This continuing proposal will translate basic research utilizing high-throughput genomic approaches and functional genomics into routine diagnostic and therapeutic tools for non-syndromic hearing loss (NSHL), the most common type of hearing impairment in children and adults. We have developed a genomic variant detection platform MiamiOtogenomics - composed of MiamiCapitalArray/MiamiOtoGenes panels/exome (WES)/genome (WGS) and developed a genotype and phenotype database ? MiamiGeneHeal. As shown in the preliminary data, we have already collected approximately 3,000 DNA samples with phenotypic data from a large international cohort (Miami Otogenetic Repository) of families with NSHL. Moreover, we have excluded all known HL genes in over 200 families, successfully identified more than 18 potential new candidate genes, created animal models for human HL, and have generated human iPSCs from patients with genetic deafness. We will build on these accomplishments and preliminary data by proposing to complete the following specific aims: 1. Apply an innovative genomics-based MiamiOtogenomics pipeline for NSHL; 2. Identify factors influencing the decision to pursue and act on genomic testing; 3. Initiate preclinical therapeutic experiments as a proof-of-concept for potential treatments for HL. The foundation of the proposal will leverage the exceptional genomics capacity of collaborators at the University of Miami into a genomic-based, minority-focused, diagnostic and treatment pipeline for HL. The overarching purpose of this application is to transit discoveries made in laboratory to patient care. This study will translate genomic analysis into clinical hearing screening to elucidate the exact molecular etiology for HL, which will enable more accurate diagnoses, better quality of care, more effective genetic counseling, as well as improved cost-effectiveness in medical care. In addition, we expect to contribute significantly to genotype-phenotype studies and to establish a robust framework for assessing long-term clinical outcomes. Moreover, this study will contribute to our fundamental understanding of HL. Finally, our innovative preclinical therapeutic experiments in our knockin mouse and human iPSC models using CRISPR will potentially discover new treatments for HL. This study will inform two important clinical aspects of precision medicine in USA populations, especially in USA minorities: general acceptance in clinical practice and clinical utility. We will perform one of the largest and most integrated clinical/genomic/functional/novel therapeutic studies on NSHL to date. Our prior results, the interdisciplinary team's expertise and our established study infrastructure and population access support feasibility of our Aims.

Public Health Relevance

We will translate our basic research findings into clinical tools. We will expand our comprehensive genomic and phenotypic deafness database for clinical care of deaf individuals, identify and characterize novel genes for hearing loss using state-of-the-art genomic tools, assess impacts of genomic testing on patients, and conduct preclinical studies of gene and cell based therapy approach of CRISPR/Cas9-mediated genome editing to treat HL. This will enhance our understanding of biology of the normal hearing and the genetic aberrations that result in hearing impairments to develop therapeutic strategies for human deafness.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC012115-06A1
Application #
9588064
Study Section
Special Emphasis Panel (ZDC1)
Program Officer
Watson, Bracie
Project Start
2013-03-08
Project End
2023-07-31
Budget Start
2018-08-07
Budget End
2019-07-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Mittal, Rahul; Patel, Amit P; Nguyen, Desiree et al. (2018) Genetic basis of hearing loss in Spanish, Hispanic and Latino populations. Gene 647:297-305
Wang, Li; Yan, Denise; Qin, Litao et al. (2018) Amino acid 118 in the Deafness Causing (DFNA20/26) ACTG1 gene is a Mutational Hot Spot. Gene Rep 11:264-269
Mittal, Rahul; Bencie, Nicole; Parrish, James M et al. (2018) An Update on Phosphodiesterase Mutations Underlying Genetic Etiology of Hearing Loss and Retinitis Pigmentosa. Front Genet 9:9
Snapp, Hillary A; Hoffer, Michael E; Liu, Xuezhong et al. (2017) Effectiveness in Rehabilitation of Current Wireless CROS Technology in Experienced Bone-Anchored Implant Users. Otol Neurotol 38:1397-1404
Li, Jia-Nan; Chen, Si; Zhai, Lei et al. (2017) The Advances in Hearing Rehabilitation and Cochlear Implants in China. Ear Hear 38:647-652
Mittal, Rahul; Nguyen, Desiree; Patel, Amit P et al. (2017) Recent Advancements in the Regeneration of Auditory Hair Cells and Hearing Restoration. Front Mol Neurosci 10:236
Diaz-Horta, Oscar; Abad, Clemer; Sennaroglu, Levent et al. (2016) ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice. Proc Natl Acad Sci U S A 113:5993-8
Mittal, Rahul; Chan, Brandon; Grati, M'hamed et al. (2016) Molecular Structure and Regulation of P2X Receptors With a Special Emphasis on the Role of P2X2 in the Auditory System. J Cell Physiol 231:1656-70
Grati, M'hamed; Yan, Denise; Raval, Manmeet H et al. (2016) MYO3A Causes Human Dominant Deafness and Interacts with Protocadherin 15-CD2 Isoform. Hum Mutat 37:481-7
Mittal, Rahul; Grati, M'hamed; Yan, Denise et al. (2016) Otopathogenic Pseudomonas aeruginosa induces MyD88-dependent auditory hair cell damage. Cell Death Discov 2:16030

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