Robert B Good

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• Zinn, N., Woodcock, H. V., Taylor, A. R., Swanton, C., Redding, M., Poeckel, D., Plate, M., Peace, S., Nanthakumar, C. B., Mercer, P. F., Martufi, M., Marshall, R. P., Maher, T. M., Karsdal, M. A., Joberty, G., Hynds, R. E., Guillotin, D., Good, R. B., Forty, E. J., , Fisher, A. J., et al. (2020). Author Correction: The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.. Nature communications, 11(1), 4680. doi:10.1038/s41467-020-18621-3
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  An amendment to this paper has been published and can be accessed via a link at the top of the paper.
• Martufi, M., Good, R. B., Rapiteanu, R., Schmidt, T., Patili, E., Tvermosegaard, K., New, M., Nanthakumar, C. B., Betts, J., Blanchard, A. D., & Maratou, K. (2019). Single-Step, High-Efficiency CRISPR-Cas9 Genome Editing in Primary Human Disease-Derived Fibroblasts.. The CRISPR journal, 2(1), 31-40. doi:10.1089/crispr.2018.0047
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  Genome editing is a tool that has many applications, including the validation of potential drug targets. However, performing genome editing in low-passage primary human cells with the greatest physiological relevance is notoriously difficult. High editing efficiency is desired because it enables gene knockouts (KO) to be generated in bulk cellular populations and circumvents the problem of having to generate clonal cell isolates. Here, we describe a single-step workflow enabling >90% KO generation in primary human lung fibroblasts via CRISPR ribonucleoprotein delivery in the absence of antibiotic selection or clonal expansion. As proof of concept, we edited two SMAD family members and demonstrated that in response to transforming growth factor beta, SMAD3, but not SMAD2, is critical for deposition of type I collagen in the fibrotic response. The optimization of this workflow can be readily transferred to other primary cell types.
• Nanthakumar, C. B., Gower, E., Good, R. B., Fisher, A. J., Eley, J. D., Butt, G., & Blanchard, A. D. (2019). A high content, phenotypic 'scar-in-a-jar' assay for rapid quantification of collagen fibrillogenesis using disease-derived pulmonary fibroblasts.. BMC biomedical engineering, 1(1), 14. doi:10.1186/s42490-019-0014-z
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  Excessive extracellular matrix (ECM) deposition is a hallmark feature in fibrosis and tissue remodelling diseases. Typically, mesenchymal cells will produce collagens under standard 2D cell culture conditions, however these do not assemble into fibrils. Existing assays for measuring ECM production are often low throughput and not disease relevant. Here we describe a robust, high content, pseudo-3D phenotypic assay to quantify mature fibrillar collagen deposition which is both physiologically relevant and amenable to high throughput compound screening. Using pulmonary fibroblasts derived from patients with idiopathic pulmonary fibrosis (IPF), we developed the 'scar-in-a-jar' assay into a medium-throughput phenotypic assay to robustly quantify collagen type I deposition and other extracellular matrix (ECM) proteins over 72 h..This assay utilises macromolecular crowding to induce an excluded volume effect and enhance enzyme activity, which in combination with TGF-β1 stimulation significantly accelerates ECM production. Collagen type I is upregulated approximately 5-fold with a negligible effect on cell number. We demonstrate the robustness of the assay achieving a Z prime of approximately 0.5, and % coefficient of variance (CV) of
• Woodcock, H. V., Eley, J. D., Guillotin, D., Plate, M., Nanthakumar, C. B., Martufi, M., Peace, S., Joberty, G., Poeckel, D., Good, R. B., Taylor, A. R., Zinn, N., Redding, M., Forty, E. J., Hynds, R. E., Swanton, C., Maher, T. M., Bergamini, G., Marshall, R. P., , Blanchard, A. D., et al. (2019). The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis.. Nature communications, 10(1), 6. doi:10.1038/s41467-018-07858-8
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  Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-β1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies.
