K16 as a novel regulator of Nrf2 function in glabrous skin: Implications for pachyonychia congenita and its treatment
| dc.contributor.advisor | Coulombe, Pierre A. | |
| dc.contributor.committeeMember | Caterina, Michael J. | |
| dc.creator | Lu, Rosemary | |
| dc.creator.orcid | 0000-0002-4918-3579 | |
| dc.date.accessioned | 2017-04-19T12:20:17Z | |
| dc.date.available | 2017-04-19T12:20:17Z | |
| dc.date.created | 2016-08 | |
| dc.date.issued | 2016-08-17 | |
| dc.date.submitted | August 2016 | |
| dc.date.updated | 2017-04-19T12:20:17Z | |
| dc.description.abstract | The painful palmoplantar keratoderma (PPK) arising in individuals with pachyonychia congenita (PC) exhibit a significant upregulation of danger-associated molecular patterns and skin barrier regulators. Mice null for keratin 16 (Krt16), one of the genes mutated in PC, faithfully reproduce the morphological and molecular features of PC-associated PPK. We show here that onset of PPK is preceded by oxidative stress in male Krt16-/- mouse footpad skin, correlating with an inability of keratinocytes to sustain Nrf2-dependent expression of enzymes involved in the synthesis of the cellular antioxidant glutathione (GSH). Hypoactivity of Nrf2 coincides with impaired PKCδ activity and reduced levels of RACK1 protein in Krt16-/- footpad skin. Topical application of the small-molecule Nrf2 activator sulforaphane (SF) in male Krt16-/- mice prevents the development of PPK alongside a normalization of redox balance via the stimulation of GSH reductase and regeneration of GSH from existing cellular pools. Relative to males, female Krt16-/- mice exhibit faulty responsiveness to SF treatment. Preliminary data suggests that dual treatment of footpad skin with SF and selective estrogen receptor β agonist diarylpropionitrile (DPN) prevents the development of PPK lesions in female Krt16-/- mice. These findings point to oxidative stress and hypoactive Nrf2 as contributors to the pathogenesis of PC-related PPK and identify K16 as a regulator of the RACK1-PKCδ-NRF2 axis in skin keratinocytes. This pathway appears to be more complex in female Krt16-/- mice due to fundamental sex-based differences and, specifically, to a significant contribution of estrogen receptor signaling to modulation of Nrf2 function in skin keratinocytes. Our findings suggest a potential avenue to treat PC-associated PPK and may extend to similar keratin-based disorders. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://jhir.library.jhu.edu/handle/1774.2/40243 | |
| dc.language | en | |
| dc.publisher | Johns Hopkins University | |
| dc.publisher.country | USA | |
| dc.subject | PPK | |
| dc.subject | Nrf2 | |
| dc.subject | oxidative stress | |
| dc.title | K16 as a novel regulator of Nrf2 function in glabrous skin: Implications for pachyonychia congenita and its treatment | |
| dc.type | Thesis | |
| dc.type.material | text | |
| thesis.degree.department | Biochemistry and Molecular Biology | |
| thesis.degree.discipline | Biochemistry | |
| thesis.degree.grantor | Johns Hopkins University | |
| thesis.degree.grantor | Bloomberg School of Public Health | |
| thesis.degree.level | Masters | |
| thesis.degree.name | Sc.M. |