Betsy Buechler Mcintosh

Publicly Accessible Penn Dissertations

Within the cell, cytoskeletal molecular motors transport and remodel membrane-bound cargos along microtubule and actin filament tracks. Typically, there are multiple actin and microtubule motors attached to the same cargo, which must coordinate to navigate a complex cytoskeletal environment and deliver their cargos to specific locations. We used an engineering, in vitro reconstitution, approach to investigate the interplay between a processive, microtubule-based motor, kinesin-1, and a non-processive, actin filament-based motor, Myo1c, in a simplified environment with increasing physiological complexity. First, we examined the interplay between purified motors attached to a membrane-coated bead at individual actin filament/microtubule intersections on the ...


Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism, Minal B. Mehta Jan 2017

Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism, Minal B. Mehta

Publicly Accessible Penn Dissertations

Genetic variants mapping to chromosome 8p23.1 have been associated with multiple metabolic traits in humans, including plasma constituents (glucose, lactate, insulin, HDL and non-HDL cholesterol), and hepatic steatosis with genome-wide significance. The closest gene of known function, PPP1R3B, (Protein Phosphatase 1 Regulatory Subunit 3B), encodes a protein (GL) that is known to regulate glycogen metabolism. We sought to test the hypothesis that hepatic PPP1R3B is the causal gene underlying the human genetic association with these metabolic attributes and to understand the mechanisms. We generated two separate mice with liver-specific deletion (Ppp1r3b∆hep) or liver-specific overexpression of Ppp1r3b. Hepatic deletion ...


Characterizing A Signaling Network That Maintains Hematopoietic Stem Cells, Michelle Nguyen-Mccarty Jan 2017

Characterizing A Signaling Network That Maintains Hematopoietic Stem Cells, Michelle Nguyen-Mccarty

Publicly Accessible Penn Dissertations

Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche can survive if they receive hematopoietic cytokines, but they then lose the ability to self-renew. However, we showed previously that simultaneous inhibition of glycogen synthase kinase-3 (GSK-3) and mammalian target of rapamycin complex 1 (mTORC1) maintains HSC function ex vivo without the need for exogenous cytokines. As these experiments were initially done in heterogeneous cell populations, I then showed that ...


Sex Differences In Μ-Opioid Regulation Of The Rat Locus Coeruleus, Herminio Manuel Guajardo Jan 2017

Sex Differences In Μ-Opioid Regulation Of The Rat Locus Coeruleus, Herminio Manuel Guajardo

Publicly Accessible Penn Dissertations

There are sex differences in disease susceptibility, time of onset of symptoms, and drug responses. Notably, sex differences are particularly prominent in pain and opioid analgesic responses, with females being less sensitive to opioid analgesia. A major site of action of opioids in the brain is the locus coeruleus (LC)-norepinephrine (NE) system. LC neurons express mu-opiate receptors (MOR), and MOR-agonists potently inhibit LC neuronal activity. Evidence suggests that endogenous opioids are released during stress, to restrain LC activation and to facilitate LC recovery when the stressor ends. On the basis of these observations, this dissertation tested the hypothesis that ...


Dna Double Strand Breaks Suppress Expression Of The Rag Recombinase: Mechanisms And Consequences, Megan Rose Fisher Jan 2017

Dna Double Strand Breaks Suppress Expression Of The Rag Recombinase: Mechanisms And Consequences, Megan Rose Fisher

Publicly Accessible Penn Dissertations

Developing B and T lymphocytes must rearrange the genomic sequence of antigen receptor genes by V(D)J recombination. The lymphocyte-specific endonuclease RAG, composed of Rag1 and Rag2, initiates this process by cleaving specific sites within antigen receptor loci. RAG expression must be carefully regulated to ensure that V(D)J recombination occurs only under appropriate circumstances. The Bassing laboratory has previously demonstrated that Igκ locus cleavage by RAG in pre-B cells initiates a feedback-inhibition signal suppressing RAG expression. Here, we show that DNA double strand breaks (DSBs) induced by a variety of genotoxic agents have a similar effect in ...


Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration, Michael Gallagher Jan 2017

Genetic Regulation Of Tmem106b In The Pathogenesis Of Frontotemporal Lobar Degeneration, Michael Gallagher

Publicly Accessible Penn Dissertations

Neurodegenerative diseases are an emerging global health crisis, with the projected global cost of dementia alone expected to exceed $1 trillion, or >1% of world GDP, by 2018. However, there are no disease-modifying treatments for the major neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis. Therefore, there is an urgent need for a better understanding of the pathophysiology underlying these diseases. While genome-wide association studies (GWAS) have identified ~200 genetic variants that are associated with risk of developing neurodegenerative disease, the biological mechanisms underlying these associations are largely unknown. This ...


Exposure To Heavy Metal Stress Regulates Intercellular Signaling Via Callose Deposition And Breakdown, Ruthsabel O'Lexy Jan 2017

Exposure To Heavy Metal Stress Regulates Intercellular Signaling Via Callose Deposition And Breakdown, Ruthsabel O'Lexy

Publicly Accessible Penn Dissertations

How organisms sense external cues and integrate them into developmental changes remains a large biological question. Plants, which are sessile organisms, are particularly vulnerable to challenges in their environment. An early response to abiotic and biotic stress in plants is the modification of intercellular signaling through plasmodesmata, cytoplasmic channels that connect adjacent cells. However, the different ways in which plasmodesmata-mediated signaling can be affected, the molecular players involved in this response, the genetic basis of this regulation, and the biological benefits of this response are still poorly understood.

Here, we take a survey of seven different agriculturally relevant stresses of ...


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 ...


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 ...


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 ...


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 ...


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 ...


Centromere Identity And The Nature Of The Cenp-A-Containing Nucleosome, Samantha Jane Falk Jan 2016

Centromere Identity And The Nature Of The Cenp-A-Containing Nucleosome, Samantha Jane Falk

Publicly Accessible Penn Dissertations

The centromere is an essential chromosomal locus that serves as the site of kinetochore formation, ensuring accurate chromosome segregation during mitosis and meiosis. While most centromeres form on repetitive DNA, the underlying DNA sequence is neither necessary nor sufficient to support centromere function, suggesting that this locus is epigenetically defined. The histone H3 variant centromere protein A (CENP-A) replaces H3 in nucleosomes at the centromere and is the best candidate to provide this epigenetic mark. This thesis aims to understand the features of the CENP-A nucleosome that impart its ability to mark and stabilize functional centromeres. In the first part ...


Nampt-Mediated Nad+ Homeostasis In Skeletal Muscle: Implications For Healthy Aging, David Frederick Jan 2016

Nampt-Mediated Nad+ Homeostasis In Skeletal Muscle: Implications For Healthy Aging, David Frederick

Publicly Accessible Penn Dissertations

Mammalian skeletal muscle is a highly dynamic organ capable of structural and metabolic remodeling in response to exercise demands, nutrient supply, and environmental insults. Muscle also plays a central role in the maintenance of whole-body energy balance, capable of both storing and oxidizing carbohydrate and lipid fuels. The course of natural aging leads to a gradual decline in the mass, strength, and oxidative capacity of skeletal muscle, which increases the susceptibility of the elderly to frailty and metabolic diseases, such as Type II Diabetes. Ectopic muscle lipids can also exacerbate the metabolic complications of obesity, prompting interest in new means ...


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 ...


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 ...


The Regulation Of Psf Activity In T Cells By Trap150 And Gsk3, Christopher Yarosh Jan 2016

The Regulation Of Psf Activity In T Cells By Trap150 And Gsk3, Christopher Yarosh

Publicly Accessible Penn Dissertations

PSF is a ubiquitously expressed and essential nuclear protein that influences many aspects of the genome maintenance and gene expression pathways. Although previous studies have identified numerous protein cofactors and nucleic acid targets of PSF, insufficient work has been done to understand how it is regulated to accomplish its various functions in a coordinated manner. Previous research in the Lynch laboratory demonstrated that, in T cells, PSF is a downstream target of the serine/threonine kinase GSK3. Phosphorylation of PSF T687 by GSK3 promotes interaction of PSF with another multifunctional nuclear factor, TRAP150. This interaction prevents PSF from binding RNA ...


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 ...


Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu Jan 2016

Interplay Between P53 And Epigenetic Pathways In Cancer, Jiajun Zhu

Publicly Accessible Penn Dissertations

The human TP53 gene encodes the most potent tumor suppressor protein p53. More than half of all human cancers contain mutations in the TP53 gene, while the majority of the remaining cases involve other mechanisms to inactivate wild-type p53 function. In the first part of my dissertation research, I have explored the mechanism of suppressed wild-type p53 activity in teratocarcinoma. In the teratocarcinoma cell line NTera2, we show that wild-type p53 is mono-methylated at Lysine 370 and Lysine 382. These post-translational modifications contribute to the compromised tumor suppressive activity of p53 despite a high level of wild-type protein in NTera2 ...


Siv Infected Chimpanzees: Consequences Of Long-Term Infection And Potential Intervention Strategies, Hannah J. Barbian Jan 2016

Siv Infected Chimpanzees: Consequences Of Long-Term Infection And Potential Intervention Strategies, Hannah J. Barbian

Publicly Accessible Penn Dissertations

Simian immunodeficiency virus of chimpanzees (SIVcpz) is widespread in wild-living chimpanzees and can cause mortality and AIDS-like immunopathology. However, due to limited access to naturally infected chimpanzees, little is known about SIVcpz pathogenesis and potential intervention strategies that might be effective in captivity or in the wild. Given the central role of the intestinal microbiome in mammalian health, I asked whether gut microbial constituents could reveal any insights into SIVcpz-associated pathogenicity. I characterized the gut microbiome and virome of SIVcpz infected and uninfected chimpanzees in Gombe National Park, Tanzania. I found that SIVcpz infected chimpanzees retain a stable gut microbiome ...


Genome-Wide Approaches To Study Rna Secondary Structure, Nathan Daniel Berkowitz Jan 2016

Genome-Wide Approaches To Study Rna Secondary Structure, Nathan Daniel Berkowitz

Publicly Accessible Penn Dissertations

The central hypothesis of molecular biology depicts RNA as an intermediary conveyor of genetic information. RNA is transcribed from DNA and translated to proteins, the molecular machines of the cell. However, many RNAs do not encode protein and instead function as molecular machines themselves. The most famous examples are ribosomal RNAs and transfer RNAs, which together form the core translational machinery of the cell. Many other non-coding RNAs have been discovered including catalytic and regulatory RNAs. In many cases RNA function is tightly linked to its secondary structure, which is the collection of hydrogen bonds between complimentary RNA sequences that ...


Dna Disentangled: Roles For Sgs1 And Top3 In Rec-X Resolution And Replication Fork Restart, Mary Rebecca Glineburg Jan 2016

Dna Disentangled: Roles For Sgs1 And Top3 In Rec-X Resolution And Replication Fork Restart, Mary Rebecca Glineburg

Publicly Accessible Penn Dissertations

Homologous recombination (HR), becomes important for repair during replication where completion of DNA synthesis relies on recombination intermediate-mediated lesion bypass. For decades, Holliday Junctions (HJs) were considered the primary recombination intermediate utilized during this repair process, but increasing evidence points out two strong discrepancies: 1) X-structures, when present, are often biochemically inconsistent with being HJs, and 2) despite HR mutants being sensitive to numerous DNA damaging agents, most insults don’t result in X-structure accumulation, suggesting alternative HR pathways are at play. The Sgs1-Top3-Rmi1 (STR) complex, in Saccharomyces cerevisiae, is vital for maintaining genome integrity, and is known to resolve ...


Deciphering The Tetrad Of Epigenetic Cytosine Modifications, Monica Yun Liu Jan 2016

Deciphering The Tetrad Of Epigenetic Cytosine Modifications, Monica Yun Liu

Publicly Accessible Penn Dissertations

A tetrad of epigenetic cytosine modifications imbues the DNA code with complex, dynamic meaning. DNA methyltransferase enzymes deposit methyl marks on the 5-carbon of cytosine, forming 5-methylcytosine (mC), which generally mediates long-term, locus-specific transcriptional repression during development and reprogramming. Ten-eleven translocation (TET) family enzymes oxidize the methyl group in three steps, forming predominantly 5-hydroxymethylcytosine (hmC) but also low levels of 5-formylcytosine (fC) and 5-carboxylcytosine (caC). These additional bases likely provide pathways for erasing methylation, but they may also harbor epigenetic functions in their own right. Questions regarding how each base forms and functions drive at the fundamental biology of the ...


