scholarly journals Animal models for the study of liver fibrosis: new insights from knockout mouse models

2011 ◽  
Vol 300 (5) ◽  
pp. G729-G738 ◽  
Author(s):  
Hiromitsu Hayashi ◽  
Takao Sakai
Keyword(s):  
Animal Models ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Clinical Importance ◽  
Genetically Engineered ◽  
Loss Of Function ◽  
Genetically Engineered Mice ◽  
Gene Knockouts ◽  
Would Healing ◽  
Excessive Accumulation

Fibrosis arises as part of a would-healing response that maintains organ structure and integrity following tissue damage but also contributes to a variety of human pathologies such as liver fibrosis. Liver fibrosis is an abnormal response of the liver to persistent injury with the excessive accumulation of collagenous extracellular matrices. Currently there is no effective treatment, and many patients end up with a progressive form of the disease, eventually requiring a liver transplant. The clarification of mechanisms underlying pathogenesis of liver fibrosis and the development of effective therapy are of clinical importance. Experimental animal models, in particular targeted gene knockouts (loss of function) in mice, have become a powerful resource to address the molecular mechanisms or significance of the targeted gene in hepatic functions and diseases. This review will focus on the recent advances in knowledge obtained from genetically engineered mice that provide novel insights into the pathophysiology of liver fibrosis.

scholarly journals miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice

2011 ◽  
Vol 208 (6) ◽  
pp. 1189-1201 ◽  
Author(s):  
Mark P. Boldin ◽  
Konstantin D. Taganov ◽  
Dinesh S. Rao ◽  
Lili Yang ◽  
Jimmy L. Zhao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Genetically Engineered ◽  
Biological Processes ◽  
Targeted Deletion ◽  
Genetically Engineered Mice ◽  
Immune Defects ◽  
Molecular Brake

Excessive or inappropriate activation of the immune system can be deleterious to the organism, warranting multiple molecular mechanisms to control and properly terminate immune responses. MicroRNAs (miRNAs), ∼22-nt-long noncoding RNAs, have recently emerged as key posttranscriptional regulators, controlling diverse biological processes, including responses to non-self. In this study, we examine the biological role of miR-146a using genetically engineered mice and show that targeted deletion of this gene, whose expression is strongly up-regulated after immune cell maturation and/or activation, results in several immune defects. Collectively, our findings suggest that miR-146a plays a key role as a molecular brake on inflammation, myeloid cell proliferation, and oncogenic transformation.

X. Trefoil peptide and EGF receptor/ligand transgenic mice

2000 ◽  
Vol 278 (4) ◽  
pp. G501-G506 ◽  
Author(s):  
Andrew S. Giraud
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Regulatory Peptides ◽  
Genetically Engineered ◽  
Loss Of Function ◽  
Transforming Growth Factor Α ◽  
Trefoil Peptides ◽  
Trefoil Peptide ◽  
Genetically Engineered Mice

The use of genetically engineered mice with both gain-of-function and loss-of-function mutations has been particularly informative about the normal and pathophysiological actions of a number of regulatory peptides of the gastrointestinal tract. This review highlights some of the major findings pertinent to the epidermal growth factor (EGF) receptor and its ligands, particularly the major gut ligand transforming growth factor-α, as well as the trefoil peptides. Both of these peptide families have important local actions in maintaining tissue homeostasis and repair after injury, and when mechanisms governing their regulation are disrupted they may contribute to disease progression. Future applications of transgenic technology to these areas are likely to be productive in furthering our understanding of the biology of these peptides in health and disease.

scholarly journals Animal models of colorectal peritoneal metastasis

2016 ◽  
Vol 1 (1) ◽  
pp. 23-43 ◽  
Author(s):  
Félix Gremonprez ◽  
Wouter Willaert ◽  
Wim Ceelen
Keyword(s):  
Colorectal Cancer ◽  
Animal Models ◽  
Peritoneal Carcinomatosis ◽  
Peritoneal Metastasis ◽  
Treatment Options ◽  
Genetically Engineered ◽  
Preclinical Research ◽  
Novel Treatment ◽  
Genetically Engineered Mice ◽  
Wide Range

AbstractColorectal cancer remains an important cause of mortality worldwide. The presence of peritoneal carcinomatosis (PC) causes significant symptoms and is notoriously difficult to treat. Therefore, informative preclinical research into the mechanisms and possible novel treatment options of colorectal PC is essential in order to improve the prognostic outlook in these patients. Several syngeneic and xenograft animal models of colorectal PC were established, studying a wide range of experimental procedures and substances. Regrettably, more sophisticated models such as those giving rise to spontaneous PC or involving genetically engineered mice are lacking. Here, we provide an overview of all reported colorectal PC animal models and briefly discuss their use, strengths, and limitations.

