Medical Specialties Commons^™

Renin Inhibition Reduces Hypercholesterolemia-Induced Atherosclerosis In Mice, Hong Lu, Debra L. Rateri, David L. Feldman, Richard Charnigo, Akiyoshi Fukamizu, Junji Ishida, Elizabeth Grace Oesterling, Lisa A. Cassis, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr^-/-) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in …

Preimplantation Embryo Programming: Transcription, Epigenetics, And Culture Environment., Veronique Duranthon, Andrew J Watson, Patrick Lonergan

Obstetrics & Gynaecology Publications

Preimplantation development directs the formation of an implantation- or attachment-competent embryo so that metabolic interactions with the uterus can occur, pregnancy can be initiated, and fetal development can be sustained. The preimplantation embryo exhibits a form of autonomous development fueled by products provided by the oocyte and also from activation of the embryo's genome. Despite this autonomy, the preimplantation embryo is highly influenced by factors in the external environment and in extreme situations, such as those presented by embryo culture or nuclear transfer, the ability of the embryo to adapt to the changing environmental conditions or chromatin to become reprogrammed …

Nitrated Alpha-Synuclein Immunity Accelerates Degeneration Of Nigral Dopaminergic Neurons., Eric J. Benner, Rebecca Banerjee, Ashley D. Reynolds, Simon Sherman, Vladimir M. Pisarev, Vladislav Tsiperson, Craig Nemachek, Pawel Ciborowski, Serge Przedborski, R. Lee Mosley, Howard Gendelman

Journal Articles: Eppley Institute

BACKGROUND: The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration.

METHODS AND FINDINGS: Nitrotyrosine (NT)-modified alpha-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN …

Novel Implications Of The Kallikrein-Kinin System In Diabetic Vasculopathy: A Proposed Role Of Prekallikrein In The Causation And Development Of Vascular Pathology In Diabetics, Rany Abdallah

MUSC Theses and Dissertations

Despite the clear association between diabetes and atherosclerotic vascular disease, the factors and mechanisms underlying the association between the two diseases are not well understood. Our preliminary studies, based on data obtained from the national Diabetes Control and Complication Trial/Epidemiology of Diabetes and Complications (DCCT/EDIC) cohort of type 1 diabetes subjects, suggest that diabetic atherosclerosis is linked to defects in the Kallikrein-Kinin System (KKS). Our research also found that apoliporotein E (ApoE) knockout mice, which have marked increase in total plasma cholesterol levels and a higher number of atherosclerotic lesions compared to wild type mice, have markedly higher plasma prekallikrein …

Large Scale Variation In Enterococcus Faecalis Illustrated By The Genome Analysis Of Strain Og1rf, Agathe Bourgogne, Danielle A Garsin, Xiang Qin, Kavindra V Singh, Jouko Sillanpaa, Shailaja Yerrapragada, Yan Ding, Shannon Dugan-Rocha, Christian Buhay, Hua Shen, Guan Chen, Gabrielle Williams, Donna Muzny, Arash Maadani, Kristina A Fox, Jason Gioia, Lei Chen, Yue Shang, Cesar A Arias, Sreedhar R Nallapareddy, Meng Zhao, Vittal P Prakash, Shahreen Chowdhury, Huaiyang Jiang, Richard A Gibbs, Barbara E Murray, Sarah K Highlander, George M Weinstock

Faculty, Staff and Student Publications

BACKGROUND: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies.