• Kolluri, K. K., Alifrangis, C., Kumar, N., Ishii, Y., Price, S., Michaut, M., Barthorpe, S., Lightfoot, H., Busacca, S., Sharkey, A., Yuan, Z., Sage, E. K., Vallath, S., Tice, D. A., Alrifai, D., Montinaro, A., Guppy, N., Waller, D. A., Nakas, A., , Walczak, H., et al. (2018). Loss of functional BAP1 augments sensitivity to TRAIL in cancer cells.. eLife, 7. doi:10.7554/elife.30224
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  Malignant mesothelioma (MM) is poorly responsive to systemic cytotoxic chemotherapy and invariably fatal. Here we describe a screen of 94 drugs in 15 exome-sequenced MM lines and the discovery of a subset defined by loss of function of the nuclear deubiquitinase BRCA associated protein-1 (BAP1) that demonstrate heightened sensitivity to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand). This association is observed across human early passage MM cultures, mouse xenografts and human tumour explants. We demonstrate that BAP1 deubiquitinase activity and its association with ASXL1 to form the Polycomb repressive deubiquitinase complex (PR-DUB) impacts TRAIL sensitivity implicating transcriptional modulation as an underlying mechanism. Death receptor agonists are well-tolerated anti-cancer agents demonstrating limited therapeutic benefit in trials without a targeting biomarker. We identify BAP1 loss-of-function mutations, which are frequent in MM, as a potential genomic stratification tool for TRAIL sensitivity with immediate and actionable therapeutic implications.
• Yuan, Z., Williams, S. P., Wessels, L. F., Waller, D., Walczak, H., Vallath, S., Tice, D. A., Sharkey, A., Sage, E. K., Quesne, J. L., Price, S., Nakas, A., Montinaro, A., Michaut, M., Mcdermott, U., Lightfoot, H., Kumar, N., Kolluri, K., Karstedt, S. V., , Janes, S. M., et al. (2018). T1 Loss of BAP1 function leads to TRAIL sensitivity in mesothelioma. Thorax, 73. doi:10.1136/thorax-2018-212555.1
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  Introduction Malignant mesothelioma (MM) has no biomarker driven therapies in routine clinical use. We used a drug screen of molecularly characterised MM lines to identify novel genomic biomarker driven therapy. This led to the discovery of a subset of MMs, defined by loss of function (LOF) of the nuclear deubiquitinase BRCA associated protein 1 (BAP1), that demonstrate heightened sensitivity to tumour necrosis factor related apoptosis inducing ligand (TRAIL). We then validated this association across in vitro, in vivo and ex vivo models and delineated the underlying mechanism. Methods 15 MM lines were characterised for mutations in five MM tumour driver genes and screened for response to 95 compounds. The identified BAP1-TRAIL association was validated in an extended panel of MM lines with apoptosis and cell viability assays. 25 early passage MM cultures, mouse xenograft and human tumour explant models were used to further validate the association. Knock-in and knock-out models in BAP1 mutant and wild type lines confirmed the effect of loss of BAP1 expression on TRAIL sensitivity. 6 mutant BAP1 constructs were generated and identified which functional BAP1 sites modulate TRAIL sensitivity. The effect of BAP1 function on the downstream death receptor/apoptosis pathway components was determined using microarray and immunoblot analysis. Results BAP1 LOF significantly correlated with TRAIL sensitivity in established MM lines (p=0.015) and primary MM cultures (p Conclusions We identify loss of BAP1 as a novel biomarker for TRAIL sensitivity in MM. BAP1 LOF is observed in up to 67% of MM tumours and BAP1 immunohistochemistry is in use as a diagnostic tool; hence this approach is validated and ready for immediate and actionable clinical use for this disease.
• Gilbane, A. J., Derrett-smith, E., Trinder, S. L., Good, R. B., Denton, C. P., Holmes, A. M., & Pearce, A. C. (2015). Impaired bone morphogenetic protein receptor II signaling in a transforming growth factor-β-dependent mouse model of pulmonary hypertension and in systemic sclerosis.. American journal of respiratory and critical care medicine, 191(6), 665-77. doi:10.1164/rccm.201408-1464oc
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  Up to 10% of patients with systemic sclerosis (SSc) develop pulmonary arterial hypertension (PAH). This risk persists throughout the disease and is time dependent, suggesting that SSc is a susceptibility factor. Outcome for SSc-PAH is poor compared with heritable or idiopathic forms, despite clinical and pathological similarities. Although susceptibility in heritable PAH and idiopathic PAH is strongly associated with gene mutations leading to reduced expression of bone morphogenetic protein receptor (BMPR) II, these mutations have not been observed in SSc-PAH..To explore BMPRII expression and function in a mouse model of SSc (TβRIIΔk-fib) that is susceptible to developing pulmonary hypertension and in SSc lung..BMPRII and downstream signaling pathways were profiled in lung tissue and fibroblasts from the TβRIIΔk-fib model, which develops pulmonary vasculopathy with pulmonary hypertension that is exacerbated by SU5416. Complementary studies examined SSc or control lung tissue and fibroblasts..Our study shows reduced BMPRII, impaired signaling, and altered receptor turnover activity in a transforming growth factor (TGF)-β-dependent mouse model of SSc-PAH. Similarly, a significant reduction in BMPRII expression is observed in SSc lung tissue and fibroblasts. Increased proteasomal degradation of BMPRII appears to underlie this and may result from heightened TGF-β activity..We found reduced BMPRII protein in patients with SSc-PAH and a relevant mouse model associated with increased proteasomal degradation of BMPRII. Collectively, these results suggest that impaired BMP signaling, resulting from TGF-β-dependent increased receptor degradation, may promote PAH susceptibility in SSc and provide a unifying mechanism across different forms of PAH.
