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Total results = 15
Relevance: Disease model for spontaneous epilepsy; in vivo studies of constitutively active form of MEK1, which is conditionally expressed in the murine brain and results in ERK activation. The caMEK1-CamKIICre transgenic mouse exhibits an epileptic phenotype, characterised by frequent, spontaneous seizures from 6-8 weeks of age. Seizures occur throughout the lifetime of the mouse, becoming less frequent in older animals. On average, caMEK1-CamKIICre mice have6.2 seizures per day. The caMEK1-CamKIICre mouse expresses a constitutively activated MAP/ERK Kinase (caMEK1) specifically in neuronal cells of the cortex, striatum and hippocampus of the mouse brain.
Relevance: Endoglin is an auxiliary receptor for TGFb signalling. Heterozygous germline Endoglin mutations have been identified in patients with the vascular abnormality, Hereditary Haemorrhagic Telangiectasia. Endoglin is upregulated in endothelial cells during angiogenesis and the loss of Endoglin in [transgenic] mice results in embryonic lethality at mid-gestation. This phenotype points to an important role of Endoglin in new blood vessel formation but precludes analysis at later stages in development and in postnatal life. To bypass this limitation and allow further investigations of the function of Endoglin a transgenic mice has been generated with a floxed Endoglin allele in which loxP sites flank exons 5 and 6. Mice homozygous for this allele are normal and in the presence of appropriate Cre lines will allow time and cell specific Endoglin deletion for in vivo analysis of function in cardiovascular development and disease.
Relevance: Disease model for psoriasis; in vivo study of human a2 and b1 integrin transgene expression in skin.
Relevance: Disease model for psoriasis; in vivo study of human a3 and b1 integrin transgene expression in skin.
Relevance: Disease model for psoriasis; in vivo study of human a5 and b1 integrin transgene expression in skin.
Relevance: Chemically-induced skin tumourigenesis model; in vivo study of a6 and b4 integrin transgene expression in skin.
Relevance: Disease model for systemic lupus erythematosus; in vivo study of IFNg expression in skin.
Relevance: Disease model for psoriasis; in vivo study of constituitively active murine MEK1 mutant (S217E/S221E) in skin.
Relevance: In vivo study of JAM-C knockout; in vivo study of spermiogenesis; in vivo study of neuronal networks and integrity.
Relevance: In vivo study of beta-catenin activation in skin; model for hair growth & follicle formation
Relevance: In vivo study of Lef1 activity in skin; model for hair growth & follicle formation; disease model for skin tumour formation (sebaceous adenoma, sebeoma, squamous papilloma).
Relevance: In vivo study of Myc activation in skin; in vivo study of skin cell proliferation & differentiation (sebocytes, epidermis)
Relevance: Transgenic mouse expressing tamoxifen-inducible creERT2 under the control of Prox1 gene promoter Allows specific and temporally controlled cre-loxP recombination (gene inactivation/activation) in Prox1-expressing tissues, including lymphatic endothelia. Efficient recombination is observed during all developmental stages (embryonic, postnatal) and in adults. Currently no other models are available that allow such efficient and specific targetting of lymphatic vasculature.
Relevance: Peripheral nerves have the remarkable ability to regenerate following trauma, after which, a coordinated period of Schwann cell demyelination and recruitment of the inflammatory response form key steps in clearing the path for axonal regrowth to take place. During the course of nerve regeneration these same processes need to be switched off and reversed in order to allow the nerve to remyelinate and regain normal function. Following Tmx treatment/withdrawal, the Schwann cell RafTR mice display striking similarities to mice in which peripheral nerves have been cut or crushed - both in the response to, and recovery from, nerve damage. Furthermore, because of the cell specific nature of the Raf signal and the lack of damage to axons observed in this model, the Schwann cell RafTR mice will serve as a key to further understanding the central role of Schwann cells in controlling and coordinating the inflammatory response - thought to be essential for the rapid clearance of myelin that precedes nerve regeneration. In many diseases that affect the peripheral nervous system, including inherited demyelinating disorders and peripheral neuropathies induced by pathogens such as Leprosy, both demyelination and inflammation form central tenants of the disease pathologies and thus are important targets for drug therapy. Using the Schwann cell RafTR mouse model a demyelinating, inflammatory state can be induced and maintained by prolonged Tmx treatment. Furthermore, this “pseudo-disease-like” phenotype can be titered by regulating the dosage of Tmx given to the animals. Thus, the Schwann cell RafTR mice may serve as a model for targeting the inflammatory symptoms that accompany and exacerbate demyelinating diseases. The Schwann cell RafTR mice may also provide an important insight into the development and treatment of Neurofibromatosis type 1, a common inherited disorder in which patients are predisposed to develop tumours of the peripheral nervous system (Neurofibromas). These tumours are initiated by Schwann cells in which the small GTPase Ras becomes basally more active. Raf is one of the key downstream effectors of Ras and it is therefore highly likely that Raf kinase activation in the Schwann cell RafTR mouse mimics some of the behavioural changes that are observed within the tumour initiating cells at the earliest stages of tumourigenesis. Within neurofibromas Schwann cells are found in an undifferentiated state with a variety of non-neoplastic cells including inflammatory cells that help to create a pro-proliferative microenvironment which closely resembles that of the injured nerve. Therefore the Schwann cell RafTR mouse model may be useful in helping to dissect the contribution of this pathway in both the initiation and maintenance of the tumour microenvironment. A gene specific promoter The transgenic construct, p0Cx32, restricts transgene expression to the myelinated Schwann cells of the peripheral nervous system. Schwann cell RafTR mice develop normally and are indistinguishable from control animals due to the silent nature of the expressed transgene. However, RafTR protein can be readily and specifically detected in the peripheral nervous system and Schwann cell Raf-kinase signalling can be rapidly induced following administration of the oestrogen analogue tamoxifen (Tmx). Activation of the RafTR protein in Schwann cells triggers a widespread programme of demyelination within the peripheral nervous system that results in severe ataxia and impaired motor function. Cellular changes within the nerves include Schwann cell dedifferentiation and proliferation together with increased permeability of the blood nerve barrier and recruitment of inflammatory cells such as macrophages. Despite this extensive tissue remodelling and loss of nerve function, axonal fibres remain structurally unaffected. Prolonged treatment with Tmx maintains the demyelinated/inflammatory state and thus the ataxic phenotype, however, the mice are able to make a full behavioural recovery following Tmx withdrawal due to remyelination of nerve fibres by Schwann cells (in which Raf is no longer activated).
Relevance: Model for preclinical study of anti-MUC1 vaccines and immunotherapies.
© Cancer Research Technology 2012