RESULTS: The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence …

Sr-Bi Protects Against Endotoxemia In Mice Through Its Roles In Glucocorticoid Production And Hepatic Clearance, Lei Cai, Ailing Ji, Frederick C. De Beer, Lisa R. Tannock, Deneys R. Van Der Westhuyzen

Internal Medicine Faculty Publications

Septic shock results from an uncontrolled inflammatory response, mediated primarily by LPS. Cholesterol transport plays an important role in the host response to LPS, as LPS is neutralized by lipoproteins and adrenal cholesterol uptake is required for antiinflammatory glucocorticoid synthesis. In this study, we show that scavenger receptor B-I (SR-BI), an HDL receptor that mediates HDL cholesterol ester uptake into cells, is required for the normal antiinflammatory response to LPS-induced endotoxic shock. Despite elevated plasma HDL levels, SR-BI–null mice displayed an uncontrollable inflammatory cytokine response and a markedly higher lethality rate than control mice in response to LPS. In addition, …

Elucidating A Normal Function Of Huntingtin By Functional And Microarray Analysis Of Huntingtin-Null Mouse Embryonic Fibroblasts., Hua Zhang, Sudipto Das, Quan-Zhen Li, Ioannis Dragatsis, Joyce Repa, Scott Zeitlin, György Hajnóczky, Ilya Bezprozvanny

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: The polyglutamine expansion in huntingtin (Htt) protein is a cause of Huntington's disease (HD). Htt is an essential gene as deletion of the mouse Htt gene homolog (Hdh) is embryonic lethal in mice. Therefore, in addition to elucidating the mechanisms responsible for polyQ-mediated pathology, it is also important to understand the normal function of Htt protein for both basic biology and for HD. RESULTS: To systematically search for a mouse Htt function, we took advantage of the Hdh +/- and Hdh-floxed mice and generated four mouse embryonic fibroblast (MEF) cells lines which contain a single copy of the Hdh …

Cyan Fluorescent Protein Expression In Ganglion And Amacrine Cells In A Thy1-Cfp Transgenic Mouse Retina, Iona D Raymond, Alejandro Vila, Uyen-Chi N Huynh, Nicholas C Brecha

Faculty, Staff and Student Publications

PURPOSE: To characterize cyan fluorescent protein (CFP) expression in the retina of the thy1-CFP (B6.Cg-Tg(Thy1-CFP)23Jrs/J) transgenic mouse line.

METHODS: CFP expression was characterized using morphometric methods and immunohistochemistry with antibodies to neurofilament light (NF-L), neuronal nuclei (NeuN), POU-domain protein (Brn3a) and calretinin, which immunolabel ganglion cells, and syntaxin 1 (HPC-1), glutamate decarboxylase 67 (GAD(67)), GABA plasma membrane transporter-1 (GAT-1), and choline acetyltransferase (ChAT), which immunolabel amacrine cells.

RESULTS: CFP was extensively expressed in the inner retina, primarily in the inner plexiform layer (IPL), ganglion cell layer (GCL), nerve fiber layer, and optic nerve. CFP fluorescent cell bodies were in all …

Application Of In Vivo Induced Antigen Technology (Iviat) To Bacillus Anthracis, Sean M Rollins, Amanda Peppercorn, John S Young, Melissa Drysdale, Andrea Baresch, Margaret V Bikowski, David A Ashford, Conrad P Quinn, Martin Handfield, Jeffrey D Hillman, C Rick Lyons, Theresa M Koehler, Stephen B Calderwood, Edward T Ryan

Faculty, Staff and Student Publications

In vivo induced antigen technology (IVIAT) is an immuno-screening technique that identifies bacterial antigens expressed during infection and not during standard in vitro culturing conditions. We applied IVIAT to Bacillus anthracis and identified PagA, seven members of a N-acetylmuramoyl-L-alanine amidase autolysin family, three P60 family lipoproteins, two transporters, spore cortex lytic protein SleB, a penicillin binding protein, a putative prophage holin, respiratory nitrate reductase NarG, and three proteins of unknown function. Using quantitative real-time PCR comparing RNA isolated from in vitro cultured B. anthracis to RNA isolated from BALB/c mice infected with virulent Ames strain B. anthracis, we confirmed induced …

Mice Deficient In Involucrin, Envoplakin, And Periplakin Have A Defective Epidermal Barrier., Lisa M Sevilla, Rachida Nachat, Karen R Groot, John F Klement, Jouni Uitto, Philippe Djian, Arto Määttä, Fiona M Watt