Mining Genomic Variants And Causal Pathways Linking Hdl And Triglycerides To Coronary Disease, Sumeet Anand Khetarpal Jan 2016

Mining Genomic Variants And Causal Pathways Linking Hdl And Triglycerides To Coronary Disease, Sumeet Anand Khetarpal

Publicly Accessible Penn Dissertations

Blood lipids are important biomarkers of risk of coronary heart disease (CHD), the leading cause of death in the world. Myriad data support a causal role of low-density lipoprotein cholesterol (LDL-C) in increasing risk of CHD. Long-standing epidemiology suggests that high-density lipoprotein cholesterol (HDL-C) may protect from disease while high triglycerides (TGs) increase CHD risk. However, the causality of HDL-C and TG to CHD remains controversial. New genetic methodologies have allowed a better look into causal pathways underlying relationships between these traits and disease. Using a combination of approaches for interrogating rare genetic variation in humans, we investigated how HDL ...


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 ...


Determination Of A Comprehensive Alternative Splicing Regulatory Network And The Combinatorial Regulation By Key Factors During The Epithelial To Mesenchymal Transition, Yueqin Yang Jan 2016

Determination Of A Comprehensive Alternative Splicing Regulatory Network And The Combinatorial Regulation By Key Factors During The Epithelial To Mesenchymal Transition, Yueqin Yang

Publicly Accessible Penn Dissertations

The epithelial to mesenchymal transition (EMT) is a process by which epithelial cells transdifferentiate into mesenchymal cells. It is essential for embryonic development and implicated in cancer metastasis. While the transcriptional regulation of EMT has been well-studied, the role of post-transcriptional regulation, particularly alternative splicing (AS) regulation in EMT, remains relatively uncharacterized. We previously showed that the epithelial cell-type-specific proteins ESRP1 and ESRP2 are important for regulation of many AS events that altered during EMT. However, the contributions of the ESRPs and other splicing regulators to the splicing regulatory network in EMT require further investigation.

In the first part of ...


Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives, David Tischfield Jan 2016

Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives, David Tischfield

Publicly Accessible Penn Dissertations

The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing ...


Insights Into Terminal Erythropoiesis Influenced By Human Genetic Variation, Elizabeth Traxler Jan 2016

Insights Into Terminal Erythropoiesis Influenced By Human Genetic Variation, Elizabeth Traxler

Publicly Accessible Penn Dissertations

Red blood cells (RBCs) carry hemoglobin, enabling delivery of oxygen to all tissues of the body. They are the products of a highly specialized differentiation process that begins with a hematopoietic stem cell and results in an enucleated, biconcave RBC. This thesis is focused on the use of human genetic studies to gain a better understanding of the molecular processes occurring during terminal erythroid differentiation. We studied the regulation and roles of two erythroid-restricted genes, Trim58 and Hemoglobin Gamma Chain (HBG1 and HBG2, γ-globin), by using a combination of loss-of-function techniques, including RNA-interference-mediated gene suppression, a mutant mouse model, and ...


Multiple Roles Of Ret Signaling In Mechanosensory Neuron Development, Michael Scott Fleming Jan 2016

Multiple Roles Of Ret Signaling In Mechanosensory Neuron Development, Michael Scott Fleming

Publicly Accessible Penn Dissertations

Somatosensation is critical for interaction with the surrounding environment. Somatosensory stimuli are detected by primary somatosensory neurons of the dorsal root ganglia and trigeminal ganglia, which detect distinct classes of stimuli, such as temperature, pain, and pressure. In Chapters 2 and 3 of this thesis, we focus on rapidly adapting low-threshold mechanoreceptors (RALTMRs), which mediate the detection of light touch. RALTMRs are molecularly defined by the early embryonic expression of the receptor tyrosine kinase Ret. Ret is required for the development of central axonal projections of RALTMRs into the dorsal spinal cord. RET responds to the glial cell line-derived family ...