Medical Pathology Commons^™

Heme Oxygenase-1 Regulates The Immune Response To Influenza Virus Infection And Vaccination In Aged Mice, Nathan W. Cummins, Eric A. Weaver, Shannon M. May, Anthony J. Croatt, Oded Foreman, Richard B. Kennedy, Gregory A. Polan, Michael A. Barry, Karl A. Nath, Andrew D. Badley

Nebraska Center for Virology: Faculty Publications

Underlying mechanisms of individual variation in severity of influenza infection and response to vaccination are poorly understood. We investigated the effect of reduced heme oxygenase-1 (HO-1) expression on vaccine response and outcome of influenza infection. HO-1-deficient and wild-type (WT) mice (kingdom, Animalia; phylum, Chordata; genus/species, Mus musculus) were infected with influenza virus A/PR/8/34 with or without prior vaccination with an adenoviral-based influenza vaccine. A genome-wide association study evaluated the expression of single-nucleotide polymorphisms (SNPs) in the HO-1 gene and the response to influenza vaccination in healthy humans. HO-1-deficient mice had decreased survival after influenza infection compared to WT mice (median …

Mir-145 Directly Targets P70s6k1 In Cancer Cells To Inhibit Tumor Growth And Angiogenesis., Qing Xu, Ling-Zhi Liu, Xu Qian, Qi Chen, Yue Jiang, Dan Li, Lihui Lai, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MiR-145 can regulate cell apoptosis, proliferation, neural development and stem cell differentiation. Previous studies indicate that miR-145 is downregulated in human colon cancer cells. However, the molecular mechanisms of miR-145 used to regulate colon carcinogenesis and angiogenesis remain to be clarified. Here, we show that the expression of miR-145 is downregulated in colon and ovarian cancer tissues and cell lines. MiR-145 inhibits p70S6K1 post-transcriptional expression by binding to its 3'-UTR. The angiogenic factors hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF), which are downstream molecules of p70S6K1, are decreased by miR-145 overexpression. P70S6K1 rescues miR-145-suppressed HIF-1 and VEGF …

Blood-Brain Barrier Abnormalities Caused By Hiv-1 Gp120: Mechanistic And Therapeutic Implications., Jean-Pierre Louboutin, David S Strayer

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and …

Graft Versus Host Disease Of The Brain Following Allogeneic Stem Cell Transplant For Myelodysplastic Syndrome, Janet Yoo, Lindsay Simon, Zi-Xuan Wang, Phd, Lawrence C. Kenyon

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Graft-versus-host disease (GVHD) is a frequent cause of morbidity and mortality following bone marrow transplantation (BMT). GVHD occurs when immune cells transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as foreign, thereby initiating an immune reaction that causes disease in the transplant recipient. GVHD, which can present either acutely or chronically, typically involves the skin, gastrointestinal tract, and liver. In contrast, GVHD involving other organs such as the heart and kidney is highly uncommon and involvement of the central nervous system has only very rarely been described in the literature. We report an unusual case …

Cop9 Signalosome Component Jab1/Csn5 Is Necessary For T Cell Signaling Through Lfa-1 And Hiv-1 Replication., Shigemi M Kinoshita, Peter O Krutzik, Garry P Nolan

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

To determine critical host factors involved in HIV-1 replication, a dominant effector genetics approach was developed to reveal signaling pathways on which HIV-1 depends for replication. A large library of short peptide aptamers was expressed via retroviral delivery in T cells. Peptides that interfered with T cell activation-dependent processes that might support HIV-1 replication were identified. One of the selected peptides altered signaling, lead to a difference in T cell activation status, and inhibited HIV-1 replication. The target of the peptide was JAB1/CSN5, a component of the signalosome complex. JAB1 expression overcame the inhibition of HIV-1 replication in the presence …

Knockdown Of Ki-67 By Dicer-Substrate Small Interfering Rna Sensitizes Bladder Cancer Cells To Curcumin-Induced Tumor Inhibition., Sivakamasundari Pichu, Swapna Krishnamoorthy, Andrei Shishkov, Bi Zhang, Peter Mccue, Biddanda C Ponnappa