Department of Dermatology and Cutaneous Biology Faculty Papers

The cornified envelope is assembled from transglutaminase cross-linked proteins and lipids in the outermost epidermal layers and is essential for skin barrier function. Involucrin, envoplakin, and periplakin form the protein scaffold on which the envelope assembles. To examine their combined function, we generated mice deficient in all three genes. The triple knockouts have delayed embryonic barrier formation and postnatal hyperkeratosis (abnormal accumulation of cornified cells) resulting from impaired desquamation. Cornified envelopes form but are ultrastructurally abnormal, with reduced lipid content and decreased mechanical integrity. Expression of proteases is reduced and the protease inhibitor, serpina1b, is highly upregulated, resulting in defective …

Human Tob, An Antiproliferative Transcription Factor, Is A Poly(A)-Binding Protein-Dependent Positive Regulator Of Cytoplasmic Mrna Deadenylation, Nader Ezzeddine, Tsung-Cheng Chang, Wenmiao Zhu, Akio Yamashita, Chyi-Ying A Chen, Zhenping Zhong, Yukiko Yamashita, Dinghai Zheng, Ann-Bin Shyu

Faculty, Staff and Student Publications

In mammalian cells, mRNA decay begins with deadenylation, which involves two consecutive phases mediated by the PAN2-PAN3 and the CCR4-CAF1 complexes, respectively. The regulation of the critical deadenylation step and its relationship with RNA-processing bodies (P-bodies), which are thought to be a site where poly(A)-shortened mRNAs get degraded, are poorly understood. Using the Tet-Off transcriptional pulsing approach to investigate mRNA decay in mouse NIH 3T3 fibroblasts, we found that TOB, an antiproliferative transcription factor, enhances mRNA deadenylation in vivo. Results from glutathione S-transferase pull-down and coimmunoprecipitation experiments indicate that TOB can simultaneously interact with the poly(A) nuclease complex CCR4-CAF1 and …

Relative Contributions Of Enterococcus Faecalis Og1rf Sortase-Encoding Genes, Srta And Bps (Srtc), To Biofilm Formation And A Murine Model Of Urinary Tract Infection, Kelvin D Kemp, Kavindra V Singh, Sreedhar R Nallapareddy, Barbara E Murray

Faculty, Staff and Student Publications

Deletion mutants of the two sortase genes of Enterococcus faecalis OG1RF were constructed. srtC (renamed here bps for biofilm and pilus-associated sortase) was previously shown to be necessary for the production of Ebp pili and important for biofilm formation and endocarditis. Here, we report that a srtA deletion mutant showed a small (5%) yet significant (P = 0.037) reduction in biofilm relative to OG1RF, while a DeltasrtA Deltabps double mutant showed a much greater reduction (74% versus OG1RF and 44% versus the Deltabps mutant). In a murine urinary tract infection (UTI), the 50% infective doses of both the DeltasrtA Deltabps …

Computational Identification And Functional Validation Of Regulatory Motifs In Cartilage-Expressed Genes, Sherri R Davies, Li-Wei Chang, Debabrata Patra, Xiaoyun Xing, Karen Posey, Jacqueline Hecht, Gary D Stormo, Linda J Sandell

Faculty, Staff and Student Publications

Chondrocyte gene regulation is important for the generation and maintenance of cartilage tissues. Several regulatory factors have been identified that play a role in chondrogenesis, including the positive transacting factors of the SOX family such as SOX9, SOX5, and SOX6, as well as negative transacting factors such as C/EBP and delta EF1. However, a complete understanding of the intricate regulatory network that governs the tissue-specific expression of cartilage genes is not yet available. We have taken a computational approach to identify cis-regulatory, transcription factor (TF) binding motifs in a set of cartilage characteristic genes to better define the transcriptional regulatory …

Pp2cdelta (Ppm1d, Wip1), An Endogenous Inhibitor Of P38 Mapk, Is Regulated Along With Trp53 And Cdkn2a Following P38 Mapk Inhibition During Mouse Preimplantation Development., Jenny A Hickson, Barry Fong, Patricia H Watson, Andrew J Watson

