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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee May 2018

Muc4 Based Immunotherapy For Pancreatic Cancer, Kasturi Banerjee

Theses & Dissertations

Pancreatic Cancer (PC) is a lethal disease claiming approximately 45000 lives in the US in 2018, and it establishes an elaborate immunosuppressive tumor microenvironment that aids in disease pathogenesis. Immunotherapy has emerged as a strategy to target tumor cells by reprogramming patient’s immune system. Challenges present in PC immunotherapy are: i) identifying a tumor-associated antigen that could be targeted, ii) identifying adjuvants that could efficiently deliver antigens, iii) eliciting robust anti-tumor responses and iv) overcoming peripheral tolerance and immunosuppression elicited by the tumor.

Firstly, we detected circulating autoantibodies to MUC4 present in PC patients and observed that IgM autoantibodies ...


Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam Dec 2017

Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam

Theses & Dissertations

Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the United States, mainly due to metastasis to the distant organ sites. However, the molecular basis of CRC metastasis is poorly understood. Therefore, identification and characterization of novel potential anti-cancer therapeutic targets CRC is of urgent need. Utilizing a 2D-DIGE proteomics approach ezrin was identified as a protein that is differentially expressed between primary colon tumors xenografts, orthotopically implanted in athymic nude mice, and corresponding and liver metastatic deposits. Ezrin, a cytoskeletal protein belonging to the ezrin–radixin–moesin (ERM) family plays important roles in cell ...


Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego Dec 2017

Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancers with a 5-year survival rate of only 8.2%. This is because PDAC is diagnosed in its advanced stages and is characterized by radio and chemotherapy resistance. Aggressiveness of PDAC tumors is attributed to its high metabolic phenotype, which is characterized by increased glycolysis rate and lactate secretion, while oxidative metabolism is reduced. These metabolic features are required to fulfill the biosynthetic demands of proliferating PDAC cells. However, this increase in metabolic activity results in acidification of the extracellular space because the dense fibrotic stroma of PDAC tumors ...


Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl Jul 2017

Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl

Theses & Dissertations

Endocytic trafficking is not only an essential process for the maintenance of cellular homeostasis but also plays a vital role in regulating diverse cellular processes such as signaling, migration and cell division. The C-terminal Eps 15 Homology Domain proteins (EHD1-4) play pivotal roles in regulating distinct steps of endocytic trafficking. Among the EHDs, EHD2 is disparate both in terms of sequence homology (70%) and its subcellular localization at the caveolae. The crystal structure of EHD2 has been solved and it contains an unstructured loop consisting of two proline-phenylalanine (PF) motifs: KPFRKLNPF. However, the other paralogs EHD1, EHD3 ...


The Rise And Fall Of The Bovine Corpus Luteum, Heather Talbott May 2017

The Rise And Fall Of The Bovine Corpus Luteum, Heather Talbott

Theses & Dissertations

This dissertation describes a study of the mechanisms regulating the genesis and subsequent involution of the temporary endocrine structure, the corpus luteum (CL), through the use of a bovine model. The CL is essential for maintaining a suitable uterine environment for embryo implantation and early development through secretion of the steroid hormone progesterone. The “Rise and Fall” of the CL occurs within each estrous cycle whereby the CL must form from the ruptured follicle, secrete sufficient progesterone for uterine maturation, and at the end of the cycle (or pregnancy) regress to allow new follicular development. During the rise of the ...


Defining The Role Of Phosphorylation And Dephosphorylation In The Regulation Of Gap Junction Proteins, Hanjun Li Dec 2016

Defining The Role Of Phosphorylation And Dephosphorylation In The Regulation Of Gap Junction Proteins, Hanjun Li

Theses & Dissertations

Gap junctions are intercellular channels that permit the free passage of ions, small metabolites, and signaling molecules between neighboring cells. In the diseased human heart, altered ventricular gap junction organization and connexin expression (i.e., remodeling) are key contributors to rhythm disturbances and contractile dysfunction. Connexin43 (Cx43) is the dominant gap junction protein isoform in the ventricle which is under tight regulation by serine/tyrosine phosphorylation. Phosphorylation and dephosphorylation regulate many aspects of Cx43 function including trafficking, assembly and disassembly, electrical and metabolic coupling at the plaque, as well as to modulate the interaction with other proteins.