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Transitional cell carcinoma (TCC) of the urinary bladder is the most common cancer of the urinary tract. Most of the TCC cases are of the superficial type and are treated with transurethral resection (TUR). However, the recurrence rate is high and the current treatments have the drawback of inducing strong systemic toxicity or cause painful cystitis. Therefore, it would be of therapeutic value to develop novel concepts and identify novel drugs for the treatment of bladder cancer. Ki-67 is a large nucleolar phosphoprotein whose expression is tightly linked to cell proliferation, and curcumin, a phytochemical derived from the rhizome Curcuma …

Decorin Protein Core Affects The Global Gene Expression Profile Of The Tumor Microenvironment In A Triple-Negative Orthotopic Breast Carcinoma Xenograft Model., Simone Buraschi, Thomas Neill, Rick T Owens, Leonardo A Iniguez, George Purkins, Rajanikanth Vadigepalli, Barry Evans, Liliana Schaefer, Stephen C Peiper, Zi-Xuan Wang, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that …

Kaempferol Nanoparticles Achieve Strong And Selective Inhibition Of Ovarian Cancer Cell Viability., Haitao Luo, Bingbing Jiang, Bingyun Li, Zhaoliang Li, Bing-Hua Jiang, Yi Charlie Chen

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ovarian cancer is one of the leading causes of cancer death for women throughout the Western world. Kaempferol, a natural flavonoid, has shown promise in the chemoprevention of ovarian cancer. A common concern about using dietary supplements for chemoprevention is their bioavailability. Nanoparticles have shown promise in increasing the bioavailability of some chemicals. Here we developed five different types of nanoparticles incorporating kaempferol and tested their efficacy in the inhibition of viability of cancerous and normal ovarian cells. We found that positively charged nanoparticle formulations did not lead to a significant reduction in cancer cell viability, whereas nonionic polymeric nanoparticles …

Temporal Changes In Innate Immune Signals In A Rat Model Of Alcohol Withdrawal In Emotional And Cardiorespiratory Homeostatic Nuclei., Kate Freeman, Anthony Brureau, Rajanikanth Vadigepalli, Mary M Staehle, Melanie M Brureau, Gregory E Gonye, Jan B Hoek, D Craig Hooper, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Chronic alcohol use changes the brain's inflammatory state. However, there is little work examining the progression of the cytokine response during alcohol withdrawal, a period of profound autonomic and emotional upset. This study examines the inflammatory response in the central nucleus of the amygdala (CeA) and dorsal vagal complex (DVC), brain regions neuroanatomically associated with affective and cardiorespiratory regulation in an in vivo rat model of withdrawal following a single chronic exposure.

METHODS: For qRT-PCR studies, we measured the expression of TNF-α, NOS-2, Ccl2 (MCP-1), MHC II invariant chain CD74, and the TNF receptor Tnfrsf1a in CeA and DVC …

Emergence Of Bimodal Cell Population Responses From The Interplay Between Analog Single-Cell Signaling And Protein Expression Noise., Marc R Birtwistle, Jens Rauch, Anatoly Kiyatkin, Edita Aksamitiene, Maciej Dobrzyński, Jan B. Hoek, Walter Kolch, Babatunde A Ogunnaike, Boris N Kholodenko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Cell-to-cell variability in protein expression can be large, and its propagation through signaling networks affects biological outcomes. Here, we apply deterministic and probabilistic models and biochemical measurements to study how network topologies and cell-to-cell protein abundance variations interact to shape signaling responses.

