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PubMed1997

New genetic technologies in alcohol research.

Recently developed approaches to creating genetically engineered animals have expanded researchers' repertoire of methods to investigate the roles of individual genes in the development of certain behaviors and diseases, including alcoholism. For example, knockout mice, in which single mouse genes have been inactivated, have allowed scientists to assess the roles of those genes in mediating some of alcohol's effects. This approach has been further refined using conditional gene knockout technology, which allows the inactivation of a gene only in certain cells or during specific developmental periods. Alternatively, transgenic mice (i.e., mice that carry a foreign gene in addition to their own genes) have been created in which researchers can activate or inactivate the foreign gene at will. Although these genetic engineering technologies have not yet been used extensively in alcohol research, they offer great promise in analyzing the functions of genes that may be involved in determining alcohol's effects on the body and the development of alcoholism.

Alcoholism↗
PubMed2003

The regulation of the complement system: insights from genetically-engineered mice.

The complement system is very tightly regulated by fluid-phase and membrane-bound factors that prevent injury to self-tissues. The study of genetically engineered animals with targeted deletion or gain of function mutations has highlighted the important role that many of the complement inhibitors play in vivo. The advantages and disadvantages of this type of approach are discussed and the insights gained from the investigation of these animals are reviewed.

Animals↗
PubMed2026

FBN1-related connective tissue disorders: unraveling cardiovascular, skeletal, and ocular complications through TGF-β signaling dysregulation and genotypic correlations.

Fibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene (FBN1) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1-related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.

Cardiovascular complications↗
PubMed2005

Clinical phenotypes and molecular genetic mechanisms of Carney complex.

Carney complex is a familial multiple neoplasia disorder with characteristic features such as cardiac and cutaneous myxomas and spotty pigmentation of the skin. Clinical genetic analyses have shown that Carney complex is transmitted in an autosomal dominant way and can present with a wide array of other tumours, such as psammomatous melanotic schwannoma, testicular Sertoli-cell tumours, and pituitary adenomas. Molecular genetic studies show that mutations in the PRKAR1A gene, encoding the R1alpha regulatory subunit of cyclic-AMP-dependent protein kinase A, are the cause of Carney complex in most patients. Investigation of genetically engineered animal models confirms the role of PRKAR1A as a tumour suppressor and has begun to elaborate mechanisms underlying tumorigenesis in this disorder. Further genetic studies in human beings have highlighted novel variant phenotypes, such as congenital contractures, which are potentially associated with Carney complex, and have identified alternative genetic pathways to cardiac tumorigenesis, including mutation of the MYH8 gene that encodes perinatal myosin.

Animals↗
PubMed1998

[Transgenic animals].

Molecular biological technique has enabled us to create numerous transgenic animals characterized by enhanced or reduced expression of target gene products. These animal models are very useful not only to study the physiological roles of target gene products but also to evaluate the clinical usefulness of newly developed drugs and other therapeutic measures. Unfortunately, we still do not have a genetically engineered animal model that spontaneously develops acute coronary syndrome. However, there are several transgenic mice showing abnormal lipid metabolism and developing premature atherosclerosis. In this chapter, recent advance in the field of atherosclerotic animal models will be summarized.

Acute Disease↗
PubMed1990

Development of expression vectors for transgenic fish.

Genetic alteration of fish is important for aquatic biotechnology as well as for investigating molecular interactions that occur during vertebrate development. The numerous, large, transparent, and externally fertilized eggs of many fish species make them ideally suitable for genetic manipulation, especially for production of transgenic animals. Genetic engineering of fish requires suitable expression vectors. Accordingly, we developed two fish expression vectors, FV-1 and FV-2, which contain the proximal promoter and enhancer regulatory elements of the carp beta-actin gene and the polyadenylation signal from the salmon growth hormone gene. The two fish expression vectors were tested in microinjected fish eggs and in tissue cultured fish and mammalian cells. These two "all-fish" expression vectors should be useful for genetic engineering of fish and have been used with growth-enhancing genes in transgenic fish.