Serine phosphorylation has ...


Dna Polymerase Zeta-Dependent Mutagenesis: Molecular Specificity, Extent Of Error-Prone Synthesis, And The Role Of Dntp Pools, Olga V. Kochenova Dec 2016

Dna Polymerase Zeta-Dependent Mutagenesis: Molecular Specificity, Extent Of Error-Prone Synthesis, And The Role Of Dntp Pools, Olga V. Kochenova

Theses & Dissertations

Despite multiple DNA repair pathways, DNA lesions can escape repair and compromise normal chromosomal replication, leading to genome instability. Cells utilize specialized low-fidelity Translesion Synthesis (TLS) DNA polymerases to bypass lesions and rescue arrested replication forks. TLS is a highly conserved two-step process that involves insertion of a nucleotide opposite a lesion and extension of the resulting aberrant primer terminus. The first step can be performed by both replicative and TLS DNA polymerases and, because of non-instructive DNA lesions, often results in a nucleotide misincorporation. The second step is almost exclusively catalyzed by DNA polymerase ζ ...


Regulation Of Alteration/Deficiency In Activation 3 (Ada3) By Acetylation And Its Role In Cell Cycle Regulation And Oncogenesis, Shashank Srivastava Dec 2016

Regulation Of Alteration/Deficiency In Activation 3 (Ada3) By Acetylation And Its Role In Cell Cycle Regulation And Oncogenesis, Shashank Srivastava

Theses & Dissertations

The ADA3 (Alteration/Deficiency in Activation 3) protein is a transcriptional adaptor protein that was initially discovered as a component of several HAT (Histone Acetyltransferase) complexes, the enzyme complex responsible for histone acetylation, which is a prerequisite for transcription. Earlier the studies from Dr. Band’s laboratory and that of others’ have deciphered a crucial role of ADA3 in cell cycle regulation (both through G1/S and G2/M phase transitions) and in maintaining the genomic stability.

While our laboratory investigated the mechanism behind the role of ADA3 in G1/S transition, the same remained unknown for ...


Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz Dec 2016

Mitogen And Morphogen Signaling Dysregulation: Pathophysiological Influence In Pancreatic Cancer And Alzheimer’S Disease, Eric Cruz

Theses & Dissertations

Although the etiology of a particular disease will vary, there are genetic and epigenetic bottlenecks that frequently converge resulting in dysregulation of mitogenic and morphogenetic signaling. This propensity is acutely experienced in malignancy and neurodegenerative disease.

Here, we have first investigated the role of dysregulated signaling in the context of pancreatic cancer (PC). Morphogenetic signaling has been regarded as a pleiotropic pathway with the potential to promote and inhibit metastatic features. Our investigation of bone morphogenetic protein 2 (BMP-2), an archetypical member of the BMP superfamily, has revealed the presence of extracellular, intracellular, and long non-coding RNA products. Our findings ...


Study Of The Structure-Related Functions Of Eukaryotic Primase-Pol Alpha Complex During Replication, Yinbo Zhang Aug 2016

Study Of The Structure-Related Functions Of Eukaryotic Primase-Pol Alpha Complex During Replication, Yinbo Zhang

Theses & Dissertations

During eukaryotic replication primase•polymerase α (prim•polα) complex synthesizes de novo chimeric primers composed of about 10 nt RNA and 20 nt DNA, which are subsequently extended by main replicative DNA polymerases (pol), polε and polδ, on leading and lagging strands, respectively. It is estimated that prim•polα initiates more than 10 millions of lagging strand Okazaki fragments in human genome in each replication cycle. A concerted action of the two active sites, RNA pol and DNA pol, is required to ensure the efficient priming. A remarkable feature of the prim•polα complex is the “programmed” synthesis of the ...