Obstetrics & Gynaecology Publications

Preimplantation embryos utilize mitogen-activated protein kinase signaling (MAPK) pathways to relay signals from the external environment to prepare appropriate responses and adaptations to a changing milieu. It is therefore important to investigate how MAPK pathways are regulated during preimplantation development. This study was conducted to investigate whether PP2Cdelta (Ppm1d, WIP1) is expressed during mouse preimplantation development and to determine the influences of p38 MAPK inhibition on expression of Trp53 (p53), Ppm1d, (WIP1), and Cdkn2a (p16) during mouse preimplantation development. Our results indicate that Trp53, Ppm1d, and Cdkn2a mRNAs and TRP53 and PP2Cdelta proteins are expressed throughout mouse preimplantation development. Treatment …

Neural Reprogramming In Retinal Degeneration, Robert E Marc, Bryan W Jones, James R Anderson, Krista Kinard, David W Marshak, John H Wilson, Theodore Wensel, Robert J Lucas

Faculty, Staff and Student Publications

PURPOSE: Early visual defects in degenerative diseases such as retinitis pigmentosa (RP) may arise from phased remodeling of the neural retina. The authors sought to explore the functional expression of ionotropic (iGluR) and group 3, type 6 metabotropic (mGluR6) glutamate receptors in late-stage photoreceptor degeneration.

METHODS: Excitation mapping with organic cations and computational molecular phenotyping were used to determine whether retinal neurons displayed functional glutamate receptor signaling in rodent models of retinal degeneration and a sample of human RP.

RESULTS: After photoreceptor loss in rodent models of RP, bipolar cells lose mGluR6 and iGluR glutamate-activated currents, whereas amacrine and ganglion …

Quantitative Diffusion Tensor Imaging Detects Dopaminergic Neuronal Degeneration In A Murine Model Of Parkinson's Disease, Michael D Boska, Khader M Hasan, Danette Kibuule, Rebecca Banerjee, Erin Mcintyre, Jay A Nelson, Theresa Hahn, Howard E Gendelman, R Lee Mosley

Faculty, Staff and Student Publications

Early diagnosis of Parkinson's disease (PD) is required to improve therapeutic responses. Indeed, a clinical diagnosis of resting tremor, rigidity, movement and postural deficiencies usually reflect >50% loss of the nigrostriatal system in disease. In a step to address this, quantitative diffusion tensor magnetic resonance imaging (DTI) was used to assess nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication model of dopaminergic nigral degeneration. We now demonstrate increased average diffusion (p

The Flagellum Of Pseudomonas Aeruginosa Is Required For Resistance To Clearance By Surfactant Protein A, Shiping Zhang, Francis X. Mccormack, Roger C. Levesque, George A. O'Toole, Gee W. Lau

Dartmouth Scholarship

Surfactant protein A (SP-A) is an important lung innate immune protein that kills microbial pathogens by opsonization and membrane permeabilization. We investigated the basis of SP-A-mediated pulmonary clearance of Pseudomonas aeruginosa using genetically-engineered SP-A mice and a library of signature-tagged P. aeruginosa mutants. A mutant with an insertion into flgE, the gene that encodes flagellar hook protein, was preferentially cleared by the SP-A(+/+) mice, but survived in the SP-A(-/-) mice. Opsonization by SP-A did not play a role in flgE clearance. However, exposure to SP-A directly permeabilized and killed the flgE mutant, but not the wild-type parental strain. P. aeruginosa …

Importance Of The Ebp (Endocarditis- And Biofilm-Associated Pilus) Locus In The Pathogenesis Of Enterococcus Faecalis Ascending Urinary Tract Infection, Kavindra V Singh, Sreedhar R Nallapareddy, Barbara E Murray

Faculty, Staff and Student Publications

BACKGROUND: We recently demonstrated that the ubiquitous Enterococcus faecalis ebp (endocarditis- and biofilm-associated pilus) operon is important for biofilm formation and experimental endocarditis. Here, we assess its role in murine urinary tract infection (UTI) by use of wild-type E. faecalis OG1RF and its nonpiliated, ebpA allelic replacement mutant (TX5475).