scholarly journals Electrophysiological phenotyping in genetically engineered mice

2003 ◽  
Vol 13 (3) ◽  
pp. 207-216 ◽  
Author(s):  
Charles I. Berul
Keyword(s):  
Molecular Mechanisms ◽  
Heart Defects ◽  
Gene Mutations ◽  
Genetically Engineered ◽  
Experimental Methodology ◽  
Cardiac Conduction ◽  
Disease States ◽  
Genetically Engineered Mice ◽  
Study Techniques

Advances in transgene and gene targeting technology have enabled sophisticated manipulation of the mouse genome, providing important insights into the molecular mechanisms underlying cardiac conduction, arrhythmogenesis, and sudden cardiac death. The mouse is currently the principal mammalian model for studying biological processes, particularly related to cardiac pathophysiology. Murine models have been engineered harboring gene mutations leading to inherited structural and electrical disorders of the heart due to transcription factor mutations, connexin protein defects, and G protein and ion channelopathies. These mutations lead to phenotypes reminiscent of human clinical disease states including congenital heart defects, cardiomyopathies, and long-QT syndrome, creating models of human electrophysiological disease. Functional analyses of the underlying molecular mechanisms of resultant phenotypes require appropriate and sophisticated experimental methodology. This paper reviews current in vivo murine electrophysiology study techniques and genetic mouse models pertinent to human arrhythmia disorders.

scholarly journals Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury

2012 ◽  
Vol 209 (2) ◽  
pp. 407-421 ◽  
Author(s):  
Helena Block ◽  
Jan M. Herter ◽  
Jan Rossaint ◽  
Anika Stadtmann ◽  
Stefanie Kliche ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adaptor Protein ◽  
Sh2 Domain ◽  
Genetically Engineered ◽  
Neutrophil Recruitment ◽  
Leukocyte Rolling ◽  
Integrin Activation ◽  
Genetically Engineered Mice

Neutrophils trigger inflammation-induced acute kidney injury (AKI), a frequent and potentially lethal occurrence in humans. Molecular mechanisms underlying neutrophil recruitment to sites of inflammation have proved elusive. In this study, we demonstrate that SLP-76 (SH2 domain–containing leukocyte phosphoprotein of 76 kD) and ADAP (adhesion and degranulation promoting adaptor protein) are involved in E-selectin–mediated integrin activation and slow leukocyte rolling, which promotes ischemia-reperfusion–induced AKI in mice. By using genetically engineered mice and transduced Slp76−/− primary leukocytes, we demonstrate that ADAP as well as two N-terminal–located tyrosines and the SH2 domain of SLP-76 are required for downstream signaling and slow leukocyte rolling. The Tec family kinase Bruton tyrosine kinase is downstream of SLP-76 and, together with ADAP, regulates PI3Kγ (phosphoinositide 3-kinase–γ)- and PLCγ2 (phospholipase Cγ2)-dependent pathways. Blocking both pathways completely abolishes integrin affinity and avidity regulation. Thus, SLP-76 and ADAP are involved in E-selectin–mediated integrin activation and neutrophil recruitment to inflamed kidneys, which may underlie the development of life-threatening ischemia-reperfusion–induced AKI in humans.

Relationship of STAT3-mediated treatment resistance on activated MAPK signaling in pancreatic cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 181-181
Author(s):  
Nagaraj S. Nagathihalli ◽  
Yugandhar Beesetty ◽  
Chanjuan Shi ◽  
Nipun B. Merchant
Keyword(s):  
Cyclin D1 ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Treatment Resistance ◽  
Mapk Signaling ◽  
Genetically Engineered ◽  
Ductal Adenocarcinoma ◽  
Pdac Cell ◽  
Genetically Engineered Mice