• Good, R. B., Gilbane, A. J., Trinder, S. L., Denton, C. P., Coghlan, G., Abraham, D. J., & Holmes, A. M. (2015). Endothelial to Mesenchymal Transition Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension.. The American journal of pathology, 185(7), 1850-8. doi:10.1016/j.ajpath.2015.03.019
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  Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial cell dysfunction and vascular remodeling. Normally, the endothelium forms an integral cellular barrier to regulate vascular homeostasis. During embryogenesis endothelial cells exhibit substantial plasticity that contribute to cardiac development by undergoing endothelial-to-mesenchymal transition (EndoMT). We determined the presence of EndoMT in the pulmonary vasculature in vivo and the functional effects on pulmonary artery endothelial cells (PAECs) undergoing EndoMT in vitro. Histologic assessment of patients with systemic sclerosis-associated PAH and the hypoxia/SU5416 mouse model identified the presence von Willebrand factor/α-smooth muscle actin-positive endothelial cells in up to 5% of pulmonary vessels. Induced EndoMT in PAECs by inflammatory cytokines IL-1β, tumor necrosis factor α, and transforming growth factor β led to actin cytoskeleton reorganization and the development of a mesenchymal morphology. Induced EndoMT cells exhibited up-regulation of mesenchymal markers, including collagen type I and α-smooth muscle actin, and a reduction in endothelial cell and junctional proteins, including von Willebrand factor, CD31, occludin, and vascular endothelial-cadherin. Induced EndoMT monolayers failed to form viable biological barriers and induced enhanced leak in co-culture with PAECs. Induced EndoMT cells secreted significantly elevated proinflammatory cytokines, including IL-6, IL-8, and tumor necrosis factor α, and supported higher immune transendothelial migration compared with PAECs. These findings suggest that EndoMT may contribute to the development of PAH.
• Trinder, S., Gilbane, A., Derrett-smith, E., Denton, C. P., Abraham, D., Holmes, A., & Good, R. B. (2015). Bromodomain Inhibitor JQ1 Modulates Smooth Muscle Cell Switching and Ameliorates Chronic Hypoxia/SU5416-Induced Pulmonary Arterial Hypertension in Mice. Arthritis & Rheumatism.
• Gilbane, A., Trinder, S., Abraham, D., Denton, C., Holmes, A., & Good, R. B. (2014). Endothelial to Mesenchymal Transition Contributes to the Development of Pulmonary Vasculopathy in Systemic Sclerosis PAH.. American College of Rheumatology.
• Gilbane, A., Trinder, S., Denton, C., Coghlan, G., Abraham, D., Holmes, A., & Good, R. B. (2014). Endothelial to Mesenchymal Transition (EndoMT) leads to a loss of normal endothelial cell function and may contribute to the development of pulmonary arterial hypertension. The American Journal of Pathology.
