ovine pulmonary adenomatosis

..provided by applicant): The object of this proposal is to study the mechanisms of oncogenesis in ovine pulmonary carcinoma (OPC), a naturally occurring lung cancer of sheep...

..transformation by jaagsiekte sheep retrovirus (JSRV), the cause of a transmissible lung cancer, ovine pulmonary carcinoma (OPA) that closely resembles human lung adenocarcinoma...

In this proposal, we will study the Jaagsiekte Sheep Retrovirus (JSRV) that induces ovine pulmonary carcinoma (PC) in sheep. OPC is an infectious neoplasm of sheep that occurs in many geographical locations...

..transformation by jaagsiekte sheep retrovirus (JSRV), the cause of a transmissible lung cancer, ovine pulmonary carcinoma (OPA) that closely resembles human lung adenocarcinoma...

..Further work is necessary to identify alternative signalling pathways of telomerase activation in tumours...

..These data support a model of opportunistic JSRV infection and tumorigenic conversion of type II pneumocytes/Clara cells in the lungs, while lymphoreticular cells serve as the principal virus reservoir...

..The presence of the Jaagsiekte retrovirus was demonstrated in the lungs by immunocytochemistry and PCR. To the best of our knowledge, this is the first report of OPA in Patagonia...

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..Detection of JSRV was evident at 1:50 dilution. Although the possibility of a viral association with BAC cannot be excluded, this study shows that the association with JSRV is probably very weak, if present at all...

..This Review summarizes our current knowledge of this unique and poorly understood disease...

..These results indicate that the JSRV Env protein is capable of inducing tumors in transgenic mice, and in other cell types besides lung epithelial cells...

..These results support the notion that JSRV lung tropism is determined by the transcriptional specificity of the JSRV LTR, which is governed by interactions with lung-specific transcription factors...

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Jaagsiekte retrovirus (JSRV) causes ovine pulmonary adenomatosis (OPA) that resembles bronchioloalveolar carcinoma (BAC) in humans...

..Thus, OPA is an exquisite model of carcinogenesis for human lung adenocarcinomas...

..However, its role in JSRV or ONAV tumorigenesis, if any, is still unclear. JSRV vectors are capable of transducing various human cells, and are being further evaluated for gene therapy purposes...

..However, c-Myc was activated only in OPA tumours. In contagious respiratory neoplasms of sheep and goats the Erk1/2 pathway appears to be important for the in-vivo generation of the transforming stimuli...

..Etiologically, they were attributed to JRSV (Jaagsiekte Sheep Retrovirus) by detection of capsid protein 24 in western blot. The significance of the disease in Switzerland is discussed, also in the context of lung adenomatosis...

..The genome is 7,434 nucleotides long and exhibits a genetic organization characteristic of type B and D oncoviruses. Enzootic nasal tumor virus is closely related to the Jaagsiekte sheep retrovirus and to sheep endogenous retroviruses...

..In sheep, a bronchiolo-alveolar carcinoma, known as ovine pulmonary carcinoma (OPC), is caused by jaagsiekte sheep retrovirus (JSRV), an exogenous type D retrovirus...

..The transcriptional regulatory elements in these viruses are quite different, indicating that tissue-specific oncogenesis is likely regulated at the level of viral gene expression...

..Also included in this chapter is a description of the morphology of the viral particles associated with OPA...

..Activation of the PI3K/Akt and MAPK pathways participates in the envelope-induced transformation. Tumour development is associated with telomerase activation. This review will focus on the induction of cancer by JSRV...

..OPA may develop from multiple independent oncogenic events and a role for insertional mutagenesis cannot be ruled out...

..Moreover, M-MuLV driven by the DeltaMo + JS LTR was > 3 logs more infectious in MLE-15 cells compared to non-lung cell lines. This chimeric virus may facilitate investigations of the tissue-specificity of JSRV...

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..Bronchoalveolar lavage samples from the breeding stock were examined by PCR in order to rule out further subclinical cases of OPA. No Jaagsiekte retrovirus was detected in any of the 488 samples...

..These findings suggest that there is at least one common integration site for JSRV in OPA and add weight to the hypothesis that insertional mutagenesis is involved in the development of this tumor...

..Histopathologically the sheep disease resembles human bronchiolar alveolar carcinoma and has been identified as a natural out bred animal model that could be used to study the human disease...

..This PCR is the only currently available blood test for detection of JSRV infected sheep and may be useful in epidemiological studies and in control programmes of OPA...

..Aside from any role in disease, enJSRV loci may serve as useful genetic markers in the sheep and their frequent expression in the reproductive tract of the ewe may portend an important physiologic role in sheep...

..The transforming potential of the JSRV envelope protein may be necessary for JSRV infection and replication in vivo...

..This novel experimental model will set up the stage for elucidating lung epithelial transformation in the JSRV-induced tumor...

..These results will help in the design of a protective vaccine against JSRV infection and the development of OPA...

..The CD4 lymphocytopaenia and neutrophilia reported previously in adult OPA cases were demonstrated but similar phenotypic changes were not identified during experimental infection...

..2 kb that would encode an independent orf-x protein of 179 amino acids. In addition, the results suggested that there may also be an internal promoter for orf-x...

..The reduced response is an early and sustained event during infection and may indicate that the failure of infected sheep to produce specific antibodies to JSRV is a direct consequence of infection...

..It is also a useful tool for the pre-clinical identification of individual infected sheep within an infected flock and therefore may prove beneficial in future control or eradication programmes...

..Control groups fed with C/M from JSRV free flock and JSRV blood test negative sheep were always negative. Together these results indicate that suckling is an important natural transmission route for JSRV...

..The feasibility of inducing OPA in older lambs and detecting JSRV viraemia in preclinical stages enables improved studies on the pathogenesis, assessment of vaccines, diagnosis and control of the disease...

..As a whole, these results suggest that the activation of the PI-3K/Akt pathway contributes to the process of JSRV-induced cell transformation but most likely is not the primary determinant both in vitro and in vivo...

..Here, we will review the data accumulated so far on the molecular biology of JSRV using the infectious and oncogenic JSRV21 molecular clone as virus of reference...

..These findings suggest that more than one mechanism may be involved in JSRV env-mediated transformation...