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Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death.

PLoS genetics | Feb 29, 2008

Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplastic agents are significant contributors. Genetic variation contributes markedly to differences in normal disease progression during aging and in susceptibility to ototoxic agents. Using the lateral line system of larval zebrafish, we developed an in vivo drug toxicity interaction screen to uncover genetic modulators of antibiotic-induced hair cell death and to identify compounds that confer protection. We have identified 5 mutations that modulate aminoglycoside susceptibility. Further characterization and identification of one protective mutant, sentinel (snl), revealed a novel conserved vertebrate gene. A similar screen identified a new class of drug-like small molecules, benzothiophene carboxamides, that prevent aminoglycoside-induced hair cell death in zebrafish and in mammals. Testing for interaction with the sentinel mutation suggests that the gene and compounds may operate in different pathways. The combination of chemical screening with traditional genetic approaches is a new strategy for identifying drugs and drug targets to attenuate hearing and balance disorders.

Pubmed ID: 18454195 RIS Download

Mesh terms: Aminoglycosides | Animals | Base Sequence | Cell Death | Cisplatin | Codon, Terminator | DNA Primers | DNA, Complementary | Drug Evaluation, Preclinical | Epistasis, Genetic | Hair Cells, Auditory, Inner | Hearing Loss | Humans | Mice | Neomycin | Point Mutation | Saccule and Utricle | Thiophenes | Zebrafish

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Associated grants

  • Agency: NIDCD NIH HHS, Id: P30 DC004661
  • Agency: NIDCD NIH HHS, Id: DC04661
  • Agency: NIDCD NIH HHS, Id: F32 DC007244
  • Agency: NIDCD NIH HHS, Id: F32 DC006998
  • Agency: NIDCD NIH HHS, Id: DC05987
  • Agency: NIDCD NIH HHS, Id: T32 DC000018
  • Agency: NIDCD NIH HHS, Id: DC00699
  • Agency: NIDCD NIH HHS, Id: R01 DC005987
  • Agency: NIDCD NIH HHS, Id: DC07244
  • Agency: NIDCD NIH HHS, Id: DC0018

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Jackson Laboratory

An independent, nonprofit organization focused on mammalian genetics research to advance human health. Their mission is to discover the genetic basis for preventing, treating, and curing human disease, and to enable research for the global biomedical community. Jackson Laboratory breeds and manages colonies of mice as resources for other research institutions and laboratories, along with providing software and techniques. Jackson Lab also conducts genetic research and provides educational material for various educational levels.

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Sanger: Danio rerio Sequencing Project

In February 2001 the Sanger Institute started sequencing the genome of the zebrafish (Danio rerio). To obtain the genome sequence we map and sequence clones from BAC libraries. The finished clones are manually annotated and accessible in Vega. To provide additional data whilst the above project is ongoing, we also generate integrated whole genome assemblies by filling in the yet existent gaps between clone contigs with whole genome shotgun sequence. These assemblies are then automatically annotated and accessible in Ensembl.

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