Document text
Principal Investigator: Marisa L. Zallocchi
Organization: CREIGHTON UNIVERSITY
Fiscal Year: 2023
Award: $520,111
Funding agency: National Institute on Deafness and Other Communication Disorders
ABSTRACT.
An organism’s perception of its surrounding environment depends on the sensory function. Neurosensory cells
from the inner ear are involved in key biological processes associated with hearing and balance. To be able to
achieve their function these cells depend on a complex array of membrane receptors, ion channels, and
signaling molecules that are concentrated at extremely sophisticated structures positioned at the apical (hair
cell bundle and kinocilium) and basal (ribbon synapses) poles. Disruption of this network due, for example, to
mutations, results in morphological and functional abnormalities and forms the bases of many human genetic
disorders. This proposal is focused on studying the role of the Pcdh15-Itga8 (Protocadherin-15-Integrin alpha8)
complex during hair cell (HC) development and function, and the downstream signaling pathways activated by
it. Our recently published work and preliminary data suggest that the absence of Pcdh15-Itga8 complex results
in HC bundle abnormalities, increase the number of outer hair cells, and alterations in the Rhoa-ERM(Ezrin-Radixin-Moesin)-Yap signaling cascade. Moreover, Itga8 hair cell-specific conditional knockout mice have
progressive hearing loss and sensibility to noise exposure. Based on this information, our central hypothesis is
that during inner ear development, environmental cues activate the Itga8-Pcdh15 complex resulting in the
modulation of cytoskeletal elements that will activate downstream signaling cascades. Lack of the complex
results in inner ear abnormalities that over time can cause progressive hearing loss. We will test this hypothesis
with two specific aims. In the first aim, we will identify the environmental cues that lead to Pcdh15-Itga8
activation and the formation of cytoskeletal structures. We will also identify and characterize the complex’s
molecular targets. In the second aim, we will investigate the contribution of supporting cells and spiral ganglion
neurons to the Pcdh15-Itga8 complex phenotype and the sensibility to noise. Collectively the studies proposed
here will clarify the functional role(s) for the Pcdh15-Itga8 complex during organ of Corti development,
introducing a direct functional link between Usher syndrome and an integrin-downstream signaling cascade.
Terms: <21+ years old><Address><Adult><Adult Human><Affect><American><Animals><Apical><Architecture><Biological Function><Biological Process><Biomechanics><Blindness><Body Tissues><Brachydanio rerio><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><Cell Body><Cell Communication and Signaling><Cell Function><Cell Maturation><Cell Process><Cell Signaling><Cell physiology><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Matrix><Cellular Physiology><Cellular Process><Cochlea><Cochlear Organ><Communities><Complex><Corti Cell><Corti ganglion><Cortis Organ><Cues><Cytoskeletal System><Cytoskeleton><Danio rerio><Data><Defect><Deposit><Deposition><Development><Disease><Disease Progression><Disorder><ECM><Ear><Elements><Engineering / Architecture><Environment><Equilibrium><Extracellular Matrix><Fishes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Graefe-Usher syndrome><Hair Cells><Hallgren syndrome><Hearing><Hearing Loss><High Frequency Deafness><High-Frequency Hearing Loss><Human Genetics><Hypoacuses><Hypoacusis><Integrin alpha Chains><Integrin alpha Subunits><Integrin α Subunits><Integrins><Integrins Extracellular Matrix><Internal Ear><Intracellular Communication and Signaling><Ion Channel><Ionic Channels><KO mice><Kinocilium><Knock-out Mice><Knockout Mice><Laboratories><Labyrinth><Link><Membrane><Membrane Channels><Mice><Mice Mammals><Molecular><Molecular Target><Morphology><Murine><Mus><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Noise><Null Mouse><Organ><Organ of Corti><Organism><Outer Hair Cells><PCDH15><PCDH15 gene><Pathology><Pathway interactions><Perception><Phenotype><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Physical distancing><Pigmentary Retinopathy><Position><Positioning Attribute><Proteins><Publishing><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Retina><Retinitis Pigmentosa><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Sensory><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Social Distance><Spiral Organ><Spiral Organ of Corti><Structure><Subcellular Process><Supporting Cell><Synaptic ribbon><Tapetoretinal Degeneration><Testing><Time><Tissues><Touch><Touch sensation><Usher Proteins><Usher Syndrome><Usher Syndrome Protein><Usher's syndrome><Visual Receptor><Work><Zebra Danio><Zebra Fish><Zebrafish><adult animal><adulthood><alpha Integrins><balance><balance function><base><bases><biological signal transduction><biomechanical><cell type><conditional knock-out><conditional knockout><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><deaf><deafened><deafness><defined contribution><developmental><dysfunctional hearing><dystrophia retinae pigmentosa-dysostosis syndrome><dystrophia retinae-dysacousis syndrome><ear hair cell><ezrin><genetic condition><genetic disorder><genome mutation><hearing defect><hearing deficit><hearing difficulty><hearing disability><hearing dysfunction><hearing impairment><inner ear><inner ear development><intracellular skeleton><living system><mature animal><membrane structure><membrane-organizing extension spike protein><moesin><mutant><neuro-sensory><neuronal><neurosensory><noise exposure><novel><pathway><phosphoprotein p81><profound hearing loss><progressive hearing loss><protein activation><protocadherin 15><protocadherin-related 15><radixin><radixin protein><receptor><retinitis pigmentosa-congenital deafness syndrome><ribbon synapse><rod and cone dystrophy><rod-cone dystrophy><sensor><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><small molecule><social role><spiral ganglion><tactile sensation><temporal measurement><temporal resolution><time measurement><transcriptome sequencing><transcriptomic sequencing><vision loss><visual loss><α-Integrins>