Role Of Ddr1 In Pancreatic Cancer, Huocong Huang Aug 2016

Role Of Ddr1 In Pancreatic Cancer, Huocong Huang

Theses & Dissertations

Pancreatic ductal adenocarcinomas are highly malignant cancers, characterized by extensive invasion into surrounding tissues, metastasis to distant organs at a very early stage, and a limited response to therapy. One of the main features of pancreatic ductal adenocarcinomas is desmoplasia, which leads to extensive deposition of collagen I. We have demonstrated that collagen I can induce epithelial-mesenchymal transition (EMT) in pancreatic cancer cells. A hallmark of EMT is an increase in the expression of a mesenchymal cadherin, N-cadherin. Our previous studies have shown that up-regulation of N-cadherin can promote tumor cell invasion and that collagen I-induced EMT is through two ...


Exploitation Of The Ligand-Binding Properties Of The Mannose 6-Phosphate/Insulin-Like Growth Factor Ii (Igf-Ii) Receptor To Inhibit Igf-Ii-Dependent Growth Of Cancer Cells, Megan Zavorka Thomas May 2016

Exploitation Of The Ligand-Binding Properties Of The Mannose 6-Phosphate/Insulin-Like Growth Factor Ii (Igf-Ii) Receptor To Inhibit Igf-Ii-Dependent Growth Of Cancer Cells, Megan Zavorka Thomas

Theses & Dissertations

The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) is a multifunctional, type I transmembrane receptor that is a member of the P-type lectin family. A large, extracytoplasmic (EC) region of the M6P/IGF2R binds various ligands, allowing the receptor to regulate multiple biological functions, including the role as a tumor suppressor. Two major classes of ligands, M6P-glycosylated (i.e. any proteins that bear M6P due to post-translational modification in the trans-Golgi network (TGN)) and non-glycosylated (i.e., the mitogen insulin-like growth factor II (IGF-II)), bind within distinct regions of the EC of the receptor and are trafficked to ...


Molecular Mechanisms Regulating Myc And Pgc1Β Expression In Colon Cancer, Jamie L. Mccall May 2016

Molecular Mechanisms Regulating Myc And Pgc1Β Expression In Colon Cancer, Jamie L. Mccall

Theses & Dissertations

Identification and characterization of pathways specific to tumor cell survival, but absent in normal tissues, provide opportunities to develop effective cancer therapies with reduced toxicity to the patient. Kinase suppressor of Ras 1 (KSR1) is required for the survival of colorectal cancer (CRC) cells, but dispensable in normal cells. Using KSR1 as a reference standard, we identified EPH (erythropoietin-producing hepatocellular carcinoma) receptor (EPHB4) as a KSR1 functional analog.

We show here that, like KSR1, EPHB4 is aberrantly overexpressed in human CRC cells and selectively required for their survival. Both KSR1 and EPHB4 support tumor cell survival by promoting the expression ...


Role Of Stemloop D In Terminally Deleted Coxsackievirus B3 Replication, Lee K. Jaramillo May 2016

Role Of Stemloop D In Terminally Deleted Coxsackievirus B3 Replication, Lee K. Jaramillo

Theses & Dissertations

Coxsackievirus B3 (CVB3) is an enterovirus with no known form of latency. However, assays designed to detect enteroviral RNA have shown that CVB3 RNA can persist for weeks beyond the acute infection both naturally and experimentally. Our previous work with coxsackievirus revealed an inhibited version of enteroviral replication where the progeny virus, termed terminally deleted (TD) virus, was missing a maximum of 49 nucleotides from the beginning of the 5’ non-translated region (NTR). The largest terminally deleted virus, TD50, effaced stem a, stemloop b, and stemloop c from the secondary structure, the cloverleaf. We hypothesized that further deletion beyond those ...


