Project Details
Description
The potential importance of a primary barrier abnormality in atopic dermatitis (AD pathogenesis is supported by recent descriptions of mutations in the gene encoding for fillagrin (FLG). Both the involved and uninvolved skin of Ad display phenotype-dependent permeability barrier abnormalities. Not only barrier-associated genetic factors, but also at least 3 key environmental stressors (relative humidity, pH, and psychological stress) can trigger/exacerbate human AD; and eac of these stressors negatively-impacts permeability barries function in normal skin. It is our central hypothesis that loss of FLG in Ad results in an increase in the pH of the SC, resulting in progressive activation of serine protease (SP), with a multitude of negative consequences. The importance of this mechanism is shown most-dramatically in the recessive disorder, Netherton Syndrome (NS), where mutations in SPINK5, resulting in loss of the SP inhibitor, LEKTI are accompanied by phenotype-dependent increases in SP activity. Sustained increases in SP activity , due to decrease LEKTI expression, can trigger severe AD-like inflammation, and high IgE levels. The fact that the severity of the AD phenotype correlates directly with the extent of SP activation strongly supports our pathogenic hypothesis, as does the association of AD in kindreds with single nucleotide polymorphisms (SNPs) in SPINK5, and putative, gain-of-function SNPs in the gene encoding the outer epidermis-specific SP (Kallikrein 7, KLK7) could contribute to AD pathogenesis, through sustained elevations in SP activity.
Acronym | OZR1808 |
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Status | Finished |
Effective start/end date | 1/01/09 → 31/12/09 |
Keywords
- Dermatology
Flemish discipline codes in use since 2023
- Basic sciences
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