Actins↗
PubMed1995

Molecular basis of common hereditary motor and sensory neuropathies in humans and in mouse models.

The Hereditary Motor and Sensory Neuropathies (HMSNs) are well known to be clinically, morphologically, and genetically heterogeneous. Yet, recent advances in the cellular and molecular biology of the peripheral nervous system coupled with remarkable progress in human and mouse genetics have provided a framework that has profoundly changed our understanding of the pathogenesis of these diseases. It now appears that most of the HMSNs are related to mutations affecting genes encoding Schwann cell proteins, specifically the Peripheral Myelin Protein PMP22, Myelin Protein Zero, and one of the gap junction proteins, connexin-32. Accordingly, these findings are discussed in the context of the clinical and pathologic features of the human HMSNs, but are interpreted in the context of basic research findings on the cellular and molecular biology of the peripheral nervous system derived from in vivo and in vitro studies in spontaneously-occurring and genetically engineered animal models for the HMSNs.

Animals↗
PubMed2001

Rodent obesity models: an overview.

Animal obesity models differ widely in type and extent of obesity. They are either based on environmental factors (eg. high fat diet induced obesity), spontaneous mutants (i.e. ob/ob mice), genetically engineered animals (eg. mice with melanocortin receptor subtype-4 gene disruption (knock-out)) or mechanical intervention (eg. chemical lesion of the ventromedial hypothalamus). This article reviews available rodent models to study obesity and attempts to highlight the greatest utility for each model.

Animals↗
PubMedDate not supplied

Trials, tribulations, and trends in tumor modeling in mice.

Selection of mouse models of cancer is often based simply on availability of a mouse strain and a known compatible tumor. Frequently this results in use of tumor models long on history but short on homology and quality control. Other factors including genetics, sex, immunological status, method and site of tumor implantation, technical competence, biological activity of the tumor, protocol sequence and timing, and selection of endpoints interact to produce outcomes in tumor models. Common reliance on survival and tumor burden data in a single mouse model often skews expectations towards high remission and cure rates; a finding seldom duplicated in clinical trials. Inherent limitations of tumor models coupled with the advent of new therapeutic targets reinforce need for careful attention to design, conduct, and stringent selection of in vivo and ex vivo endpoints. Preclinical efficacy testing for anti-tumor therapies should progress through a series of models of increasing sophistication that includes incorporation of genetically engineered animals, and orthotopic and combination therapy models. Pharmacology and safety testing in tumor-bearing animals may also help to improve predictive value of these models for clinical efficacy. Trends in bioinformatics, genetic refinements, and specialized imaging techniques are helping to maintain mice as the most scientifically and economically powerful model of malignant neoplasms.

Animals↗
PubMed2006

Xenotransplantation-current status and future perspectives.

Research efforts have shed light on the immunological obstacles to long-term survival of pig organs transplanted into primates and allowed the identification of targets for specific immune intervention. Accordingly, the development of genetically engineered animals has overcome the hyperacute rejection barrier, with acute humoral xenograft rejection (AHXR) currently remaining the most important immunological obstacle. At this stage, a better control of the elicited anti-pig humoral immune response and avoidance of coagulation disorders are the two primary research fronts being pursued in order to overcome AHXR. Nonetheless, it is encouraging that porcine xenografts can sustain the life of non-human primates for several months. Proactive research aimed at the development of a safer organ source is also underway. It is anticipated that ongoing research in several fields, including accommodation, tolerance, immune suppression and genetic engineering, will result in further improvements in non-human primate survival. However, until convincing efficacy data and a more favourable risk/benefit ratio can be established in relevant animal models, progression to the clinic should not be viewed as an option.

Animals↗
PubMed2006

In vivo veritas: thrombosis mechanisms in animal models.

