QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing
Purpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves have been postulated to stimulate limbal stem cells (LSCs), hence governing corneal epithelial maintenance and...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer
2021-07-01
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| Series: | Plastic and Reconstructive Surgery, Global Open |
| Online Access: | http://journals.lww.com/prsgo/fulltext/10.1097/01.GOX.0000770032.15565.2d |
| _version_ | 1819118359340384256 |
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| author | Kiana Tajdaran Konstantin Feinberg Seyed Kaveh Mirmoeini Jennifer Zhang Tessa Gordon Gregory Borschel |
| author_facet | Kiana Tajdaran Konstantin Feinberg Seyed Kaveh Mirmoeini Jennifer Zhang Tessa Gordon Gregory Borschel |
| author_sort | Kiana Tajdaran |
| collection | DOAJ |
| description | Purpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves have been postulated to stimulate limbal stem cells (LSCs), hence governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is the human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies make this therapeutic approach less effective2. Development of the small molecule ligands for neurotrophins receptors that have better pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative conditions in the recent years3. In this study, we were prompted to investigate the molecular mechanism of NK and the role of NGF receptors, TrkA and p75NTR, in corneal healing. We hypothesized that TrkA inhibition would delay corneal wound healing and p75NTR inhibition accelerates corneal healing. This knowledge will lay the basis for a new non-invasive approach for NK.
Methods: For this experiment, we took advantage of commercially available Ntrk1 mutant mice, which allow for pharmacological inhibition of TrkA receptor with an inhibitor known as not mammalian kinase inhibitor (1-NM-PP1)4. Ntrk1 mice (n=20) were divided into three groups, which received saline injection as a control. In one experimental group animals were received TrkA inhibitor and the other group received both TrkA and p75 inhibitor for 5 days. On day six we removed the corneal epithelium with a 0.5 mm rotating brush. To measure epithelial healing, we performed digital imaging of fluorescein staining daily for four days after injury. We then harvested the corneas for immunofluorescent and biochemical analyses.
Results: Our results show a significant delay in corneal epithelial healing following TrkA inhibition and acceleration in corneal healing after p75NTR inhibition.
Conclusion: A selective TrkA agonist or p75NTR inhibitors could be a new therapeutic approach for NK. |
| first_indexed | 2024-12-22T05:47:37Z |
| format | Article |
| id | doaj.art-5b1a8b0acf1b40efa30a7ec5f3ff2b64 |
| institution | Directory Open Access Journal |
| issn | 2169-7574 |
| language | English |
| last_indexed | 2024-12-22T05:47:37Z |
| publishDate | 2021-07-01 |
| publisher | Wolters Kluwer |
| record_format | Article |
| series | Plastic and Reconstructive Surgery, Global Open |
| spelling | doaj.art-5b1a8b0acf1b40efa30a7ec5f3ff2b642022-12-21T18:36:58ZengWolters KluwerPlastic and Reconstructive Surgery, Global Open2169-75742021-07-0197S202010.1097/01.GOX.0000770032.15565.2d202107001-00028QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound HealingKiana Tajdaran0Konstantin Feinberg1Seyed Kaveh Mirmoeini2Jennifer Zhang3Tessa Gordon4Gregory Borschel5University of Toronto, Toronto, ON, Canada, The Hospital for Sick Children, Toronto, ON, Canada, Indiana University, Indianapolis, IndianaUniversity of Toronto, Toronto, ON, Canada, The Hospital for Sick Children, Toronto, ON, Canada, Indiana University, Indianapolis, IndianaUniversity of Toronto, Toronto, ON, Canada, The Hospital for Sick Children, Toronto, ON, Canada, Indiana University, Indianapolis, IndianaUniversity of Toronto, Toronto, ON, Canada, The Hospital for Sick Children, Toronto, ON, Canada, Indiana University, Indianapolis, IndianaUniversity of Toronto, Toronto, ON, Canada, The Hospital for Sick Children, Toronto, ON, Canada, Indiana University, Indianapolis, IndianaUniversity of Toronto, Toronto, ON, Canada, The Hospital for Sick Children, Toronto, ON, Canada, Indiana University, Indianapolis, IndianaPurpose: The cornea is the window through which we see the world and is one of the most densely innervated structures in the body. Besides providing protective sensory input, corneal nerves have been postulated to stimulate limbal stem cells (LSCs), hence governing corneal epithelial maintenance and recovery. Loss of corneal innervation, through injury, diabetes, tumors, infections, and even improper contact lens use, leads to neurotrophic keratopathy (NK), a degenerative corneal disease that is characterized by corneal epithelial breakdown, scarring, and permanent vision loss1. The only non-invasive treatment option for NK is the human recombinant nerve growth factor (rhNGF), but the short half-life of exogenous neurotrophins-based therapies make this therapeutic approach less effective2. Development of the small molecule ligands for neurotrophins receptors that have better pharmacokinetics and plasma stability showed promising results in the treatment of several neurodegenerative conditions in the recent years3. In this study, we were prompted to investigate the molecular mechanism of NK and the role of NGF receptors, TrkA and p75NTR, in corneal healing. We hypothesized that TrkA inhibition would delay corneal wound healing and p75NTR inhibition accelerates corneal healing. This knowledge will lay the basis for a new non-invasive approach for NK. Methods: For this experiment, we took advantage of commercially available Ntrk1 mutant mice, which allow for pharmacological inhibition of TrkA receptor with an inhibitor known as not mammalian kinase inhibitor (1-NM-PP1)4. Ntrk1 mice (n=20) were divided into three groups, which received saline injection as a control. In one experimental group animals were received TrkA inhibitor and the other group received both TrkA and p75 inhibitor for 5 days. On day six we removed the corneal epithelium with a 0.5 mm rotating brush. To measure epithelial healing, we performed digital imaging of fluorescein staining daily for four days after injury. We then harvested the corneas for immunofluorescent and biochemical analyses. Results: Our results show a significant delay in corneal epithelial healing following TrkA inhibition and acceleration in corneal healing after p75NTR inhibition. Conclusion: A selective TrkA agonist or p75NTR inhibitors could be a new therapeutic approach for NK.http://journals.lww.com/prsgo/fulltext/10.1097/01.GOX.0000770032.15565.2d |
| spellingShingle | Kiana Tajdaran Konstantin Feinberg Seyed Kaveh Mirmoeini Jennifer Zhang Tessa Gordon Gregory Borschel QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing Plastic and Reconstructive Surgery, Global Open |
| title | QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing |
| title_full | QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing |
| title_fullStr | QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing |
| title_full_unstemmed | QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing |
| title_short | QS8: The Roles of the TrkA and p75NTR NGF Receptors in Corneal Wound Healing |
| title_sort | qs8 the roles of the trka and p75ntr ngf receptors in corneal wound healing |
| url | http://journals.lww.com/prsgo/fulltext/10.1097/01.GOX.0000770032.15565.2d |
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