METHODS: OG1RF and TX5475 were administered transurethrally either at an ~1 : 1 ratio (competition assay) or individually (monoinfection). Kidney pairs and urinary bladders were cultured 48 h after infection. These strains were also tested in a peritonitis model.

RESULTS: No differences were observed in the peritonitis model. In mixed UTIs, …

The Modifier Of Min 2 (Mom2) Locus: Embryonic Lethality Of A Mutation In The Atp5a1 Gene Suggests A Novel Mechanism Of Polyp Suppression., Amy A Baran, Karen A Silverman, Joseph Zeskand, Revati Koratkar, Ashley Palmer, Kristen Mccullen, Walter J Curran, Tina Bocker Edmonston, Linda D Siracusa, Arthur M Buchberg

Kimmel Cancer Center Faculty Papers

Inactivation of the APC gene is considered the initiating event in human colorectal cancer. Modifier genes that influence the penetrance of mutations in tumor-suppressor genes hold great potential for preventing the development of cancer. The mechanism by which modifier genes alter adenoma incidence can be readily studied in mice that inherit mutations in the Apc gene. We identified a new modifier locus of ApcMin-induced intestinal tumorigenesis called Modifier of Min 2 (Mom2). The polyp-resistant Mom2R phenotype resulted from a spontaneous mutation and linkage analysis localized Mom2 to distal chromosome 18. To obtain recombinant chromosomes for use in refining the Mom2 …

Na/K-Atpase Beta1 Subunit Expression Is Required For Blastocyst Formation And Normal Assembly Of Trophectoderm Tight Junction-Associated Proteins., Pavneesh Madan, Keeley Rose, Andrew J Watson

Obstetrics & Gynaecology Publications

Na/K-ATPase plays an important role in mediating blastocyst formation. Despite the expression of multiple Na/K-ATPase alpha and beta isoforms during mouse preimplantation development, only the alpha1 and beta1 isoforms have been localized to the basolateral membrane regions of the trophectoderm. The aim of the present study was to selectively down-regulate the Na/K-ATPase beta1 subunit employing microinjection of mouse 1 cell zygotes with small interfering RNA (siRNA) oligos. Experiments comprised of non-injected controls and two groups microinjected with either Stealthtrade mark Na/K-ATPase beta1 subunit oligos or nonspecific Stealthtrade mark siRNA as control. Development to the 2-, 4-, 8-, and 16-cell and …

Effects Of Low Dose Gm-Csf On Microglial Inflammatory Profiles To Diverse Pathogen-Associated Molecular Patterns (Pamps)., Nilufer Esen, Tammy Kielian

Journal Articles: Pathology and Microbiology

BACKGROUND: It is well appreciated that obtaining sufficient numbers of primary microglia for in vitro experiments has always been a challenge for scientists studying the biological properties of these cells. Supplementing culture medium with granulocyte-macrophage colony-stimulating factor (GM-CSF) partially alleviates this problem by increasing microglial yield. However, GM-CSF has also been reported to transition microglia into a dendritic cell (DC)-like phenotype and consequently, affect their immune properties.

METHODS: Although the concentration of GM-CSF used in our protocol for mouse microglial expansion (0.5 ng/ml) is at least 10-fold less compared to doses reported to affect microglial maturation and function (>/= …

The Nestin Progenitor Lineage Is The Compartment Of Origin For Pancreatic Intraepithelial Neoplasia, Catherine Carriere, Elliot S. Seeley, Tobias Goetze, Daniel S. Longnecker, Murray Korc

Dartmouth Scholarship

To determine the cell compartment in which initial oncogenic mutations occur in pancreatic ductal adenocarcinoma (PDAC), we generated a mouse model in which endogenous expression of mutated Kras (Kras(G12D)) was initially directed to a population of pancreatic exocrine progenitors characterized by the expression of Nestin. Targeting of oncogenic Kras to such a restricted cell compartment was sufficient for the formation of pancreatic intraepithelial neoplasias (PanINs), putative precursors to PDAC. PanINs appeared with the same grade and frequency as observed when Kras(G12D) was targeted to the whole pancreas by a Pdx1-driven Cre recombinase strategy. Thus, the Nestin cell lineage is highly …

