Development and translational imaging of a TP53 porcine tumorigenesis model

Sieren, Jessica C.; Meyerholz, David K.; Wang, Xiaojun; Davis, Bryan T.; Newell, John D.; Hammond, Emily; Rohret, Judy A.; Rohret, Frank; Struzynski, Jason T.; Goeken, J. Adam; Naumann, Paul W.; Leidinger, Mariah; Taghiyev, Agshin F.; Rheeden, Richard Van; Hagen, Jussara; Darbro, Benjamin W.; Quelle, Dawn E.; Rogers, Christopher S.

doi:10.1172/jci75447

Cited by 89 publications

(90 citation statements)

References 71 publications

(75 reference statements)

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“…TP53 plays a vital role in cancer prevention through activation of DNA repair proteins, halting the cell cycle such that DNA repair proteins have time to complete reparation, and are able to initiate apoptosis in the case of DNA repair failure (Levine and Oren, 2009). We have previously demonstrated that TP53 R167H/R167H pigs develop cancer (including lymphoma, osteosarcoma and Wilms tumor) but have detected no cases of lung cancer in the TP53 R167H/R167H or the TP53 R167H/+ pigs (Sieren et al , 2014a). Necropsy of one of the silica exposed pigs confirmed persistent silica deposition in the lung and localized fibrosis development.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the pig lung anatomy is comparable to human structure, with similar lung volumes, airway dimensions and cardio-pulmonary rates; facilitating investigations of lung function (Kotoulas et al , 2014), novel bronchoscopy techniques (Henne et al , 2015, Tan et al , 2012) and novel medical imaging methods (O’Connell et al , 2015). Recently, genetically modified pig models have been developed of cancer and cystic fibrosis in which medical imaging has been used to provide valuable in-vivo insight (Sieren et al , 2014a, Rogers et al , 2008b, Rogers et al , 2008a). Focus on longitudinal pulmonary assessment is of interest for these genetically modified models as well as for toxicological exposure models in pigs.…”

Section: Introductionmentioning

confidence: 99%

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Computed Tomography and Magnetic Resonance Imaging for Longitudinal Characterization of Lung Structure Changes in a Yucatan Miniature Pig Silicosis Model

et al. 2016

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Medical imaging is a rapidly advancing field enabling the repeated, non-invasive assessment of physiological structure and function. These beneficial characteristics can supplement studies in swine by mirroring the clinical functions of detection, diagnosis, and monitoring in humans. In addition, swine may serve as a human surrogate, facilitating the development and comparison of new imaging protocols for translation to humans. This study presents methods for pulmonary imaging developed for monitoring pulmonary disease initiation and progression in a pig exposure model with CT and MRI. In particular, a focus was placed on systematic processes, including positioning, image acquisition, and structured reporting to monitor longitudinal change. The image-based monitoring procedure was applied to six Yucatan miniature pigs. A subset of animals (n = 3) were injected with crystalline silica into the apical bronchial tree to induce silicosis. The methodology provided longitudinal monitoring and evidence of progressive lung disease while simultaneously allowing for a cross-modality comparative study highlighting the practical application of medical image data collection in swine. The integration of multi-modality imaging with structured reporting allows for cross-comparison of modalities, refinement of CT and MRI protocols, and consistently monitors potential areas of interest for guided biopsy and/or necropsy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Computed Tomography and Magnetic Resonance Imaging for Longitudinal Characterization of Lung Structure Changes in a Yucatan Miniature Pig Silicosis Model

et al. 2016

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“…Pigs can live much longer (10 to 15+ years) than rodents with a generation interval of about 12 months and year-long breeding capacity. More specific to modeling CF lung disease [19], pigs have been used as models of pneumonia including viral [20] and bacterial [21] diseases, pigs have lung tissue markers that are similar to humans [22] and pigs are of similar size for translational lung imaging [19, 23]. Anatomically, pigs have submucosal glands, relevant target tissues for CF pathogenesis, which extend along cartilagineus airways into the pulmonary parenchyma [24, 25].…”

Section: Cf Pig Developmentmentioning

confidence: 99%

Lessons learned from the cystic fibrosis pig

Meyerholz

2016

Theriogenology

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Deficient function in the anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is the fundamental cause for cystic fibrosis (CF). This is a monogenic condition that causes lesions in several organs including the respiratory tract, pancreas, liver, intestines, and reproductive tract. Lung disease is most notable given it is the leading cause of morbidity and mortality in people with CF. Shortly after the identification of CFTR, CF mouse models were developed that did not show spontaneous lung disease as seen in humans and this spurred development of additional CF animal models. Pig models were considered a leading choice for several reasons including their similarity to humans in respiratory anatomy, physiology and in size for translational imaging. The first CF pig models were reported in 2008 and have been extremely valuable to help clarify persistent questions in the field and advance understanding of disease pathogenesis. Because CF pigs are susceptible to lung disease like humans, they have direct utility in translational research. In addition, CF pig models are useful to compare and contrast with current CF mouse models, human clinical studies and even newer CF animal models being characterized. This “triangulation” strategy could help identify genetic differences that underlie phenotypic variations, so as to focus and accelerate translational research.

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“…1B). A similar approach has been used to target porcine CFTR, LDLR, TP53 and SCN5A (29)(30)(31)(32). Following antibiotic selection and PCR screening, ATM +/− clones were used for SCNT to generate ATM +/− piglets.…”

Section: Engineering Of At Pigsmentioning

confidence: 99%

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

et al. 2015

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Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions. † These authors contributed equally.

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Development and translational imaging of a TP53 porcine tumorigenesis model

Cited by 89 publications

References 71 publications

Computed Tomography and Magnetic Resonance Imaging for Longitudinal Characterization of Lung Structure Changes in a Yucatan Miniature Pig Silicosis Model

Computed Tomography and Magnetic Resonance Imaging for Longitudinal Characterization of Lung Structure Changes in a Yucatan Miniature Pig Silicosis Model

Lessons learned from the cystic fibrosis pig

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease

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