Experimental models have enhanced our understanding of atherothrombosis pathophysiology and have played a major role in the search for adequate therapeutic interventions. Various animal models have been developed to simulate thrombosis and to study in vivo parameters related to hemodynamics and rheology that lead to thrombogenesis. Although no model completely mimics the human condition, much can be learned from existing models about specific biologic processes in disease causation and therapeutic intervention. In general, large animals such as pigs and monkeys have been better suited to study atherosclerosis and arterial and venous thrombosis than smaller species such as rats, rabbits, and dogs. On the other hand, mouse models of arterial and venous thrombosis have attracted increasing interest over the past two decades, owing to direct availability of a growing number of genetically modified mice, improved technical feasibility, standardization of new models of local thrombosis, and low maintenance costs. To simulate rupture of an atherosclerotic plaque, models of arterial thrombosis often involve vascular injury, which can be achieved by several means. There is no animal model that is sufficiently tall, that can mimic the ability of humans to walk upright, and that possesses the calf muscle pump that plays an important role in human venous hemodynamics. A number of spontaneous or genetically engineered animals with overexpression or deletion of various elements in the coagulation, platelet, and fibrinolysis pathways are now available. These animal models can replicate important aspects of thrombosis in humans, and provide a valuable resource in the development of novel concepts of disease mechanisms in human patients.

Animals↗
PubMed2006

Growth hormone signalling: sprouting links between pathways, human genetics and therapeutic options.

Our molecular understanding of growth hormone-induced signal transduction has improved significantly over the past decades. At the same time, human population genetics and the analysis of genetically engineered animals have led to the discovery of genes that control specific aspects of the overall growth process. Although, currently, growth disorders are still diagnosed and treated on empirical bases, it might soon be possible to stratify patients predominantly by genetic defect, with treatment based on our molecular understanding of the role of the affected gene in the disease.

Animals↗
PubMed1994

Methods in the Virtual Wetlab I: rule-based reasoning driven by nearest-neighbor lattice dynamics.

We describe a discrete dynamical systems approach to exploring the hypothesis-trees associated with wetlab experiments. On-going applications of the method to experimental research using a genetically engineered mouse animal model with severe combined immune deficiency (SCID) in the area of HIV infection are outlined as an example. In conclusion, we survey how this method can be used to engineer an informational murine, called Cybermouse [Mus Cyberspacea], that can be experimented upon using current immersion technologies.

Animals↗
PubMed2004

Neuronal pathology in Parkinson's disease.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra leading to the major clinical and pharmacological abnormalities of PD. In order to establish causal or protective treatments for PD, it is necessary to identify the cascade of deleterious events that lead to the dysfunction and death of dopaminergic neurons. Based on genetic, neuropathological, and biochemical data in patients and experimental animal models, dysfunction of the ubiquitin-proteasome pathway, protein aggregation, mitochondrial dysfunction, oxidative stress, activation of the c-Jun N-terminal kinase pathway, and inflammation have all been identified as important pathways leading to excitotoxic and apoptotic death of dopaminergic neurons. Toxin-based and genetically engineered animal models allow (1) the study of the significance of these aspects and their interaction with each other and (2) the development of causal treatments to stop disease progression.

Animals↗
PubMedDate not supplied

Genetic approaches to CNS disorders with particular reference to GABAA-receptor mutations.

The tools of molecular biology will bring the field of human genetics into a new era by permitting the analysis of the genetic contribution to disease. Most single gene disorders, inherited in a Mendelian fashion, will be molecularly diagnosed. In addition, the genetic susceptibility of common, complex diseases such a schizophrenia can be clarified, even though the conditions are not inherited as Mendelian characteristics. The mapping of the human genome will increase the rate at which new disease genes are identified and isolated. Finally, the development of genetically engineered animal models will help to dissect the steps involved in physiological and pathophysiological processes and thereby enhance our understanding of complex biological systems.

Alcoholism↗
PubMed2005

Learning from failure: congestive heart failure in the postgenomic age.

The prognosis of heart failure is worse than that of most cancers, but new therapeutic interventions using stem and other cell-based therapies are succeeding in the fight against it, and old drugs, with new twists, are making a comeback. Genetically engineered animal models are driving insights into the molecular mechanisms that cause hearts to fail, accelerating drug discoveries, and inspiring cell-based therapeutic interventions for both acquired and inheritable cardiac diseases.

Animals↗