Aldosterone-Induced Sgk1 Relieves Dot1a-Af9-Mediated Transcriptional Repression Of Epithelial Na+ Channel Alpha, Wenzheng Zhang, Xuefeng Xia, Mary Rose Reisenauer, Timo Rieg, Florian Lang, Dietmar Kuhl, Volker Vallon, Bruce C Kone

Faculty, Staff and Student Publications

Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases. Many aldosterone-regulated genes--including that encoding the epithelial Na+ channel (ENaC), a key arbiter of Na+ transport in the kidney and other epithelia--have been identified, but the mechanisms by which the hormone modifies chromatin structure and thus transcription remain unknown. We previously described the basal repression of ENaCalpha by a complex containing the histone H3 Lys79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) and the putative transcription factor ALL1-fused gene from chromosome 9 (Af9) as well as the release …

Mouse Preimplantation Embryo Responses To Culture Medium Osmolarity Include Increased Expression Of Ccm2 And P38 Mapk Activation., Barry Fong, Patricia H Watson, Andrew J Watson

Obstetrics & Gynaecology Publications

BACKGROUND: Mechanisms that confer an ability to respond positively to environmental osmolarity are fundamental to ensuring embryo survival during the preimplantation period. Activation of p38 mitogen-activated protein kinase (MAPK) occurs following exposure to hyperosmotic treatment. Recently, a novel scaffolding protein called Osmosensing Scaffold for MEKK3 (OSM) was linked to p38 MAPK activation in response to sorbitol-induced hypertonicity. The human ortholog of OSM is cerebral cavernous malformation 2 (CCM2). The present study was conducted to investigate whether CCM2 is expressed during mouse preimplantation development and to determine whether this scaffolding protein is associated with p38 MAPK activation following exposure of preimplantation …

Department Of Pathology, Thomas Jefferson University, Identification Of Conserved Gene Expression Features Between Murine Mammary Carcinoma Models And Human Breast Tumors., Jason I Herschkowitz, Karl Simin, Victor J Weigman, Igor Mikaelian, Jerry Usary, Zhiyuan Hu, Karen E Rasmussen, Laundette P Jones, Shahin Assefnia, Subhashini Chandrasekharan, Michael G Backlund, Yuzhi Yin, Andrey I Khramtsov, Roy Bastein, John Quackenbush, Robert I Glazer, Powel H Brown, Jeffrey E Green, Levy Kopelovich, Priscilla A Furth, Juan P Palazzo, Olufunmilayo I Olopade, Philip S Bernard, Gary A Churchill, Terry Van Dyke, Charles M Perou

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Although numerous mouse models of breast carcinomas have been developed, we do not know the extent to which any faithfully represent clinically significant human phenotypes. To address this need, we characterized mammary tumor gene expression profiles from 13 different murine models using DNA microarrays and compared the resulting data to those from human breast tumors. RESULTS: Unsupervised hierarchical clustering analysis showed that six models (TgWAP-Myc, TgMMTV-Neu, TgMMTV-PyMT, TgWAP-Int3, TgWAP-Tag, and TgC3(1)-Tag) yielded tumors with distinctive and homogeneous expression patterns within each strain. However, in each of four other models (TgWAP-T121, TgMMTV-Wnt1, Brca1Co/Co;TgMMTV-Cre;p53+/- and DMBA-induced), tumors with a variety of …

Proteomic Identification Of In Vivo Substrates For Matrix Metalloproteinases 2 And 9 Reveals A Mechanism For Resolution Of Inflammation, Kendra J Greenlee, David B Corry, David A Engler, Risë K Matsunami, Philippe Tessier, Richard G Cook, Zena Werb, Farrah Kheradmand