Secretory Mucin Muc5ac In Gastrointestinal Malignancies, Shiv Ram Krishn May 2016

Secretory Mucin Muc5ac In Gastrointestinal Malignancies, Shiv Ram Krishn

Theses & Dissertations

Secretory mucin MUC5AC is an extensively glycosylated high molecular weight protein that forms a polymeric gel layer over the epithelial layers under physiological conditions, to protect these surfaces from myriad of insults. MUC5AC is known to be implicated in various malignancies including pancreatic cancer and colorectal cancer. MUC5AC is overexpressed in pancreatic cancer compared to no expression in normal pancreas. However, its functional implications and associated mechanistic basis in pancreatic cancer remains obscure. Therefore, we investigated the role of MUC5AC in onset and progression of pancreatic cancer. Our study showed that MUC5AC expression is elevated during pancreatic cancer progression while ...


Control Of The Basal Recycling And Surface Expression Of Epidermal Growth Factor Receptor By The Endocytic Recycling Regulator Ehd1 Utilizing A Pathway Shared By Rusc2, Eric Tom Dec 2015

Control Of The Basal Recycling And Surface Expression Of Epidermal Growth Factor Receptor By The Endocytic Recycling Regulator Ehd1 Utilizing A Pathway Shared By Rusc2, Eric Tom

Theses & Dissertations

The epidermal growth factor receptor (EGFR) is a prototype receptor tyrosine kinase (RTK) and oncogene aberrantly expressed or mutated in solid tumors. Its surface expression is dynamically regulated. Display of an activation-competent pool is essential for response to ligands. Internalization and degradation of EGFR following stimulation has received the most attention, fewer studies have characterized the recycling arm of EGFR transit, basal traffic and surface display are poorly understood. Thus, we evaluated the endocytic recycling of EGFR for its therapeutic potential in EGFR driven cancers. The C-Terminal Eps15 homology (EH) domain-containing proteins have emerged as regulators of surface receptor recycling ...


Regulation Of The Transmembrane Mucin Muc4 By Wnt/Β-Catenin In Gastrointestinal Cancers, Priya Pai Dec 2015

Regulation Of The Transmembrane Mucin Muc4 By Wnt/Β-Catenin In Gastrointestinal Cancers, Priya Pai

Theses & Dissertations

The transmembrane mucin MUC4 is a high molecular weight glycoprotein that is expressed de novo in pancreatic ductal adenocarcinoma (PDAC). MUC4 has been shown to play a tumor-promoting role in malignancies such as PDAC, ovarian cancer and breast cancer. Unlike the normal pancreas, MUC4 is ordinarily expressed by goblet and absorptive cells in the normal colonic epithelium. However, its expression/role in colorectal cancer (CRC) is not well studied.

In this dissertation, the goal was to identify factor(s) that may differentially regulate MUC4 in these two disparate malignancies. Furthermore, in light of its pro-tumorigenic role in other malignancies, we ...


Transcriptional And Post-Transcriptional Regulation Of Hepcidin And Iron Metabolism By Lipid Signaling In The Liver, Sizhao Lu Aug 2015

Transcriptional And Post-Transcriptional Regulation Of Hepcidin And Iron Metabolism By Lipid Signaling In The Liver, Sizhao Lu

Theses & Dissertations

Although iron is required for essential biological processes, excess iron is detrimental due to oxidative damage induced by iron-mediated Fenton reactions, which promote tissue injury. Cellular iron uptake, transport and storage must therefore be tightly regulated. This task is accomplished mainly through hepcidin, the key iron-regulatory hormone. Hepcidin is synthesized primarily in hepatocytes as a circulatory antimicrobial peptide. It controls iron metabolism by inhibiting iron absorption from the duodenum and iron release from reticuloendothelial macrophages. Besides synthesizing hepcidin, the liver plays an important role in maintaining iron homeostasis by serving as the main storage organ for excess iron. Patients with ...


