Therapeutic targeting of endothelial calcium signaling accelerates the resolution of lung injury
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| Publicat a: | Signal Transduction and Targeted Therapy vol. 10, no. 1 (2025), p. 375-396 |
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| Altres autors: | , , , , , , , , , , , , , , , , , , , , |
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Nature Publishing Group
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| 024 | 7 | |a 10.1038/s41392-025-02461-y |2 doi | |
| 035 | |a 3273107189 | ||
| 045 | 2 | |b d20250101 |b d20251231 | |
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| 100 | 1 | |a Chan, Wan Ching |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 245 | 1 | |a Therapeutic targeting of endothelial calcium signaling accelerates the resolution of lung injury | |
| 260 | |b Nature Publishing Group |c 2025 | ||
| 513 | |a Journal Article | ||
| 520 | 3 | |a Acute respiratory distress syndrome (ARDS) is a severe pulmonary disease characterized by acute, noncardiogenic pulmonary edema and hypoxemia leading to respiratory failure. It is induced by a diverse array of etiologies, including recent SARS-CoV-2 infection. The current standard of care for ARDS remains predominantly supportive, underscoring the urgent need for targeted pharmacological interventions. To address this critical gap, we developed an inhibitor of the microtubule accessory factor end-binding protein 3 (EB3), a key mediator of pathological calcium signaling in endothelial cells. During injury, EB3 facilitates inositol 1,4,5-trisphosphate receptor 3 (IP3R3) clustering on the endoplasmic reticulum membrane, activating widespread calcium release from intracellular stores and leading to endothelial barrier disruption. Using nuclear magnetic resonance (NMR)-guided approaches, we designed and optimized a synthetic EB3 inhibitor, termed vascular therapeutics (VT)-109, with enhanced physicochemical properties. We evaluated the therapeutic potential of VT-109 across a wide range of preclinical models in which pathogenic insults target epithelial or endothelial barriers. Treatment with VT-109 promptly restored the tissue‒fluid balance in the injured lung by inducing the reannealing of VE-cadherin junctions and restoring the endothelial barrier. In addition to vascular protection, VT-109 improved lung architecture and function, normalized immune responses, and significantly reduced both morbidity and mortality in ARDS models. At the molecular level, VT-109 blocks inflammatory NFAT and NFκB signaling while concurrently activating FOXM1-dependent endothelial regeneration. These findings support EB3 inhibition as a promising therapeutic strategy for ARDS and highlight VT-109 as a versatile drug candidate capable of addressing the multifaceted pathophysiology of this disease. | |
| 653 | |a Morbidity | ||
| 653 | |a Calcium signalling | ||
| 653 | |a Endoplasmic reticulum | ||
| 653 | |a Severe acute respiratory syndrome coronavirus 2 | ||
| 653 | |a Mortality | ||
| 653 | |a Sepsis | ||
| 653 | |a Physicochemical properties | ||
| 653 | |a Therapeutic targets | ||
| 653 | |a Respiratory distress syndrome | ||
| 653 | |a Amino acids | ||
| 653 | |a NF-κB protein | ||
| 653 | |a Calcium (intracellular) | ||
| 653 | |a Peptides | ||
| 653 | |a NF-AT protein | ||
| 653 | |a Drug development | ||
| 653 | |a Kinases | ||
| 653 | |a Nuclear magnetic resonance--NMR | ||
| 653 | |a Proteins | ||
| 653 | |a COVID-19 | ||
| 653 | |a Calcium (reticular) | ||
| 653 | |a Immune response | ||
| 653 | |a Hypoxemia | ||
| 653 | |a Edema | ||
| 653 | |a Pneumonia | ||
| 653 | |a Pathophysiology | ||
| 653 | |a Lung diseases | ||
| 653 | |a Design | ||
| 653 | |a Endothelial cells | ||
| 653 | |a Inositol trisphosphate | ||
| 700 | 1 | |a Kwok, Man Long |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Qu, Xinyan |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Abdelkarim, Hazem |u Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Le, Jonathan |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Yang, Deying |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Banerjee, Avik |u Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Zhao, Shuangping |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Class, Jacob |u Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Gonzalez, Marlen |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Hailemeskel, Harry |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Singh, Raman Ghotra |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Gallardo-Macias, Ricardo |u Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, USA (ROR: https://ror.org/017zqws13) (GRID: grid.17635.36) (ISNI: 0000 0004 1936 8657) | |
| 700 | 1 | |a Gurvich, Vadim J. |u Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, MN, USA (ROR: https://ror.org/017zqws13) (GRID: grid.17635.36) (ISNI: 0000 0004 1936 8657) | |
| 700 | 1 | |a Maienschein-Cline, Mark |u Research Informatics Core, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Lindeblad, Matthew |u Toxicology Research Laboratory, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Kabirov, Kasim |u Toxicology Research Laboratory, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Lyubimov, Alexander V. |u Toxicology Research Laboratory, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Belvitch, Patrick |u Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Richner, Justin |u Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Gaponenko, Vadim |u Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 700 | 1 | |a Komarova, Yulia A. |u Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, USA (ROR: https://ror.org/02mpq6x41) (GRID: grid.185648.6) (ISNI: 0000 0001 2175 0319) | |
| 773 | 0 | |t Signal Transduction and Targeted Therapy |g vol. 10, no. 1 (2025), p. 375-396 | |
| 786 | 0 | |d ProQuest |t Health & Medical Collection | |
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