[K08] The Impact of TrpA1/TrpV1 activity on the Ocular Mucinome
Ente: National Eye Institute
Scadenza: 2031-02-28
Importo max: 175.293 EUR
Paese: US
Descrizione
Project Summary/Abstract:
In the USA, most bacterial infections of the cornea are caused by Pseudomonas aeruginosa and Staphylococcus
aureus, each recognized by the CDC as highly antimicrobial resistant ESKAPE pathogens. Such infections are
difficult to treat and can cause irreversible vision loss. Fortunately, the healthy cornea possesses factors making
it intrinsically resistant to bacterial adhesion, and therefore infection. Over three decades, the Fleiszig lab has
uncovered multiple contributors to this resistance, which include both cell membrane associated and soluble
mucins, antimicrobial peptides, aggregating proteins, and corneal epithelial cell polarity and their junctions. In
addition to acting directly, mucins can modulate the other adhesion defenses, e.g. by sequestering antimicrobial
peptides, interacting with tear proteins, and influencing the biology of epithelial cells.
The cornea is the most innervated tissue in the body. Transient Receptor Potential (TRP) cation channels
on sensory nerves respond to a range of thermal, noxious, and potentially pathogenic stimuli. In the cornea they
are primarily TRPV1 (Vanilloid), with TRPA1 (Ankyrin) on a subset of TRPV1 expressing nerves. Recently our
lab reported that TRPV1 and TRPA1 differentially contribute to defense against bacterial adhesion; with TRPV1
countering S. aureus, and TRPA1 instead countering P. aeruginosa. Only the latter depends on nerve firing.
While TRP channels have been shown to modulate mucin expression in some systems, that has not yet
been studied in the eye in vivo. Here, I will test the hypothesis that TRPV1 and TRPA1 differentially modulate
mucin expression at the corneal surface. Aim 1 will compare the impact on mucin-related transcription in corneal
epithelial and conjunctival cells using RNAseq validated by qRT-PCR, with Aim 2 employing novel strategies to
assay mucins directly using both mass spectrometry and confocal imaging. This project is a necessary step
towards understanding the contribution of mucins to TRP-receptor dependent bacterial adhesion defenses. This
research could lead to novel strategies for protecting corneas against infection. Since mucin dysregulation has
been linked to other pathologies relevant to TRPA1 and TRPV1, including Dry Eye Disease, Sjogren’s
Syndrome, and complications secondary to contact lenses, the relevance could extend to pathology beyond
infection. Moreover, the experimental design will also advance our understanding of the mucinome in healthy
eyes. The results might be relevant to other mucosal surfaces, e.g. the gastrointestinal, respiratory, and
reproductive systems which are also lined with both mucins and TRP channels. Completing this particular project
with guidance from leaders in both eye research and mucin biology, completing aims that build upon on their
collective discoveries using tools that they developed, and with the necessary resources at hand in the labs of
my mentors, will help me reach my goal of estab
Istituzione: UNIVERSITY OF CALIFORNIA BERKELEY
PI: Sara Abboud
Progetto: 1K08EY039016-01
Settori: National Eye Institute
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