181 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult human malignancies to treat due to its intrinsic (de novo) and extrinsic (acquired) chemoresistance. We have previously identified constitutively activated STAT3 as a mediator of treatment resistance. Src or EGFR activate STAT3 and promote STAT3 mediated tumor progression and mediate communication within the tumor microenvironment (TME). The purpose of this study was to further understand the molecular mechanisms of stromal-mediated chemoresistance in PDAC to generate new and promising targeted therapies. Methods: We characterized the expression of total and activated STAT3 and MAPK proteins in human pancreatic tissues (n=106), PDAC cell lines (n=9) and in PanIn lesions, primary PDAC and liver metastasis cell lines generated from tumors established in genetically engineered mice. Effects of STAT3 and MAPK inhibition (drug or siRNA) were assessed for phosphorylation of STAT3, Src, MAPK, EGFR and GSK3β and expression of cyclin-D1, SPARC, VEGF, fibronectin, CD31 and tumorigenicity in vitro and in vivo. Results: STAT3 activation is necessary for the malignant phenotype and affects survival in PDAC. In both human and mouse PDAC cell lines and tissues, there is an inverse correlation between activation of STAT3 on MAPK and GSK3β signaling. Inhibition of STAT3 reciprocally activated MAPK, GSK3β, Src and EGFR which led to subsequent reactivation of STAT3. Targeting both STAT3 and MAPK inhibited activation of STAT3, MAPK, GSK3β, Src, EGFR and cyclin-D1. Combined inhibition of STAT3 and MAPK overcame STAT3 mediated resistance and resulted in synergistic inhibition of tumorigenicity as well as inhibition of the tumor stroma, angiogenesis and hypoxia within the TME. Conclusions: The mechanism of STAT3-mediated treatment resistance is dependent on activation of MAPK signaling which in turn leads to reactivation of multiple oncogenic signaling pathways. Combined inhibition of STAT3 and MAPK overcomes therapeutic resistance, targets the TME and reduces tumorigenicity in PDAC. Targeting STAT3 and MAPK is a potent treatment regimen and may be a novel approach to enhance drug delivery and improve therapeutic response in PDAC.

scholarly journals A Treasure Trove of Hypothalamic Neurocircuitries Governing Body Weight Homeostasis

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Claudia R. Vianna ◽  
Roberto Coppari
Keyword(s):  
Body Weight ◽  
Energy Expenditure ◽  
Molecular Mechanisms ◽  
Feeding Habits ◽  
Genetically Engineered ◽  
Central Neurons ◽  
Genetically Engineered Mice ◽  
Normal Body Weight ◽  
Critical Components ◽  
Neuronal Groups

Abstract Changes in physical activities and feeding habits have transformed the historically rare disease of obesity into a modern metabolic pandemic. Obesity occurs when energy intake exceeds energy expenditure over time. This energy imbalance significantly increases the risk for cardiovascular disease and type 2 diabetes mellitus and as such represents an enormous socioeconomic burden and health threat. To combat obesity, a better understanding of the molecular mechanisms and neurocircuitries underlying normal body weight homeostasis is required. In the 1940s, pioneering lesion experiments unveiled the importance of medial and lateral hypothalamic structures. In the 1980s and 1990s, several neuropeptides and peripheral hormones critical for appropriate feeding behavior, energy expenditure, and hence body weight homeostasis were identified. In the 2000s, results from metabolic analyses of genetically engineered mice bearing mutations only in selected neuronal groups greatly advanced our knowledge of the peripheral/brain feedback-loop modalities by which central neurons control energy balance. In this review, we will summarize these recent progresses with particular emphasis on the biochemical identities of hypothalamic neurons and molecular components underlying normal appetite, energy expenditure, and body weight homeostasis. We will also parse which of those neurons and molecules are critical components of homeostatic adaptive pathways against obesity induced by hypercaloric feeding.

scholarly journals Ovarian Cancer Animal Models for Preclinical Studies and Development of Ovarian Cancer Drugs

2019 ◽  
Vol 17 (2) ◽  
pp. 139
Author(s):  
Ni Made Dwi Sandhiutami ◽  
Puspita Eka Wuyung ◽  
Wawaimuli Arozal ◽  
Melva Louisa ◽  
Deni Rahmat
Keyword(s):  
Ovarian Cancer ◽  
Animal Models ◽  
Treatment Strategies ◽  
Reproductive Factors ◽  
Experimental Models ◽  
Genetically Engineered ◽  
Human Ovarian Cancer ◽  
Preneoplastic Lesions ◽  
Genetically Engineered Mice ◽  
New Treatment

Treatment for ovarian carcinoma is still far from optimal, animal models are still needed to study human epithelial ovarian cancer. Animal models of ovarian cancer are very important for understanding the pathogenesis of the disease and for testing new treatment strategies. Ovarian carcinogenesis models in mice have been modified and repaired to produce preneoplastic lesions and neoplastic ovaries that are pathogens resembling human ovarian cancer. Although spontaneous ovarian tumors in mice have been reported, some of the shortcomings of existing studies preclude their use as animal models of ovarian cancer. Because of this, many efforts have been made to develop animal models that are relevant for ovarian cancer. Experimental animal models are developed accurately to represent cellular and molecular changes associated with the initiation and development of human ovarian cancer. Accurate experimental models have significant potential in facilitating the development of better methods for early detection and treatment of ovarian cancer. Several animal models of ovarian cancer have been reported, including manipulation of various reproductive factors or exposure to carcinogens. The latest advance in ovarian cancer modeling is using genetically engineered mice.