RESULTS: We observe bimodal distributions of extracellular signal-regulated kinase (ERK) responses to epidermal growth factor (EGF) stimulation, which are generally thought to indicate bistable or ultrasensitive signaling behavior in single cells. Surprisingly, we find that a simple MAPK/ERK-cascade model with negative feedback that displays graded, analog ERK responses at a single cell level can explain the experimentally …

Integrative Gene Regulatory Network Analysis Reveals Light-Induced Regional Gene Expression Phase Shift Programs In The Mouse Suprachiasmatic Nucleus., Haisun Zhu, Rajanikanth Vadigepalli, Rachel Rafferty, Gregory E Gonye, David R Weaver, James S Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We use the multigenic pattern of gene expression across suprachiasmatic nuclei (SCN) regions and time to understand the dynamics within the SCN in response to a circadian phase-resetting light pulse. Global gene expression studies of the SCN indicate that circadian functions like phase resetting are complex multigenic processes. While the molecular dynamics of phase resetting are not well understood, it is clear they involve a "functional gene expression program", e.g., the coordinated behavior of functionally related genes in space and time. In the present study we selected a set of 89 of these functionally related genes in order to further …

Utility Of Fdg Pet-Ct Scan In Determining Pathological Response To Neo-Adjuvant Chemo-Radiation Therapy In Non-Small Cell Lung Cancer (Nsclc), Eliot L. Friedman Md, Michael F. Szwerc Md, Robert Kruklitis Md, Michael J. Weiss Mph, Robert Rienzo Md, Wen Young Md

Department of Medicine

No abstract provided.

Cns Recruitment Of Cd8+ T Lymphocytes Specific For A Peripheral Virus Infection Triggers Neuropathogenesis During Polymicrobial Challenge., Christine M Matullo, Kevin J O'Regan, Mark Curtis, Glenn F Rall

Department of Microbiology and Immunology Faculty Papers

Although viruses have been implicated in central nervous system (CNS) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. Here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger CNS pathology. To test this idea, we utilized a transgenic mouse model in which we found that immune cells responding to a peripheral infection are recruited to the CNS, where they trigger neurological damage. In this model, mice are infected with …

Mutant Tdp-43 In Motor Neurons Promotes The Onset And Progression Of Als In Rats, Cao Huang, Jianbin Tong, Fangfang Bi, Hongxia Zhou, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration, which ultimately leads to paralysis and death. Mutation of TAR DNA binding protein 43 (TDP-43) has been linked to the development of an inherited form of ALS. Existing TDP-43 transgenic animals develop a limited loss of motor neurons and therefore do not faithfully reproduce the core phenotype of ALS. Here, we report the creation of multiple lines of transgenic rats in which expression of ALS-associated mutant human TDP-43 is restricted to either motor neurons or other types of neurons and skeletal muscle and can be switched on and off. …

The Role Of Receptor Tyrosine Kinase Axl In Pancreatic Ductal Adenocarcinoma And Its Regulation By Hematopoietic Progenitor Kinase 1, Xianzhou Song

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with less than 5% of five year survival rate. New molecular markers and new therapeutic targets are urgently needed for patients with PDA. Oncogenic receptor tyrosine kinase Axl has been reported to be overexpressed in many types of human malignancies, including diffuse glioma, melanoma, osteosarcoma, and carcinomas of lung, colon, prostate, breast, ovary, esophagus, stomach, and kidney. However, the expression and functions of Axl in PDA are unclear. We hypothesized that Axl contributes to the development and progression of PDA. We examined Axl expression in 54 human PDA samples …

Switches, Excitable Responses And Oscillations In The Ring1b/Bmi1 Ubiquitination System., Lan K Nguyen, Javier Muñoz-García, Helene Maccario, Aaron Ciechanover, Walter Kolch, Boris N Kholodenko

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

In an active, self-ubiquitinated state, the Ring1B ligase monoubiquitinates histone H2A playing a critical role in Polycomb-mediated gene silencing. Following ubiquitination by external ligases, Ring1B is targeted for proteosomal degradation. Using biochemical data and computational modeling, we show that the Ring1B ligase can exhibit abrupt switches, overshoot transitions and self-perpetuating oscillations between its distinct ubiquitination and activity states. These different Ring1B states display canonical or multiply branched, atypical polyubiquitin chains and involve association with the Polycomb-group protein Bmi1. Bistable switches and oscillations may lead to all-or-none histone H2A monoubiquitination rates and result in discrete periods of gene (in)activity. Switches, overshoots …

Characterization Of Palmitic Acid Induced Lipotoxicity In Schwann Cells, Amelia Padilla

