scholarly journals Biochemical and Functional Comparisons ofmdxandSgcg−/−Muscular Dystrophy Mouse Models

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Nathan W. Roberts ◽  
Jenan Holley-Cuthrell ◽  
Magdalis Gonzalez-Vega ◽  
Aaron J. Mull ◽  
Ahlke Heydemann
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Models ◽  
Time Course ◽  
Genetically Engineered ◽  
Blue Dye ◽  
Null Mouse ◽  
Human Genetic Disease ◽  
Mild Disease ◽  
Diagnosis And Prognosis ◽  
Genetically Engineered Mice

Mouse models have provided an essential platform to investigate facets of human diseases, from etiology, diagnosis, and prognosis, to potential treatments. Muscular dystrophy (MD) is the most common human genetic disease occurring in approximately 1 in 2500 births. Themdxmouse, which is dystrophin-deficient, has long been used to model this disease. However, this mouse strain displays a rather mild disease course compared to human patients. Themdxmice have been bred to additional genetically engineered mice to worsen the disease. Alternatively, other genes which cause human MD have been genetically disrupted in mice. We are now comparing disease progression from one of these alternative gene disruptions, theγ-sarcoglycan null mouseSgcg−/−on the DBA2/J background, to themdxmouse line. This paper aims to assess the time-course severity of the disease in the mouse models and determine which is best for MD research. TheSgcg−/−mice have a more severe phenotype than themdxmice. Muscle function was assessed by plethysmography and echocardiography. Histologically theSgcg−/−mice displayed increased fibrosis and variable fiber size. By quantitative Evan’s blue dye uptake and hydroxyproline content two key disease determinants, membrane permeability and fibrosis respectively, were also proven worse in theSgcg−/−mice.

Factor IX: Insights from knock-out and genetically engineered mice

2008 ◽  
Vol 100 (10) ◽  
pp. 563-575 ◽  
Author(s):  
Paul E. Monahan
Keyword(s):  
Mouse Models ◽  
Positional Cloning ◽  
Coagulation Factors ◽  
Genetically Engineered ◽  
Factor Ix ◽  
Mouse Strains ◽  
Knock Out ◽  
Haemophilia B ◽  
Genetically Engineered Mice ◽  
Knock Out Mice

SummaryThe study of coagulation factors has been rapidly advanced by studies performed in genetically engineered mouse strains. Investigation of factor IX (FIX) has benefited from excellent genedeleted mouse models that recapitulate many of the features of human haemophilia B. Moreover, advanced positional cloning techniques and availability of technology to allow not only knock-out mice, but also knock-in and knock-down mice, provide new opportunities to observe genotype-phenotype and structure-function correlations regarding FIX, as well as the interaction of FIX with inflammatory, immune, and tissue repair systems. In this paper, available FIX knock-out mice and additional haemophilia B mouse models are reviewed specifically in regards to observations these models have facilitated concerning: factor IX gene expression and factor IX protein pharmacokinetics; the role of FIX in haemostasis, thrombosis and wound healing; insights into coagulation FIX arising out of gene therapy applications in haemophilia mouse models; immunology of tolerance or loss of tolerance of FIX and inhibitor antibody formation.

scholarly journals The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

Blood ◽  
2012 ◽  
Vol 120 (26) ◽  
pp. 5118-5127 ◽  
Author(s):  
Vinod Pant ◽  
Alfonso Quintás-Cardama ◽  
Guillermina Lozano
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Mouse Models ◽  
Cell Function ◽  
Cell Cycle Control ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
Hematopoietic Stem ◽  
Genetically Engineered Mice ◽  
Dependent Cell

Abstract Aberrations in the p53 tumor suppressor pathway are associated with hematologic malignancies. p53-dependent cell cycle control, senescence, and apoptosis functions are actively involved in maintaining hematopoietic homeostasis under normal and stress conditions. Whereas loss of p53 function promotes leukemia and lymphoma development in humans and mice, increased p53 activity inhibits hematopoietic stem cell function and results in myelodysplasia. Thus, exquisite regulation of p53 activity is critical for homeostasis. Most of our understanding of p53 function in hematopoiesis is derived from genetically engineered mice. Here we summarize some of these models, the various mechanisms that disrupt the regulation of p53 activity, and their relevance to human disease.

Physiological assessment of complex cardiac phenotypes in genetically engineered mice

1997 ◽  
Vol 272 (6) ◽  
pp. H2513-H2524 ◽  
Author(s):  
G. Christensen ◽  
Y. Wang ◽  
K. R. Chien
Keyword(s):  
Heart Disease ◽  
Mouse Models ◽  
Human Heart ◽  
Volume Overload ◽  
Genetically Engineered ◽  
Cardiac Physiology ◽  
Developmental Defects ◽  
Genetically Engineered Mice ◽  
Human Heart Disease

The recent development of techniques for surgical manipulation and for the assessment of cardiac physiology in genetically engineered mice has allowed scientists to address some of the most fundamental questions related to congenital and acquired forms of human heart disease. This review discusses recent advances in the techniques for studying cardiac disease using the mouse as a model system. Because cardiac overload is one of the most important stimuli for development of hypertrophy and heart failure in humans, various models of cardiac pressure and volume overload, as well as myocardial ischemia, have been developed and characterized. Moreover, it is possible to reliably examine murine cardiac physiology in vivo with microtransducers, echocardiography, and other miniaturized techniques. Sophisticated methods have also been developed to enable an examination of single-cell phenotypes of isolated cardiomyocytes derived from genetically engineered mice. These physiological assessments, coupled with conventional histology and molecular markers, have allowed the characterization of several gene-targeted and transgenic mouse models of hypertrophy and dilated cardiomyopathy, as well as mouse models of cardiac developmental defects. Such mouse models of heart disease will ultimately allow the molecular dissection of the interplay between the various factors leading to heart disease, and they may serve as a guide to appropriate therapeutic strategies for human heart disease.

