A A A
Project 1
Project 2
Project 3

Projects

Homeostasis in the inner ear

Summary

Normal hearing relies on the maintenance of a constant chemical environment within the tissues of the inner ear. This so-called “homeostasis” protects the sensory “hair cells” from damage, ensuring the exquisite sensitivity and frequency selectivity of our hearing. Inner ear homeostasis is carried out by numerous cellular mechanisms, often which are reliant on each other. Failure of any of these processes can result in hair cell death, and permanent hearing loss. It is our aim to gain a better understanding of these mechanisms, and to learn how we can translate these findings into clinical treatments to prevent hearing loss

Continuing recent research, we are working closely with Andy Forge’s lab to decipher the regulation of homeostasis in the cochlea and vestibular organs, including changes occurring during ageing and regeneration. In particular, we are studying the function of connexins (gap junction channel subunits) in supporting cells, and how they work to protect hair cells from damage. During his PhD funded by Deafness Research UK, John Kelly has mapped the development of gap junctional intercellular communication (GJIC) within the cochlear lateral wall, demonstrating a cytoplasmic continuity between spiral ligament fibrocytes and basal cells and intermediate cells in stria vascularis. In other work we collaborate with David Kelsell (Barts & The London, Queen Mary University) to study human connexin mutations, and David Furness (University of Keele) to examine the role of glutamate transporters in the lateral wall.

 Relevant Publications

  • Kelly JJ, Forge A, Jagger DJ. Development of gap junctional intercellular communication within the lateral wall of the rat cochlea. Neuroscience 180, 360-369, 2011.
  • Jagger DJ, Nevill G, Forge A. The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering. JARO 11, 435-448, 2010.
  • Furness DN, Lawton DM, Mahendrasingam S, Hodierne L, Jagger DJ. Quantitative analysis of the expression of the glutamate-aspartate transporter and identification of functional glutamate uptake reveal a role for cochlear fibrocytes in glutamate homeostasis. Neuroscience 162, 1307-1321, 2009.
  • Matos TD, Caria H, Simões-Teixeira H, Aasen T, Nickel R, Jagger DJ, O'Neill A, Kelsell DP, Fialho G. A novel hearing-loss-related mutation occurring in the GJB2 basal promoter. Journal of Medical Genetics 44, 721-725, 2007.
  • Jagger DJ, Forge A. Compartmentalized and signal-selective gap junctional coupling in the hearing cochlea. Journal of Neuroscience 26, 1260-1268, 2006.

Pharmacology of SGN ion channels

Summary

Spiral ganglion neurons (SGN) are the first nerve cells in the auditory pathway. They are activated by hair cells in the cochlea, and transmit an electrical code which describes the auditory world to the brain. These nerve cells are stimulated by the electrodes of a “cochlear implant”, and so act as a potential gateway to the hearing brain for profoundly deaf people. Although they are an essential part of the machinery of our hearing, the function of SGN is not well understood. We aim to characterize the signaling mechanisms within these cells, to create a better understanding of their primary functions, and to reveal potential therapeutic manipulations to alleviate hearing loss.

We are resuming our interests in the ion channels of SGN, in collaboration with the pharmaceutical company Autifony Therapeutics, and with David McAlpine, Jen Linden and Roland Schaette at the Ear Institute. We will be investigating candidate molecules and their ability to modulate voltage-gated ion channel subtypes. In a separate study funded by a Crucible Studentship, Lorcan Browne (co-supervised by David McAlpine and Dave Selwood, Wolfson Institute UCL) will be designing drugs to regulate auditory nerve firing.

Relevant Publications

  • Greenwood D, Jagger DJ, Huang LC, Hoya N, Thorne PR, Wildman SS, King BF, Pak K, Ryan AF, Housley GD. P2X receptor signaling inhibits BDNF-mediated spiral ganglion neuron development in the neonatal rat cochlea. Development 134, 1407-1417, 2007.
  • Dulon D, Jagger DJ, Lin X, Davis RL. Neuromodulation in the spiral ganglion: shaping signals from the organ of Corti to the CNS. Journal of Membrane Biology 209, 167-175, 2006.

Role of ciliary genes in the development and maintenance of hearing

Summary

Cilia are antenna-like membrane-associated structures which play essential roles during development, and during the normal function of many cells throughout the body. Dysfunction of these organelles can lead to serious illnesses, involving deafness and blindness, as well as life-threatening complications such as kidney and liver disease, diabetes, respiratory problems, and obesity. These so-called “ciliopathies” are usually genetically inherited, and at present there are few, if any cures.

Following a successful collaboration with Phil Beales (Institute of Child Health, UCL) investigating the role of cilia in the development of hair cells, we are continuing to work in the field of human ciliary diseases. We recently characterized the causes of deafness in a poorly understood ciliopathy called Alström Syndrome, working with Jan Marshall’s group at the Jackson Labs to describe the cochlear pathology in a mouse model of the disease. In this work we found that mutations of the Alms1 gene that cause Alström Syndrome lead to developmental peculiarities within the outer hair cell stereociliary bundle. In addition to accelerated hair cell death, we also demonstrated pathological cell loss within stria vascularis.

In related public engagement projects I have been working with several ciliopathy patient support groups to describe our lab work, and to explain the causes of genetic hearing loss. Since 2008 I have been a member of the Board of Directors at Alström Syndrome UK (www.alstrom.org.uk), and was appointed Chair in 2009. I work with the clinical teams at Torbay Hospital, QEH Birmingham, and the Children’s Hospital Birmingham who specialize in the syndrome. In 2010 I helped to co-found the Ciliopathy Alliance (www.ciliopathyalliance.org), which acts to promote awareness of these debilitating diseases, and to encourage novel research to improve the lives of patients. The Alliance is currently organizing the first international conference on the role of cilia in health and disease (www.cilia2012.org).

Relevant Publications

  • Jagger D, Collin G, Kelly J, Towers E, Nevill G, Longo-Guess C, Benson J, Halsey K, Dolan D, Marshall J, Naggert J, Forge A. Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity. Human Molecular Genetics 20, 466-481, 2011.
  • Jagger DJ & Forge A . Assessing PCP in the cochlea of mammalian ciliopathy models. Methods in Molecular Biology vol. 839 (in press).
  • May-Simera HL, Ross A, Rix S, Forge A, Beales PL, Jagger DJ. Patterns of expression of Bardet-Biedl syndrome proteins in the mammalian cochlea suggest noncentrosomal functions. Journal of Comparative Neurology 514, 174-188, 2009.
  • Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nature Genetics 37, 1135-1140, 2005.
Ciliopathy ASUK Cilia 2012

Page last modified on 16 nov 11 09:31