Loma Linda University Electronic Theses, Dissertations & Projects

Lipotoxicity is a response to lipid overload that has been associated with cellular dysfunction leading to cellular death. The mechanism of lipotoxicity and its impact on the nervous system is critical as it can lead to debilitating neurological conditions. This study examines key cellular events induced by palmitic acid lipotoxicity (PA-LTx) in Schwann cells cultured in euglycemic and hyperglycemic conditions. The data show that immortalized Schwann cell (iSC), as well as primary Schwann cell (pSC) cultures exposed to elevated levels of PA induced an apoptotic cell death that is dose and time-dependent. The earliest indication of cellular dysfunction was a …

Hiv-1 Tat Protein Promotes Neuronal Dysfunction Through Disruption Of Micrornas, J Robert Chang, Ruma Mukerjee, Asen Bagashev, Luis Del Valle, Tinatin Chabrashvili, Brian J. Hawkins, Johnny J. He, Bassel E. Sawaya

School of Medicine Faculty Publications

Over the last decade, small noncoding RNA molecules such as microRNAs (miRNAs) have emerged as critical regulators in the expression and function of eukaryotic genomes. It has been suggested that viral infections and neurological disease outcome may also be shaped by the influence of small RNAs. This has prompted us to suggest that HIV infection alters the endogenous miRNA expression patterns, thereby contributing to neuronal deregulation and AIDS dementia. Therefore, using primary cultures and neuronal cell lines, we examined the impact of a viral protein (HIV-1 Tat) on the expression of miRNAs due to its characteristic features such as release …

Species D Adenoviruses As Oncolytics Against B-Cell Cancers, Christopher Y. Chen, Julien S. Senac, Eric A. Weaver, Shannon M. May, Diane F. Jelinek, Philip Greipp, Thomas Witzig, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Purpose: Oncolytic viruses are self-amplifying anticancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B-cell cancers because these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine whether other adenoviruses might have better potency, we "mined" the adenovirus virome of 55 serotypes for viruses that could kill B-cell cancers.

Experimental Design: Fifteen adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B-cell cancers …

Expression Of Cancer Stem Cell Biomarkers In Male Breast Cancer, Ping Gong, Md, Juan P. Palazzo, Md

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Male breast cancer is an uncommon disease, representing <1% of all breast cancer diagnoses. The prognostic factors and expression of molecular markers in male breast carcinomas are similar to female cancer. Cancer stem cell (CSC)s have been associated with tumor aggressiveness and drug resistance. CSCs are characterized by CD44 and/or ALDH1 expression. We investigated their expression in male breast cancer.

Deregulation Of Micrornas By Hiv-1 Vpr Protein Leads To The Development Of Neurocognitive Disorders, Ruma Mukerjee, J Robert Chang, Luis Del Valle, Asen Bagashev, Monika M. Gayed, Randolph B. Lyde, Brian J. Hawkins, Eugen Brailoiu, Eric Cohen, Chris Power, S Ausim Azizi, Benjamin B. Gelman, Bassel E. Sawaya

School of Medicine Faculty Publications

Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic …

A Non-Randomized, Observational Trial Of Short-Term Pre-Operative Endocrine Therapy In Er Positive Breast Cancer To Investigate Changes In Genomic Expression Using The Oncotype Dx® Recurrence Score®, Aaron D. Bleznak Md, Facs, Elizabeth A. Dellers Md, B G. Porter, Sharon R. Kimmel Phd, Mha, Heiwon Chung Md, Facs, Carl N. Yoshizawa, Emily Burke, D S. Davison, Calvin Chao

Department of Pathology & Laboratory Medicine

No abstract provided.

Rip1-Dependent And Independent Effects Of Necrostatin-1 In Necrosis And T Cell Activation., Youngsik Cho, Thomas Mcquade, Haibing Zhang, Jianke Zhang, Francis Ka-Ming Chan

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Programmed necrosis/necroptosis is an emerging form of cell death that plays important roles in mammalian development and the immune system. The pro-necrotic kinases in the receptor interacting protein (RIP) family are crucial mediators of programmed necrosis. Recent advances in necrosis research have been greatly aided by the identification of chemical inhibitors that block programmed necrosis. Necrostatin-1 (Nec-1) and its derivatives were previously shown to target the pro-necrotic kinase RIP1/RIPK1. The protective effect conferred by Nec-1 and its derivatives in many experimental model systems was often attributed to the inhibition of RIP1 function.