scholarly journals Manipulation of DNA Repair Proficiency in Mouse Models of Colorectal Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Michael A. Mcilhatton ◽  
Gregory P. Boivin ◽  
Joanna Groden
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Mouse Models ◽  
Cancer Biology ◽  
Genetically Engineered ◽  
Biologically Relevant ◽  
Dna Repair Mechanisms ◽  
Genetically Engineered Mice ◽  
Repair Mechanisms

Technical and biological innovations have enabled the development of more sophisticated and focused murine models that increasingly recapitulate the complex pathologies of human diseases, in particular cancer. Mouse models provide excellentin vivosystems for deciphering the intricacies of cancer biology within the context of precise experimental settings. They present biologically relevant, adaptable platforms that are amenable to continual improvement and refinement. We discuss how recent advances in our understanding of tumorigenesis and the underlying deficiencies of DNA repair mechanisms that drive it have been informed by using genetically engineered mice to create defined, well-characterized models of human colorectal cancer. In particular, we focus on how mechanisms of DNA repair can be manipulated precisely to createin vivomodels whereby the underlying processes of tumorigenesis are accelerated or attenuated, dependent on the composite alleles carried by the mouse model. Such models have evolved to the stage where they now reflect the initiation and progression of sporadic cancers. The review is focused on mouse models of colorectal cancer and how insights from these models have been instrumental in shaping our understanding of the processes and potential therapies for this disease.

scholarly journals Genetically engineered ERα-positive breast cancer mouse models

2014 ◽  
Vol 21 (3) ◽  
pp. R195-R208 ◽  
Author(s):  
Sarah A Dabydeen ◽  
Priscilla A Furth
Keyword(s):  
Mouse Models ◽  
Mammary Cancer ◽  
Human Cancer ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genetically Engineered ◽  
Spontaneous Mutant ◽  
Breast Cancers ◽  
Pparγ Agonist ◽  
Genetically Engineered Mice

The majority of human breast cancers are estrogen receptor-positive (ER+), but this has proven challenging to model in genetically engineered mice. This review summarizes information on 21 mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent.ESR1,CCDN1, prolactin,TGFα,AIB1,ESPL1, andWNT1overexpression,PIK3CAgain of function, as well as loss ofP53(Trp53) orSTAT1are associated with ER+ mammary cancer. Treatment with the PPARγ agonist efatutazone in a mouse withBrca1andp53deficiency and 7,12-dimethylbenz(a)anthracene exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from 3 to 26 months and the percentage of cancers that are ER+ vary from 21 to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1, and NIH nude. Most models have only been studied on one strain background. In summary, while a range of models are available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization, and opportunity for development of new models remains.

scholarly journals Mouse Models for Blistering Skin Disorders

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Radhika Ganeshan ◽  
Jiangli Chen ◽  
Peter J. Koch
Keyword(s):  
Mouse Models ◽  
Skin Diseases ◽  
Pemphigus Vulgaris ◽  
Genetically Engineered ◽  
Human Diseases ◽  
Desmosomal Cadherins ◽  
Genetically Engineered Mice ◽  
Blistering Skin Disorders ◽  
The Relationship ◽  
Mouse Lines

Genetically engineered mice have been essential tools for elucidating the pathological mechanisms underlying human diseases. In the case of diseases caused by impaired desmosome function, mouse models have helped to establish causal links between mutations and disease phenotypes. This review focuses on mice that lack the desmosomal cadherins desmoglein 3 or desmocollin 3 in stratified epithelia. A comparison of the phenotypes observed in these mouse lines is provided and the relationship between the mutant mouse phenotypes and human diseases, in particular pemphigus vulgaris, is discussed. Furthermore, we will discuss the advantages and potential limitations of genetically engineered mouse lines in our ongoing quest to understand blistering skin diseases.

scholarly journals Preclinical Experimental Therapeutics

2014 ◽  
Author(s):  
Gillian P. Bates ◽  
Christian Landles
Keyword(s):  
Mouse Models ◽  
Best Practice ◽  
Nonhuman Primates ◽  
Mouse Genome ◽  
Therapeutic Targets ◽  
Genetically Engineered ◽  
Experimental Therapeutics ◽  
Development Programs ◽  
Genetically Engineered Mice ◽  
Large Animals

This chapter begins by reviewing the mammalian models of Huntington’s disease (HD) that have been developed using mice, rats, and a number of large animals, including sheep, pigs, and nonhuman primates. Analysis of these models, together with genetically engineered mice created through specific manipulations of the mouse genome, has provided considerable insights into the molecular pathogenesis of HD. The number of potential therapeutic targets that have been proposed for HD is considerable, and their preclinical evaluation in HD mouse models is being used to select targets that should be pursued in drug development programs. Hence, mouse models have been used extensively to validate therapeutic targets and in the preclinical testing of therapeutic strategies. The limitations of these studies are discussed, and best-practice approaches are highlighted. The chapter concludes with a summary of the gene therapy approaches that are being developed, including strategies to lower the levels of huntingtin.

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