Structure-function studies of aquaporin 0 in lens development and physiology

Active Project Grant Awarded Last action

Award ID
R01EY031587
Recipient
Awarding agency
Obligated
$5,483,051

Award facts

Assistance listing
93.867 Vision Research
Completion date 96% complete
Originally
Funding
  • $4,992,327.00 Federal
  • $490,724.00 Non-federal
Place of performance
California, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Cataract, the opacification of the eye lens, is the leading cause of blindness worldwide. Aquaporin 0 (AQP0), the most abundant membrane protein in the lens, functions as a water channel and as an adhesive protein. Defects in AQP0 can produce cataract, as well as have adverse effects on lens development. Despite its critical role in lens physiology, the functions of AQP0 are not fully understood. Our proposed research seeks to advance our understanding of how AQP0 water permeability (PF), the exquisite control of which is required to maintain lens clarity, is regulated by CA2+ and protons, whose concentrations depend on the AQP0 location within the lens. The proposed studies also seek to identify the amino acid residues that are crucial for PF regulation and for the adhesive function of AQP0, through protein-protein and/or protein-membrane interactions, and to determine the effects of genetic modifications of AQP0 on lens physiology and development. To these ends, we will employ a tightly coupled, multi- disciplinary approach, unique within the field of aquaporin research, which employs techniques ranging in scale from the atomic/molecular to the cellular and organismal level. Specifically, in aim 1 we propose to use in vitro xenopus oocyte permeability measurements on a panel of mammalian and fish AQP0 mutants to assess the contribution of particular residues to AQP0 PF and its regulation, along with adhesion assays on lens fiber cells from zebrafish containing wild-type and mutant AQP0S. These experimental approaches will be complemented in aim 1 with in silico multi-ΜS molecular dynamics simulations, validated by comparison with experimental PF measurements, to elucidate mechanistic aspects of the influence of CA2+ via calmodulin binding, PH, including the effects of a variety of strategically chosen mutations on the PF of mammalian and fish AQP0S. The computer simulations proposed in aim 1 will also address the relative role of protein-protein and protein-membrane interactions in the adhesive function of AQP0. Aim 2 will use genetically modified zebrafish to determine how AQP0 contributes to the structure and function of the lens and its development in vivo. Our work will improve understanding of lens physiology and the molecular mechanisms of water channel gating and its regulation by CA2+ and PH, and uncover fundamental principles that could inform the future development of therapeutic strategies for delaying or eliminating cataract formation.

Transactions

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Amendment $490,724 $0
Original award $490,724 $490,724
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Subawards

Subrecipient Amount Awarded
Auckland Uniservices LIMITED The Donaldson lab at the University of Auckland will make a suite of measurements on zebrafish lenses to determine how water transport, its regulation, and… $23,715
The University Of Auckland $39,253

Quick answers

Who received award R01EY031587?

R01EY031587 was awarded to University Of California Irvine by National Eye Institute (National Institutes of Health) on February 1, 2021.

How much is award R01EY031587 worth?

$5,483,051 has been obligated on R01EY031587: $4,992,327 in federal funding and $490,724 in non-federal funding.

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