Altered Cd161bright Cd8+ Mucosal Associated Invariant T (Mait)-Like Cell Dynamics And Increased Differentiation States Among Juvenile Type 1 Diabetics., Robert Z. Harms, Kristina M. Lorenzo, Kevin P. Corley, Monina S. Cabrera, Nora Sarvetnick Jan 2015

Altered Cd161bright Cd8+ Mucosal Associated Invariant T (Mait)-Like Cell Dynamics And Increased Differentiation States Among Juvenile Type 1 Diabetics., Robert Z. Harms, Kristina M. Lorenzo, Kevin P. Corley, Monina S. Cabrera, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Type 1A diabetes (T1D) is believed to be caused by immune-mediated destruction of β-cells, but the immunological basis for T1D remains controversial. Microbial diversity promotes the maturation and activation of certain immune subsets, including CD161bright CD8+ mucosal associated invariant T (MAIT) cells, and alterations in gut mucosal responses have been reported in type 1 diabetics (T1Ds). We analyzed T cell populations in peripheral blood leukocytes from juvenile T1Ds and healthy controls. We found that proportion and absolute number of MAIT cells were similar between T1Ds and controls. Furthermore, while MAIT cell proportions increased with age among healthy controls, this trend ...


Methamphetamine Administration Targets Multiple Immune Subsets And Induces Phenotypic Alterations Suggestive Of Immunosuppression., Robert Z. Harms, Brenda M. Morsey, Craig W. Boyer, Howard S. Fox, Nora E. Sarvetnick Jan 2012

Methamphetamine Administration Targets Multiple Immune Subsets And Induces Phenotypic Alterations Suggestive Of Immunosuppression., Robert Z. Harms, Brenda M. Morsey, Craig W. Boyer, Howard S. Fox, Nora E. Sarvetnick

Journal Articles: Regenerative Medicine

Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1(high) monocytes/macrophages were also decreased in abundance while Gr-1 ...


Differential Il-21 Signaling In Apcs Leads To Disparate Th17 Differentiation In Diabetes-Susceptible Nod And Diabetes-Resistant Nod.Idd3 Mice., Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo Nov 2011

Differential Il-21 Signaling In Apcs Leads To Disparate Th17 Differentiation In Diabetes-Susceptible Nod And Diabetes-Resistant Nod.Idd3 Mice., Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo

Journal Articles: Regenerative Medicine

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with ...


The Incidence Of Type-1 Diabetes In Nod Mice Is Modulated By Restricted Flora Not Germ-Free Conditions., Cecile King, Nora Sarvetnick Jan 2011

The Incidence Of Type-1 Diabetes In Nod Mice Is Modulated By Restricted Flora Not Germ-Free Conditions., Cecile King, Nora Sarvetnick

Journal Articles: Regenerative Medicine

In the NOD mouse, the incidence of type-1 diabetes is thought to be influenced by the degree of cleanliness of the mouse colony. Studies collectively demonstrate that exposure to bacterial antigen or infection in the neonatal period prevents diabetes [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], supporting the notion that immunostimulation can benefit the maturation of the postnatal immune system [11]. A widely accepted extrapolation from this data has been the notion that NOD mice maintained under germ-free conditions have an increased incidence of diabetes. However, evidence supporting this influential concept is surprisingly limited [12]. In this ...


Il-21 Limits Peripheral Lymphocyte Numbers Through T Cell Homeostatic Mechanisms., Shrimati Datta, Nora E. Sarvetnick Jan 2008

Il-21 Limits Peripheral Lymphocyte Numbers Through T Cell Homeostatic Mechanisms., Shrimati Datta, Nora E. Sarvetnick

Journal Articles: Regenerative Medicine

BACKGROUND: IL-21, a member of the common gamma-chain utilizing family of cytokines, participates in immune and inflammatory processes. In addition, the cytokine has been linked to autoimmunity in humans and rodents.

