9 results on '"Andrew M. Tager"'
Search Results
2. Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis
- Author
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Yang Yang, Daniela M. Santos, Lorena Pantano, Rachel Knipe, Elizabeth Abe, Amanda Logue, Gina Pronzati, Katharine E. Black, Jillian J. Spinney, Francesca Giacona, Michael Bieler, Cedrickx Godbout, Paul Nicklin, David Wyatt, Andrew M. Tager, Peter Seither, Franziska E. Herrmann, and Benjamin D. Medoff
- Subjects
Cell Nucleus ,Pulmonary and Respiratory Medicine ,Pulmonary Fibrosis ,Clinical Biochemistry ,Cell Cycle Proteins ,YAP-Signaling Proteins ,Cell Biology ,Fibroblasts ,Phosphoproteins ,Idiopathic Pulmonary Fibrosis ,Mice ,Transforming Growth Factor beta ,Animals ,Humans ,Molecular Biology ,Original Research ,Adaptor Proteins, Signal Transducing ,Aurora Kinase A - Abstract
Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.
- Published
- 2022
3. Reply to Kalverda et al.: Endobronchial Optical Coherence Tomography: Shining New Light on Diagnosing Usual Interstitial Pneumonitis?
- Author
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Sreyankar Nandy, Rebecca A. Raphaely, Ashok Muniappan, Angela Shih, Benjamin W. Roop, Amita Sharma, Colleen M. Keyes, Thomas V. Colby, Hugh G. Auchincloss, Henning A. Gaissert, Michael Lanuti, Christopher R. Morse, Harald C. Ott, John C. Wain, Cameron D. Wright, Maria L. Garcia-Moliner, Maxwell L. Smith, Paul A. VanderLaan, Sarita R. Berigei, Mari Mino-Kenudson, Nora K. Horick, Lloyd L. Liang, Diane L. Davies, Margit V. Szabari, Peter Caravan, Benjamin D. Medoff, Andrew M. Tager, Melissa J. Suter, and Lida P. Hariri
- Subjects
Pulmonary and Respiratory Medicine ,Critical Care and Intensive Care Medicine - Published
- 2022
4. Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model
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Anna Axelsson Raja, Hiroko Wakimoto, Daniel M. DeLaughter, Daniel Reichart, Joshua Gorham, David A. Conner, Mingyue Lun, Clemens K. Probst, Norihiko Sakai, Rachel S. Knipe, Sydney B. Montesi, Barry Shea, Leonard P. Adam, Leslie A. Leinwand, William Wan, Esther Sue Choi, Eric L. Lindberg, Giannino Patone, Michela Noseda, Norbert Hübner, Christine E. Seidman, Andrew M. Tager, J. G. Seidman, and Carolyn Y. Ho
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Disease Models, Animal ,Mice ,Multidisciplinary ,Cardiovascular and Metabolic Diseases ,Animals ,Endothelial Cells ,Hypertrophy ,Cardiomyopathy, Hypertrophic ,Receptors, Lysophosphatidic Acid ,Carrier Proteins ,Fibrosis - Abstract
Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM. Lysphosphatidic acid receptor 1 (LPAR1), a cell surface receptor, is required for lysophosphatidic acid mediation of fibrosis. We bred HCM mice carrying a pathogenic myosin heavy-chain variant (403 +/− ) with Lpar1 -ablated mice to create mice carrying both genetic changes (403 +/− LPAR1 −/− ) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403 +/− LPAR1 WT , 403 +/− LPAR1 −/− mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that Lpar1 was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts. Lpar1 ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for Reln and Ccl21a . Lpar1 ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that Lpar1 is expressed predominantly by LECs and fibroblasts in the heart and is required for development of hypertrophy and fibrosis in an HCM mouse model. LPAR1 antagonism, including agents in clinical trials for other fibrotic diseases, may be beneficial for HCM.
- Published
- 2023
5. Reply to Kalverda
- Author
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Sreyankar, Nandy, Rebecca A, Raphaely, Ashok, Muniappan, Angela, Shih, Benjamin W, Roop, Amita, Sharma, Colleen M, Keyes, Thomas V, Colby, Hugh G, Auchincloss, Henning A, Gaissert, Michael, Lanuti, Christopher R, Morse, Harald C, Ott, John C, Wain, Cameron D, Wright, Maria L, Garcia-Moliner, Maxwell L, Smith, Paul A, VanderLaan, Sarita R, Berigei, Mari, Mino-Kenudson, Nora K, Horick, Lloyd L, Liang, Diane L, Davies, Margit V, Szabari, Peter, Caravan, Benjamin D, Medoff, Andrew M, Tager, Melissa J, Suter, and Lida P, Hariri
- Published
- 2022
6. Specialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules
- Author
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Kristin Rattay, Ki-Wook Kim, Elisabeth H. Vollmann, Steffen Jung, Ulrich H. von Andrian, Vladimir Vrbanac, Andrew M. Tager, Rebecca A Fuhlbrigge, Olga Barreiro, and Aude Thiriot
- Subjects
Chemokine ,Stromal cell ,Central tolerance ,Science ,Antigen-presenting cells ,CX3C Chemokine Receptor 1 ,General Physics and Astronomy ,Thymus Gland ,Autoantigens ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Negative selection ,Antigen ,Cell Movement ,Animals ,Humans ,Antigen-presenting cell ,CX3CL1 ,Thymic T cell selection ,Thymocytes ,Multidisciplinary ,biology ,Chemokine CX3CL1 ,Chemistry ,Endothelial Cells ,Cell Differentiation ,Dendritic Cells ,General Chemistry ,Thymus ,Cell biology ,Mice, Inbred C57BL ,Blood ,Self Tolerance ,biology.protein - Abstract
T cells undergo rigorous selection in the thymus to ensure self-tolerance and prevent autoimmunity, with this process requiring innocuous self-antigens (Ags) to be presented to thymocytes. Self-Ags are either expressed by thymic stroma cells or transported to the thymus from the periphery by migratory dendritic cells (DCs); meanwhile, small blood-borne peptides can access the thymic parenchyma by diffusing across the vascular lining. Here we describe an additional pathway of thymic Ag acquisition that enables circulating antigenic macromolecules to access both murine and human thymi. This pathway depends on a subset of thymus-resident DCs, distinct from both parenchymal and circulating migratory DCs, that are positioned in immediate proximity to thymic microvessels where they extend cellular processes across the endothelial barrier into the blood stream. Transendothelial positioning of DCs depends on DC-expressed CX3CR1 and its endothelial ligand, CX3CL1, and disrupting this chemokine pathway prevents thymic acquisition of circulating proteins and compromises negative selection of Ag-reactive thymocytes. Thus, transendothelial DCs represent a mechanism by which the thymus can actively acquire blood-borne Ags to induce and maintain central tolerance., T cells are selected in the thymus, through interaction with self-antigens, to remove autoreactive cells. Here the authors show that a specialized thymic dendritic cell subset juxtaposes to microvessels, requires CX3CR1/CX3CL1 for this positioning, and has processes extruding into the blood stream to sample soluble macromolecules and assist in T cell selection.
