Damage repair mechanisms in sensory hair cells

Allen, Nicola Jayne (2015) Damage repair mechanisms in sensory hair cells. Doctoral thesis (PhD), University of Sussex.

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Abstract

Aminoglycoside antibiotics are a class of drug used to treat bacterial infections but have the unfortunate side effect of being both oto- and nephro-toxic. Deafness caused by aminoglycoside ototoxicity results from a loss of sensory hair cells from the inner ear. In vitro, two early effects of aminoglycoside exposure can be observed. First, membrane blebs are formed around the perimeter of the hair-cell apical surface. Secondly phosphatidylserine (PS), an aminophospholipid that is normally restricted to the inner leaflet of the plasma membrane, flops to the outer leaflet. This membrane damage occurs rapidly, within 90-120 seconds of drug exposure and can be completely reversed. The aim of this thesis was to determine the molecular mechanisms underlying damage repair in sensory hair cells recovering from aminoglycoside damage. TEM studies using cationic ferritin as a tracer indicates the repair process involves membrane internalisation, but recovery cannot be blocked by inhibitors of macropinocytosis, the clathrin-independent carrier (CLIC) pathway, PI3 kinase, PKC, Pak1 or of the clathrin-coated pit pathway. Damage repair is, however, prevented by the actin stabiliser jasplakinolide and the inhibitor of Protein kinase A, H-89. In addition, the CLIC pathway inhibitor EIPA has been uncovered as a reversible blocker of aminoglycoside entry into hair cells.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0573 Cytology
Depositing User: Library Cataloguing
Date Deposited: 15 Oct 2015 09:33
Last Modified: 15 Oct 2015 09:33
URI: http://sro.sussex.ac.uk/id/eprint/57127

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