METHODOLOGY/PRINCIPAL FINDINGS: To investigate the mechanism whereby IL-21 affects the immune system, we investigated its role in T cell homeostasis and autoimmunity in both non-autoimmune C57BL/6 and autoimmune NOD mice. Our data indicate that IL-21R knockout C57BL/6 and NOD mice show increased size of their lymphocyte population and decreased homeostatic proliferation. In addition, our experimental results demonstrate that IL-21 inhibits T cell survival. These data suggest ...


Resistance Of The Target Islet Tissue To Autoimmune Destruction Contributes To Genetic Susceptibility In Type 1 Diabetes., Natasha J. Hill, Aleksandr Stotland, Michelle Solomon, Patrick Secrest, Elizabeth Getzoff, Nora Sarvetnick Jan 2007

Resistance Of The Target Islet Tissue To Autoimmune Destruction Contributes To Genetic Susceptibility In Type 1 Diabetes., Natasha J. Hill, Aleksandr Stotland, Michelle Solomon, Patrick Secrest, Elizabeth Getzoff, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Type 1 diabetes occurs when self-reactive T lymphocytes destroy the insulin-producing islet beta cells of the pancreas. The defects causing this disease have often been assumed to occur exclusively in the immune system. We present evidence that genetic variation at the Idd9 diabetes susceptibility locus determines the resilience of the targets of autoimmunity, the islets, to destruction. Susceptible islets exhibit hyper-responsiveness to inflammatory cytokines resulting in enhanced cell death and increased expression of the death receptor Fas. Fas upregulation in beta cells is mediated by TNFR2, and colocalization of TNFR2 with the adaptor TRAF2 in NOD beta cells is altered ...


Identification And Expansion Of Pancreatic Stem/Progenitor Cells., You-Qing Zhang, Marcie Kritzik, Nora Sarvetnick Apr 2005

Identification And Expansion Of Pancreatic Stem/Progenitor Cells., You-Qing Zhang, Marcie Kritzik, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Pancreatic islet transplantation represents an attractive approach for the treatment of diabetes. However, the limited availability of donor islets has largely hampered this approach. In this respect, the use of alternative sources of islets such as the ex vivo expansion and differentiation of functional endocrine cells for treating diabetes has become the major focus of diabetes research. Adult pancreatic stem cells /progenitor cells have yet to be recognized because limited markers exist for their identification. While the pancreas has the capacity to regenerate under certain circumstances, questions where adult pancreatic stem/progenitor cells are localized, how they are regulated, and ...


The Stromal Cell-Derived Factor-1alpha/Cxcr4 Ligand-Receptor Axis Is Critical For Progenitor Survival And Migration In The Pancreas., Ayse G. Kayali, Kurt Van Gunst, Iain L. Campbell, Aleksandr Stotland, Marcie Kritzik, Guoxun Liu, Malin Flodström-Tullberg, You-Qing Zhang, Nora Sarvetnick Nov 2003

The Stromal Cell-Derived Factor-1alpha/Cxcr4 Ligand-Receptor Axis Is Critical For Progenitor Survival And Migration In The Pancreas., Ayse G. Kayali, Kurt Van Gunst, Iain L. Campbell, Aleksandr Stotland, Marcie Kritzik, Guoxun Liu, Malin Flodström-Tullberg, You-Qing Zhang, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The SDF-1alpha/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1alpha and CXCR4 expression in fetal pancreas. We have found that SDF-1alpha and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) gamma-nonobese diabetic mouse. We show that SDF-1alpha stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1alpha on ductal cell migration ...