scholarly journals A novel bioreactor technology for modelling fibrosis in human and rodent precision-cut liver slices

2018 ◽  
Author(s):  
Hannah L Paish ◽  
Lee H Reed ◽  
Helen Brown ◽  
Mark C Bryan ◽  
Olivier Govaere ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Models ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
List Type ◽  
Bioreactor Culture ◽  
Albumin Secretion ◽  
Liver Slices ◽  
New Findings ◽  
Alk5 Inhibitor

Summary boxWhat is already known about this subject?Currently there are no effective anti-fibrotic drugs to treat liver fibrosis and there is an urgent unmet need to increase our knowledge of the disease process and develop better tools for anti-fibrotic drug discovery.Preclinical in vitro cell cultures and animal models are widely used to study liver fibrosis and test anti-fibrotic drugs, but have shortfalls; cell culture models lack the relevant complex cell-cell interactions of the liver and animal models only reproduce some features of human disease.Precision Cut Liver Slices (PCLS) are structurally representative of the liver and can be used to model liver fibrosis and test anti-fibrotic drugs. However, PCLS are typically cultured in elevated, non-physiological oxygen levels and only have a healthy lifespan of 48h.What are the new findings?We have developed a novel bioreactor culture system that increases the longevity of functional PCLS to up to 6 days under normoxic conditions.Bioreactor cultured PCLS can be used to model fibrogenesis in both normal and fibrotic PCLS using a combination of biochemical and histological outputs.Administration of an Alk5 inhibitor effectively limits fibrogenesis in normal rodent and human PCLS and in rodent PCLS with established fibrosis.How might it impact on clinical practice in the foreseeable future?The extended longevity of bioreactor cultured PCLS represent a novel pre-clinical tool to investigate the cellular and molecular mechanisms of liver fibrosis.Bioreactor cultured human PCLS offer a clinically relevant system to test efficacy of anti-fibrotic drugs.AbstractObjectivePrecision cut liver slices (PCLS) retain the structure and cellular composition of the native liver and represent an improved system to study liver fibrosis compared to two-dimensional mono or co-cultures. The objective of this study was to develop a bioreactor system to increase the healthy lifespan of PCLS and model fibrogenesis.DesignPCLS were generated from normal rat or human liver, or 4-week carbon tetrachloride-fibrotic rat liver and cultured in our patented bioreactor. PCLS function was quantified by albumin ELISA. Fibrosis was induced in PCLS by TGFβ1 and PDGFββ stimulation. Alk5 inhibitor therapy was used. Fibrosis was assessed by fibrogenic gene expression, Picrosirius Red and αSmooth Muscle Actin staining, hydroxyproline assay and collagen 1a1, fibronectin and hyaluronic acid ELISA.ResultsBioreactor cultured PCLS are viable, maintaining tissue structure and stable albumin secretion for up to 6 days under normoxic culture conditions. Conversely, standard static transwell cultured PCLS rapidly deteriorate and albumin secretion is significantly impaired by 48 hours. TGFβ1 and PDGFββ stimulation of rat or human PCLS induced fibrogenic gene expression, release of extracellular matrix proteins, activation of hepatic myofibroblasts and histological fibrosis. Fibrogenesis slowly progresses over 6-days in cultured fibrotic rat PCLS without exogenous challenge. Alk5 inhibitor limited fibrogenesis in both TGFβ1 and PDGFββ stimulated PCLS and fibrotic PCLS.ConclusionWe describe a new bioreactor technology which maintains functional PCLS cultures for 6 days. Bioreactor cultured PCLS can be successfully used to model fibrogenesis and demonstrate efficacy of an anti-fibrotic therapy.

scholarly journals Genetically engineered mice as animal models for NIDDM

FEBS Letters ◽  
1997 ◽  
Vol 401 (2-3) ◽  
pp. 99-103 ◽  
Author(s):  
Rajiv L Joshi ◽  
Betty Lamothe ◽  
Danielle Bucchini ◽  
Jacques Jami
Keyword(s):  
Animal Models ◽  
Genetically Engineered ◽  
Genetically Engineered Mice
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