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  Background/Purpose Vascular complications in Scleroderma (SSc) patients are associated with high mortality, particularly in patients who develop pulmonary arterial hypertension (SSc-PAH). Vascular complications, thought to arise from initial activation and dysfunction of the endothelium can lead to: elevated vascular leak, inflammation, mesenchymal hypertrophy by activation of resident smooth muscle cells and fibroblasts, and neointima formation. Recent studies suggest that as well as resident mesenchymal cells, endothelial cells can undergo endothelial-mesenchymal transition (EndoMT), and acquire a mesenchymal phenotype which may contribute to the expansion of the mesenchymal cell population. Here we sought to determine the prevalence of EndoMT in SSc-PAH patients and pre-clinical models of PAH, and assess the cellular effects on pulmonary artery endothelial cells (PAECs) functions. Methods Using lung tissue from SSc-PAH patients (n=3), healthy control (HC) donors (n=3), and from the hypoxia/SU5416 pre-clinical murine model of PAH (n=5), EndoMT was determined by immunofluorescence based on co-expression of vWF and αSMA. EndoMT was induced in human PAECs (n=3) in vitro by TNFα [5ng/ml], IL-1β [0.1ng/m;] and TGFβ [5ng/ml] in combination. Morphological changes were assessed by light microscopy and phalloidin staining. Western blotting and immunofluorescence was used to quantify: CD31, vWF, occludin, VE-cadherin, αSMA, calponin and collagen type 1 expression. Conditioned media was collected from PAECs, PAECs following treatment to initiate EndoMT and SSc-PAH and HC fibroblasts; levels of inflammatory secretion was quantified by MSD arrays. The capacity of homogenous EndoMT monolayers (n=6) and mixed cultures of 1:10 EndoMT:PAECs (n=6) cells to form exclusion barriers was assessed using trans-well permeability FITC-albumin assays. Results Co-localisation of vWF and αSMA was observed in ≤5% of pulmonary arteries from SSc-PAH patients and hypoxia/SU5416 mice. PAECs treated with TNFα, IL-1β and TGFβ exhibited significant changes in morphology, loss of endothelial markers and elevated expression of mesenchymal markers by day 6. There was a significant (P 0.01) 5-fold increase in permeability compared to PAECs alone. Consistent with this, EndoMT cells co-cultured with PAECs in a ratio of 1:10 led to 2.5-fold significant (P>0.05) increase in permeability. Conclusion The co-localisation of vWF and αSMA present in the pulmonary arteries of SSc-PAH patients and pre-clinical models of PAH, is indicative of EndoMT. We demonstrate EndoMT leads to a loss of normal PAEC morphology and an enhanced secretion of pro-inflammatory chemokines. Furthermore EndoMT cells failed to form integral biological barriers and contributed to enhanced permeability of PAEC barriers. Collectively our data suggests that EndoMT may contribute to the loss of normal endothelium function and the development of SSc-PAH.
• Trinder, S., Abdi, S., Yu, R., Denton, C., Abraham, D., Holmes, A., & Good, R. B. (2014). Characterisation of late-outgrowth endothelial progenitor cells from systemic sclerosis patients. Clinical and Experimental Rheumatology 32(2):S32-S33.
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  Introduction. Vascular complications associated with systemic sclerosis (SSc) including pulmonary arterial hypertension (PAH-SSc), result from endothelial damage and loss of barrier function. The causes of endothelial dysfunction are unclear, but the integrity of the endothelium is likely to be significantly diminished in SSc. Endothelial progenitor cells (EPCs) derived from peripheral blood mononuclear cells (PBMCs) express endothelial and haematopoietic markers. It is thought they home to sites of vascular injury and differentiate into endothelial cells and restore the barrier. In SSc patients circulating levels of EPCs are reduced. This study aimed to: (i) develop a robust method to isolate and grow healthy control (HC) and SSc EPCs from PBMCs. (ii) Compare the cellular functions of EPCs to mature endothelial cells. Methods. Peripheral blood was taken from HC (n=10) and SSc donors (n=10). EPCs were cultured from PBMCs, and EPC colonies grown to passage 4. EPCs and human pulmonary artery endothelial cells (hPAECs) were seeded into transwell inserts and grown to confluence. Cells were incubated with TNF-α (10ng/ S-33 3rd Systemic Sclerosis World Congress Poster Tours - Clinical ml), and their capacity to form biological barriers and support immune cell influx was assessed using FITC-albumin (0.5mg/ml) and neutrophil transmigration. We further assessed the responses of EPCs to TNF-α stimulation by ELISA to quantify pro-inflammatory cytokine release. Results. We demonstrate that EPCs form biological barriers with similar capabilities as mature hPAECs in vitro. TNF-α significantly enhanced permeability of EPCs (p
• Trinder, S., Shiwen, X., Ahmed-abdi, B., Gilbane, A., Denton, C., Budd, D. C., Abraham, D., Holmes, A., & Good, R. B. (2014). THE ROLE OF MCSF AND ENDOTHELIN 1 IN FIBROCYTE DIFFERENTIATION. Clinical and Experimental Rheumatology 32(2):S59-S60.
• Ciuclan, L., Hussey, M. J., Duggan, N., Beach, S., Jones, P., Fox, R., Clay, I., Bonneau, O., Konstantinova, I., Rowlands, D. J., Jarai, G., Westwick, J., Maclean, M. R., Thomas, M., Pearce, A. C., Good, R. B., & Burton, V. J. (2013). Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression.. American journal of respiratory and critical care medicine, 187(1), 78-89. doi:10.1164/rccm.201206-1028oc
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  Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH..Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates..We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH..Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-β pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1-deficient mice (Tph1(-/-)). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1(-/-) mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1(-/-) mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo..We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-β signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis.