- Published
- 2021
7. Author Correction: An injectable bone marrow–like scaffold enhances T cell immunity after hematopoietic stem cell transplantation
- Author
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David T. Scadden, Matthew D Kerr, Theresa M. Raimondo, Vladimir Vrbanac, Angelo S. Mao, James C. Weaver, Azeem Sharda, Nisarg J. Shah, David J. Mooney, Maud Deruaz, Ting-Yu Shih, and Andrew M. Tager
- Subjects
Scaffold ,business.industry ,medicine.medical_treatment ,Biomedical Engineering ,Bioengineering ,Hematopoietic stem cell transplantation ,Applied Microbiology and Biotechnology ,Injectable bone ,Cancer research ,T cell immunity ,Molecular Medicine ,Medicine ,business ,Biotechnology - Published
- 2021
8. Myofibroblast-specific inhibition of the Rho kinase-MRTF-SRF pathway using nanotechnology for the prevention of pulmonary fibrosis.
- Author
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Knipe RS, Nurunnabi M, Probst CK, Spinney JJ, Abe E, Bose RJC, Ha K, Logue A, Nguyen T, Servis R, Drummond M, Haring A, Brazee PL, Medoff BD, and McCarthy JR
- Subjects
- Humans, Animals, Mice, Myofibroblasts metabolism, Serum Response Factor metabolism, rho-Associated Kinases metabolism, Fibrosis, Lung metabolism, Nanotechnology, Cell Differentiation, Transcription Factors metabolism, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis drug therapy, Pulmonary Fibrosis prevention & control
- Abstract
Pulmonary fibrosis is characterized by the accumulation of myofibroblasts in the lung and progressive tissue scarring. Fibroblasts exist across a spectrum of states, from quiescence in health to activated myofibroblasts in the setting of injury. Highly activated myofibroblasts have a critical role in the establishment of fibrosis as the predominant source of type 1 collagen and profibrotic mediators. Myofibroblasts are also highly contractile cells and can alter lung biomechanical properties through tissue contraction. Inhibiting signaling pathways involved in myofibroblast activation could therefore have significant therapeutic value. One of the ways myofibroblast activation occurs is through activation of the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) pathway, which signals through intracellular actin polymerization. However, concerns surrounding the pleiotropic and ubiquitous nature of these signaling pathways have limited the translation of inhibitory drugs. Herein, we demonstrate a novel therapeutic antifibrotic strategy using myofibroblast-targeted nanoparticles containing a MTRF/SRF pathway inhibitor (CCG-1423), which has been shown to block myofibroblast activation in vitro. Myofibroblasts were preferentially targeted via the angiotensin 2 receptor, which has been shown to be selectively upregulated in animal and human studies. These nanoparticles were nontoxic and accumulated in lung myofibroblasts in the bleomycin-induced mouse model of pulmonary fibrosis, reducing the number of these activated cells and their production of profibrotic mediators. Ultimately, in a murine model of lung fibrosis, a single injection of these drugs containing targeted nanoagents reduced fibrosis as compared with control mice. This approach has the potential to deliver personalized therapy by precisely targeting signaling pathways in a cell-specific manner, allowing increased efficacy with reduced deleterious off-target effects.
- Published
- 2023
- Full Text
- View/download PDF
9. Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis.
- Author
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Knipe RS, Spinney JJ, Abe EA, Probst CK, Franklin A, Logue A, Giacona F, Drummond M, Griffith J, Brazee PL, Hariri LP, Montesi SB, Black KE, Hla T, Kuo A, Cartier A, Engelbrecht E, Christoffersen C, Shea BS, Tager AM, and Medoff BD
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- Animals, Bleomycin, Blood Coagulation, Gene Deletion, Idiopathic Pulmonary Fibrosis blood, Lung blood supply, Lung pathology, Lysophospholipids blood, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, RNA-Seq, Single-Cell Analysis, Sphingosine analogs & derivatives, Sphingosine blood, Mice, Capillary Permeability, Endothelial Cells metabolism, Idiopathic Pulmonary Fibrosis metabolism, Idiopathic Pulmonary Fibrosis pathology, Sphingosine-1-Phosphate Receptors metabolism
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell-(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC- S1pr1
-/- ) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC- S1pr1-/- mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC- S1pr1-/- mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.- Published
- 2022
- Full Text
- View/download PDF
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