METHODOLOGY/PRINCIPAL FINDINGS: We compared the effect of …

Comparison Of Adenoviruses As Oncolytics And Cancer Vaccines In An Immunocompetent B Cell Lymphoma Model, Eric A. Weaver, Christopher Y. Chen, Shannon M. May, Mary E. Barry, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

We have screened human adenoviruses (Ads) for oncolytic activity against a variety of mouse and hamster cell lines and have found a number that are susceptible to a variety of Ad serotypes. A20 lymphoma is derived from BALB/c mice and is susceptible to infection and killing by a variety of human Ads. A20 is also a suitable cancer vaccine model, because these cells express a unique immunoglobulin variable region that can be targeted by vaccination. To compare Ads as cancer vaccines versus Ads as oncolytics, A20 tumors were initiated in immunocompetent BALB/c mice. Mice immunized with first-generation Ad5 expressing the …

Generation Of A Kupffer Cell-Evading Adenovirus For Systemic And Liver-Directed Gene Transfer, Reeti Khare, Shannon M. May, Francesco Vetrini, Eric A. Weaver, Donna Palmer, Amanda Rosewell, Nathan Grove, Philip Ng, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

As much as 90% of an intravenously (i.v.) injected dose of adenovirus serotype 5 (Ad5) is absorbed and destroyed by liver Kupffer cells. Viruses that escape these cells can then transduce hepatocytes after binding factor X (FX). Given that interactions with FX and Kupffer cells are thought to occur on the Ad5 hexon protein, we replaced its exposed hypervariable regions (HVR) with those from Ad6. When tested in vivo in BALB/c mice and in hamsters, the Ad5/6 chimera mediated >10 times higher transduction in the liver. This effect was not due to changes in FX binding. Rather, Ad5/6 appeared to …

Role And Mechanism Of Arsenic In Regulating Angiogenesis., Ling-Zhi Liu, Yue Jiang, Richard L Carpenter, Yi Jing, Stephen C Peiper, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS) generation, which activates AKT …

Mitostatin Is Down-Regulated In Human Prostate Cancer And Suppresses The Invasive Phenotype Of Prostate Cancer Cells., Matteo Fassan, Domenico D'Arca, Juraj Letko, Andrea Vecchione, Marina P Gardiman, Peter Mccue, Bernadette Wildemore, Massimo Rugge, Dolores Shupp-Byrne, Leonard G Gomella, Andrea Morrione, Renato V Iozzo, Raffaele Baffa

Kimmel Cancer Center Faculty Papers

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in …

Mir-21 Induced Angiogenesis Through Akt And Erk Activation And Hif-1Α Expression., Ling-Zhi Liu, Chongyong Li, Qi Chen, Yi Jing, Richard Carpenter, Yue Jiang, Hsiang-Fu Kung, Lihui Lai, Bing-Hua Jiang

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1α and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated …

Advances And Future Challenges In Adenoviral Vector Pharmacology And Targeting, Reeti Khare, Christopher Y. Chen, Eric A. Weaver, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Adenovirus is a robust vector for therapeutic applications, but its use is limited by our understanding of its complex in vivo pharmacology. In this review we describe the necessity of identifying its natural, widespread, and multifaceted interactions with the host since this information will be crucial for efficiently redirecting virus into target cells. In the rational design of vectors, the notion of overcoming a sequence of viral “sinks” must be combined with re-targeting to target populations with capsid as well as shielding the vectors from pre-existing or toxic immune responses. It must also be noted that most known adenoviral pharmacology …

Fus Transgenic Rats Develop The Phenotypes Of Amyotrophic Lateral Sclerosis And Frontotemporal Lobar Degeneration., Cao Huang, Hongxia Zhou, Jianbin Tong, Han Chen, Yong-Jian Liu, Dian Wang, Xiaotao Wei, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and …