• Ciuclan, L., Duggan, N., Hussey, M., Bonneau, O., Rowlands, D. J., Burton, V. J., Jarai, G., Westwick, J., Thomas, M., & Good, R. B. (2012). Reduction in serotonin signaling via TPH1 inhibition attenuates the progression of PAH in mice with genetic ablation of endothelial BMPR-II. European Respiratory Journal, 40.
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  Introduction. Genetic studies in familial PAH have revealed heterozygous germline mutations in the BMPR2 gene and dysfunction of serotonin (5-HT) signaling has been implicated in other forms of PAH. Here we investigate a genetic model of PAH, where BMPR2 deletion is restricted to endothelial cells (ECs)-BMPR2 f/f ;ALK1-Cre strain, aiming to determine a relationship between pathologies mediated by 5-HT and BMPR2 signaling. Methods. We investigated the effects of p-chlorophenylalanine (pCPA; 200mg/kg- inhibits 5-HT synthesis by blocking tryptophan hydroxylase (TPH)), on hemodynamics, vascular remodeling and plasma signatures in wild-type (WT) and BMPR2 f/f ;ALK1-Cre mice (BMPR2-KO) exposed to chronic hypoxia under VEGFR inhibition (SU5416) for 3 weeks. Results. Pathobiology development profile of BMPR2-KO mice at 2 and 5 months of age, demonstrated that the older age group tended to have a higher frequency of increased right ventricular pressure (RVP) and hypertrophy (RVH). 2 month old BMPR2-KO mice exposed to chronic hypoxia/SU5416 developed higher RVP and RVH compared with WT controls. Normoxic WT and BMPR2-KO mice did not display significant changes in the above measurements when compared between groups. Treatment with pCPA reduced all measures of PAH pathology observed in chronic hypoxic/SU5416 treated BMPR2-KO mice. These changes were observed in accordance with a fall in platelet rich plasma 5-HT. Conclusion. Genetic ablation of the BMPR2 gene in pulmonary ECs is sufficient to predispose to PAH. Our data reveal interplay between BMPR2 signaling and the 5-HT system in ECs within PAH, leading to increased susceptibility to PAH progression.
• Ciuclan, L., Bonneau, O., Hussey, M., Duggan, N., Holmes, A. M., Stringer, R., Morrell, N. W., Jarai, G., Walker, C., Westwick, J., Thomas, M., Jones, P. L., & Good, R. B. (2011). A novel murine model of severe pulmonary arterial hypertension.. American journal of respiratory and critical care medicine, 184(10), 1171-82. doi:10.1164/rccm.201103-0412oc
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  The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in humans have been a challenge to reproduce in mice due to the subtle phenotype displayed to PAH stimuli..Here we aim to develop a novel murine model of PAH that recapitulates more of the pathologic processes, such as complex vascular remodeling and cardiac indices, that are not characteristic of alternative mouse models..Inhibition of vascular endothelial growth factor receptor (VEGFR) with SU5416 combined with 3 weeks of chronic hypoxia was investigated. Hemodynamics, cardiac function, histological assessment of pulmonary vasculature, and molecular pathway analysis gauged the extent of PAH pathology development..The combination of VEGFR inhibition with chronic hypoxia profoundly exacerbated all measures of PAH-like pathology when compared with hypoxia alone (> 45 mm Hg right ventricular pressure, > 0.35 right ventricular hypertrophy). The changes in pulmonary vascular remodeling in response to hypoxia were further enhanced on SU5416 treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased cardiac output, indicating incipient heart failure. Molecular analysis showed a dysregulated transforming growth factor-β/bone morphogenetic protein/Smad axis in SU5416- and/or hypoxia-treated mice as well as augmented induction of IL-6 and Hif-1α levels. These changes were observed in accordance with up-regulation of Tph1 and Pdgfr gene transcripts as well as a rise in platelet-rich serotonin. Biomarker analysis in response to VEGFR inhibition and/or hypoxia revealed distinct signatures that correlate with cytokine profiles of patients with idiopathic PAH..These data describe a novel murine model of PAH, which displays many of the hallmarks of the human disease, thus opening new avenues of investigation to better understand PAH pathophysiology.

Proceedings Publications

• Ciuclan, L. I., Hussey, M., Duggan, N., Burton, V. J., Beach, S., Jones, P., Fox, R., Konstantinova, I., Bonneau, O., Maclean, M. R., Jarai, G., Westwick, J., Thomas, M., Rowlands, D. J., Pearce, A. C., & Good, R. B. (2012). Imatinib Attenuates Hypoxia-Induced PAH Pathology Via Reduction In Serotonin Through Inhibition Of Tryptophan Hydroxylase 1 Expression. In A29. PATHOGENESIS OF PULMONARY HYPERTENSION.