The vast majority of hearing and balance impairments are thought to be due to death of sensory hair cells, the receptor cells of the inner ear. These cells are unusually metabolically active and hypersensitive to damage from overstimulation, exposure to some therapeutic drugs and environmental toxins, and to aging. However, there is enormous variability in structural and functional outcomes of these challenges to the inner ear among both humans and laboratory animals. The goals of our research program are to facilitate development of therapeutic agents to prevent hearing loss through understanding the cellular pathways and molecular identities of potential therapeutic targets that regulate death and survival of inner ear hair cells. During the proposed grant period we will: i) use the genetic potential and the accessibility of zebrafish lateral line neuromasts to better define cellular and molecular cascades that control hair cell death and survival following exposure to potentially ototoxic agents;ii) characterize drugs and small molecules that influence the susceptibility of hair cells when challenged by ototoxic agents;and iii) determine the efficacy of newly discovered genes and drugs in mammal inner ear and initiate preclinical development. Three groups of experiments are proposed: a) further examine intracellular calcium trafficking and ototoxin trafficking as determinants in the fate of ototoxin-exposed zebrafish and mammalian hair cells;b) determine intracellular pathways and mammalian efficacy of mutations in the Cc2d2a gene for hair cell protection in zebrafish and mammals;and c) further development of drugs and small molecule """"""""hits"""""""" from completed screens toward preclinical efficacy for hearing protection.
In the US, over 36 million adults have trouble hearing. There are a variety of causes but no clinically proven treatments to restore normal hearing or prevent hearing loss. Our research will reveal how the sound sensing cells of the ear are damaged, identify pathways that may underlie the variation in susceptibility to hearing loss, and discover drugs that may prevent hearing loss.
|Stawicki, Tamara M; Hernandez, Liana; Esterberg, Robert et al. (2016) Cilia-Associated Genes Play Differing Roles in Aminoglycoside-Induced Hair Cell Death in Zebrafish. G3 (Bethesda) 6:2225-35|
|Suli, Arminda; Pujol, Remy; Cunningham, Dale E et al. (2016) Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells. J Cell Sci 129:2250-60|
|Yoshimatsu, Takeshi; D'Orazi, Florence D; Gamlin, Clare R et al. (2016) Presynaptic partner selection during retinal circuit reassembly varies with timing of neuronal regeneration in vivo. Nat Commun 7:10590|
|Esterberg, Robert; Linbo, Tor; Pickett, Sarah B et al. (2016) Mitochondrial calcium uptake underlies ROS generation during aminoglycoside-induced hair cell death. J Clin Invest 126:3556-66|
|Thomas, Eric D; Cruz, Ivan A; Hailey, Dale W et al. (2015) There and back again: development and regeneration of the zebrafish lateral line system. Wiley Interdiscip Rev Dev Biol 4:1-16|
|Thomas, Andrew J; Wu, Patricia; Raible, David W et al. (2015) Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line. Otol Neurotol 36:519-25|
|Stawicki, Tamara M; Owens, Kelly N; Linbo, Tor et al. (2014) The zebrafish merovingian mutant reveals a role for pH regulation in hair cell toxicity and function. Dis Model Mech 7:847-56|
|Suli, Arminda; Guler, Ali D; Raible, David W et al. (2014) A targeted gene expression system using the tryptophan repressor in zebrafish shows no silencing in subsequent generations. Development 141:1167-74|
|Esterberg, Robert; Hailey, Dale W; Rubel, Edwin W et al. (2014) ER-mitochondrial calcium flow underlies vulnerability of mechanosensory hair cells to damage. J Neurosci 34:9703-19|
|Thomas, Andrew J; Hailey, Dale W; Stawicki, Tamara M et al. (2013) Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line. J Neurosci 33:4405-14|
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