Ccr4-Bearing T Cells Participate In Autoimmune Diabetes., Soon H. Kim, Mary M. Cleary, Howard S. Fox, Icos Coporation, Nora Sarvetnick Dec 2002

Ccr4-Bearing T Cells Participate In Autoimmune Diabetes., Soon H. Kim, Mary M. Cleary, Howard S. Fox, Icos Coporation, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Chemokine receptor expression is exquisitely regulated on T cell subsets during the course of their migration to inflammatory sites. In the present study we demonstrate that CCR4 expression marks a pathogenic population of autoimmune T cells. CCR4 was found exclusively on memory CD4(+) T cells during the progression of disease in NOD mice. Cells expressing the CCR4 ligand TARC (thymus- and activation-regulated chemokine) were detected within infiltrated islets from prediabetic mice. Interestingly, neutralization of macrophage-derived chemokine (MDC) with Ab caused a significant reduction of CCR4-positive T cells within the pancreatic infiltrates and inhibited the development of insulitis and diabetes. Furthermore ...


Presented Antigen From Damaged Pancreatic Beta Cells Activates Autoreactive T Cells In Virus-Mediated Autoimmune Diabetes., Marc S. Horwitz, Alex Ilic, Cody Fine, Enrique Rodriguez, Nora Sarvetnick Jan 2002

Presented Antigen From Damaged Pancreatic Beta Cells Activates Autoreactive T Cells In Virus-Mediated Autoimmune Diabetes., Marc S. Horwitz, Alex Ilic, Cody Fine, Enrique Rodriguez, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The induction of autoimmunity by viruses has been attributed to numerous mechanisms. In mice, coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) resembling the final step of disease progression in humans. The immune response following the viral insult clearly precipitates IDDM. However, the molecular pathway between viral infection and the subsequent activation of T cells specific for islet antigen has not been elucidated. These T cells could become activated through exposure to sequestered antigens released by damaged beta cells, or they could have responded to factors secreted by the inflammatory response itself. To distinguish between these possibilities, we treated mice ...


A Defect In Interleukin 12-Induced Activation And Interferon Gamma Secretion Of Peripheral Natural Killer T Cells In Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms For Insulin-Dependent Diabetes Mellitus., Marika Falcone, Brian Yeung, Lee Tucker, Enrique Rodriguez, Nora Sarvetnick Oct 1999

A Defect In Interleukin 12-Induced Activation And Interferon Gamma Secretion Of Peripheral Natural Killer T Cells In Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms For Insulin-Dependent Diabetes Mellitus., Marika Falcone, Brian Yeung, Lee Tucker, Enrique Rodriguez, Nora Sarvetnick

Journal Articles: Regenerative Medicine

The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell-mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion ...


Interferon Gamma (Ifn-Gamma) Is Necessary For The Genesis Of Acetylcholine Receptor-Induced Clinical Experimental Autoimmune Myasthenia Gravis In Mice., Balaji Balasa, Caishu Deng, Jae Lee, Linda M. Bradley, Dyanna K. Dalton, Premkumar Christadoss, Nora Sarvetnick Aug 1997

Interferon Gamma (Ifn-Gamma) Is Necessary For The Genesis Of Acetylcholine Receptor-Induced Clinical Experimental Autoimmune Myasthenia Gravis In Mice., Balaji Balasa, Caishu Deng, Jae Lee, Linda M. Bradley, Dyanna K. Dalton, Premkumar Christadoss, Nora Sarvetnick

Journal Articles: Regenerative Medicine

Experimental autoimmune myasthenia gravis (EAMG) is an animal model of human myasthenia gravis (MG). In mice, EAMG is induced by immunization with Torpedo californica acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA). However, the role of cytokines in the pathogenesis of EAMG is not clear. Because EAMG is an antibody-mediated disease, it is of the prevailing notion that Th2 but not Th1 cytokines play a role in the pathogenesis of this disease. To test the hypothesis that the Th1 cytokine, interferon (IFN)-gamma, plays a role in the development of EAMG, we immunized IFN-gamma knockout (IFN-gko) (-/-) mice and wild-type ...