Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza
dissertation The mature capillary network, comprised of a quiescent endothelial cell monolayer, utilizes tight cell-cell interactions to maintain vascular stability and limit vascular leak. An essential component of these intercellular contacts is the adherens junction protein vascular endothelial c...
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ftunivutah:oai:collections.lib.utah.edu:ir_etd/196322 2023-05-15T15:34:34+02:00 Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza Doctor of Philosophy London, Jr. Nyall R. School of Medicine Oncological Sciences University of Utah 2011-08 application/pdf 39,996,636 bytes https://collections.lib.utah.edu/ark:/87278/s6vb1h8w eng eng University of Utah Digital reproduction of Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections. https://collections.lib.utah.edu/ark:/87278/s6vb1h8w Copyright © Nyall R. London Jr. 2011 Original in Marriott Library Special Collections, QR6.5 2011.L66 Receptors Cell Surface Signal Transduction Sepsis Neovascularization Pathologic Influenza Human Vascular Endothelial Growth Factors Cytokines Hypercytokinemia Text 2011 ftunivutah 2021-12-02T18:17:46Z dissertation The mature capillary network, comprised of a quiescent endothelial cell monolayer, utilizes tight cell-cell interactions to maintain vascular stability and limit vascular leak. An essential component of these intercellular contacts is the adherens junction protein vascular endothelial cadherin (VE-cadherin). In multiple disease settings such as macular degeneration, sepsis, and pandemic influenza, the endothelium is activated and destabilized by cytokines such as vascular endothelial growth factor (VEGF), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). While an innate immune response is necessary to combat infection, an exuberant cytokine release can paradoxically injure the host endothelium, resulting in vascular damage, tissue edema, and death. In this dissertation we demonstrate that an endogenous, endothelial-specific Roundabout (Robo), Robo4, maintains vascular stability and quiescence. Administration of Slit, an endogenous activator of Robo receptors, strengthens endothelial barrier function and limits vascular leak in a Robo4-dependent manner. Furthermore, Slit treatment enhanced survival during sepsis and avian flu infection, diseases both characterized by hypercytokinemia. We also discovered that Slit strengthens the vascular barrier by increasing VE-cadherin localization at the cell surface. Slit also increases p120-catenin localization at the cell surface and enhances the interaction of p120-catenin with VE-cadherin, preventing the internalization of VE-cadherin. Furthermore, Robo4 activation leads to the recruitment of a paxillin-GIT1 signaling module that inactivates Arf6. Arf6 plays a known role in regulating endocytic recycling, thus perhaps defining Robo4-dependent Slit signaling as a paxillin-GIT1-Arf6-p120-catenin-VE-cadherin stabilization pathway. Our studies fundamentally demonstrate that by specifically blunting the vascular response to hypercytokinemia, mortality can be reduced during severe experimental infections. Activation of a vascular stabilizing pathway such as Robo4 may therefore provide a platform for treating multiple infectious threats characterized by an exuberant cytokine response. Text Avian flu The University of Utah: J. Willard Marriott Digital Library |
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The University of Utah: J. Willard Marriott Digital Library |
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ftunivutah |
language |
English |
topic |
Receptors Cell Surface Signal Transduction Sepsis Neovascularization Pathologic Influenza Human Vascular Endothelial Growth Factors Cytokines Hypercytokinemia |
spellingShingle |
Receptors Cell Surface Signal Transduction Sepsis Neovascularization Pathologic Influenza Human Vascular Endothelial Growth Factors Cytokines Hypercytokinemia London, Jr. Nyall R. Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
topic_facet |
Receptors Cell Surface Signal Transduction Sepsis Neovascularization Pathologic Influenza Human Vascular Endothelial Growth Factors Cytokines Hypercytokinemia |
description |
dissertation The mature capillary network, comprised of a quiescent endothelial cell monolayer, utilizes tight cell-cell interactions to maintain vascular stability and limit vascular leak. An essential component of these intercellular contacts is the adherens junction protein vascular endothelial cadherin (VE-cadherin). In multiple disease settings such as macular degeneration, sepsis, and pandemic influenza, the endothelium is activated and destabilized by cytokines such as vascular endothelial growth factor (VEGF), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α). While an innate immune response is necessary to combat infection, an exuberant cytokine release can paradoxically injure the host endothelium, resulting in vascular damage, tissue edema, and death. In this dissertation we demonstrate that an endogenous, endothelial-specific Roundabout (Robo), Robo4, maintains vascular stability and quiescence. Administration of Slit, an endogenous activator of Robo receptors, strengthens endothelial barrier function and limits vascular leak in a Robo4-dependent manner. Furthermore, Slit treatment enhanced survival during sepsis and avian flu infection, diseases both characterized by hypercytokinemia. We also discovered that Slit strengthens the vascular barrier by increasing VE-cadherin localization at the cell surface. Slit also increases p120-catenin localization at the cell surface and enhances the interaction of p120-catenin with VE-cadherin, preventing the internalization of VE-cadherin. Furthermore, Robo4 activation leads to the recruitment of a paxillin-GIT1 signaling module that inactivates Arf6. Arf6 plays a known role in regulating endocytic recycling, thus perhaps defining Robo4-dependent Slit signaling as a paxillin-GIT1-Arf6-p120-catenin-VE-cadherin stabilization pathway. Our studies fundamentally demonstrate that by specifically blunting the vascular response to hypercytokinemia, mortality can be reduced during severe experimental infections. Activation of a vascular stabilizing pathway such as Robo4 may therefore provide a platform for treating multiple infectious threats characterized by an exuberant cytokine response. |
author2 |
School of Medicine Oncological Sciences University of Utah |
format |
Text |
author |
London, Jr. Nyall R. |
author_facet |
London, Jr. Nyall R. |
author_sort |
London, Jr. Nyall R. |
title |
Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
title_short |
Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
title_full |
Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
title_fullStr |
Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
title_full_unstemmed |
Targeting Robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
title_sort |
targeting robo4-dependent slit signaling to survive the cytokine storm in sepsis and influenza |
publisher |
University of Utah |
publishDate |
2011 |
url |
https://collections.lib.utah.edu/ark:/87278/s6vb1h8w |
genre |
Avian flu |
genre_facet |
Avian flu |
op_source |
Original in Marriott Library Special Collections, QR6.5 2011.L66 |
op_relation |
Digital reproduction of Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections. https://collections.lib.utah.edu/ark:/87278/s6vb1h8w |
op_rights |
Copyright © Nyall R. London Jr. 2011 |
_version_ |
1766364913648795648 |