Faculty, Staff and Student Publications

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic …

Cdx4 Dysregulates Hox Gene Expression And Generates Acute Myeloid Leukemia Alone And In Cooperation With Meis1a In A Murine Model, Dimple Bansal, Claudia Scholl, Stefan Frohling, Elizabeth Mcdowell, Benjamin H. Lee, Konstanze Döhner, Patricia Ernst

Dartmouth Scholarship

HOX genes have emerged as critical effectors of leukemogenesis, but the mechanisms that regulate their expression in leukemia are not well understood. Recent data suggest that the caudal homeobox transcription factors CDX1, CDX2, and CDX4, developmental regulators of HOX gene expression, may contribute to HOX gene dysregulation in leukemia. We report here that CDX4 is expressed normally in early hematopoietic progenitors and is expressed aberrantly in approximately 25% of acute myeloid leukemia (AML) patient samples. Cdx4 regulates Hox gene expression in the adult murine hematopoietic system and dysregulates Hox genes that are implicated in leukemogenesis. Furthermore, bone marrow progenitors that …

P5l Mutation In Ank Results In An Increase In Extracellular Inorganic Pyrophosphate During Proliferation And Nonmineralizing Hypertrophy In Stably Transduced Atdc5 Cells, Raihana Zaka, David Stokes, Arnold S. Dion, Anna Kusnierz, Fei Han, Charlene J. Williams

Center for Translational Medicine Faculty Papers

Ank is a multipass transmembrane protein that regulates the cellular transport of inorganic pyrophosphate. In the progressive ankylosis (ank) mouse, a premature termination mutation at glutamic acid 440 results in a phenotype characterized by inappropriate deposition of basic calcium phosphate crystals in skeletal tissues. Mutations in the amino terminus of ANKH, the human homolog of Ank, result in familial calcium pyrophosphate dihydrate deposition disease. It has been hypothesized that these mutations result in a gain-of-function with respect to the elaboration of extracellular inorganic pyrophosphate. To explore this issue in a mineralization-competent system, we stably transduced ATDC5 cells with wild-type Ank …

Cd80 And Cd86 Control Antiviral Cd8+ T-Cell Function And Immune Surveillance Of Murine Gammaherpesvirus 68, Shinichiro Fuse, Joshua J. Obar, Sarah Bellfy, Erica K. Leung, Weijun Zhang, Edward J. Usherwood

Dartmouth Scholarship

The interactions between CD80 and CD86 on antigen-presenting cells and CD28 on T cells serve as an important costimulatory signal in the activation of T cells. Although the simplistic two-signal hypothesis has been challenged in recent years by the identification of different costimulators, this classical pathway has been shown to significantly impact antiviral humoral and cellular immune responses. How the CD80/CD86-CD28 pathway affects the control of chronic or latent infections has been less well characterized. In this study, we investigated its role in antiviral immune responses against murine gammaherpesvirus 68 (MHV-68) and immune surveillance using CD80/CD86^−/− mice. In the …

Role Of A2b Adenosine Receptor Signaling In Adenosine-Dependent Pulmonary Inflammation And Injury, Chun-Xiao Sun, Hongyan Zhong, Amir Mohsenin, Eva Morschl, Janci L Chunn, Jose G Molina, Luiz Belardinelli, Dewan Zeng, Michael R Blackburn

Faculty, Staff and Student Publications

Adenosine has been implicated in the pathogenesis of chronic lung diseases such as asthma and chronic obstructive pulmonary disease. In vitro studies suggest that activation of the A2B adenosine receptor (A2BAR) results in proinflammatory and profibrotic effects relevant to the progression of lung diseases; however, in vivo data supporting these observations are lacking. Adenosine deaminase-deficient (ADA-deficient) mice develop pulmonary inflammation and injury that are dependent on increased lung adenosine levels. To investigate the role of the A2BAR in vivo, ADA-deficient mice were treated with the selective A2BAR antagonist CVT-6883, and pulmonary inflammation, fibrosis, and airspace integrity were assessed. Untreated and …