When sensory hair cells in the ears of humans and other mammals are killed by loud sounds, drug toxicity, infections, or other causes, they are not effectively replaced. As a result, millions of people have permanent, acquired hearing and balance deficits. That is not the case in non-mammals, like fish, amphibians, and birds. In their ears, hair cell loss triggers the regenerative replacement of lost hair cells and that is soon followed by the restoration of hearing and balance. The new hair cells arise from supporting cells within the same epithelia. This application seeks support for a project that began in 1982, which will test the hypothesis that the unique intercellular junctions and massively thickened actin bands in postnatal mammalian supporting cells play a role in limiting the regeneration of hair cells in mammals. Intercellular junctions have recently been identified as signaling sites tha play crucial roles in the regulation of organ growth and in regenerative turnover that occurs in many epithelia. The proposed investigations also will seek to define the supramolecular organization and protein composition of the actin bands that grow to occupy nearly 90% of the area inside the junctions average supporting cells in the vestibular epithelia of adult humans and rodents. Rodent supporting cells lose regenerative plasticity in a manner that is almost perfectly correlated with the postnatal thickening of these junctional actin bands. Thickening does not occur in the supporting cells of non-mammals that regenerate hair cells. The central hypothesis will be tested in vitro and in vivo using mouse genetics and pharmacological inhibitors. Outcome from the proposed tests and the answers to other questions addressed in the proposed investigations will identify specific proteins which hold the potential to become targets for therapeutic approaches aimed at translating laboratory discoveries into treatments for millions of patients who are affected by permanent, highly forms of hearing loss and balance dysfunctions that contribute to communication disorders as well as to instability and falls in the elderly.
This proposal seeks to investigate the possibility that radical changes in the intercellular junctions and their associated cytoskeletons in the supporting cells of mammalian ears limit their capacity to regeneratively replace damaged hearing and balance hair cells.
|Mann, Zoë F; Thiede, Benjamin R; Chang, Weise et al. (2014) A gradient of Bmp7 specifies the tonotopic axis in the developing inner ear. Nat Commun 5:3839|
|Burns, Joseph C; Corwin, Jeffrey T (2014) Responses to cell loss become restricted as the supporting cells in mammalian vestibular organs grow thick junctional actin bands that develop high stability. J Neurosci 34:1998-2011|
|Thiede, Benjamin R; Mann, Zoë F; Chang, Weise et al. (2014) Retinoic acid signalling regulates the development of tonotopically patterned hair cells in the chicken cochlea. Nat Commun 5:3840|
|Burns, Joseph C; Corwin, Jeffrey T (2013) A historical to present-day account of efforts to answer the question: "what puts the brakes on mammalian hair cell regeneration?". Hear Res 297:52-67|
|Burns, Joseph C; Collado, Maria Sol; Oliver, Eric R et al. (2013) Specializations of intercellular junctions are associated with the presence and absence of hair cell regeneration in ears from six vertebrate classes. J Comp Neurol 521:1430-48|
|Collado, Maria Sol; Thiede, Benjamin R; Baker, Wendy et al. (2011) The postnatal accumulation of junctional E-cadherin is inversely correlated with the capacity for supporting cells to convert directly into sensory hair cells in mammalian balance organs. J Neurosci 31:11855-66|
|Collado, Maria Sol; Burns, Joseph C; Meyers, Jason R et al. (2011) Variations in shape-sensitive restriction points mirror differences in the regeneration capacities of avian and mammalian ears. PLoS One 6:e23861|
|Goodyear, Richard J; Legan, P Kevin; Christiansen, Jeffrey R et al. (2010) Identification of the hair cell soma-1 antigen, HCS-1, as otoferlin. J Assoc Res Otolaryngol 11:573-86|
|Collado, Maria Sol; Burns, Joseph C; Hu, Zhengqing et al. (2008) Recent advances in hair cell regeneration research. Curr Opin Otolaryngol Head Neck Surg 16:465-71|
|Burns, Joseph; Christophel, J Jared; Collado, Maria Sol et al. (2008) Reinforcement of cell junctions correlates with the absence of hair cell regeneration in mammals and its occurrence in birds. J Comp Neurol 511:396-414|
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