The blood-labyrinth barrier (BLB) in the stria vascularis of the cochlea maintains endocochlear potential, ion transport, and fluid balance in the inner ear. Disruption of the BLB has long been considered a major etiologic factor in a variety of hearing disorders, including autoimmune inner ear disease, Meniere's disease, meningitis-associated labyrinthitis, and several genetically-linked diseases. Despite the importance of the BLB, however, the mechanisms that control BLB permeability remain largely unknown. A recent study from our lab unexpectedly found a large number of perivascular resident macrophage (PVMs) in the BLB, in addition to endothelial cells (ECs), basement membrane, and surrounding pericytes. The PVMs are in close contact with vessels through cytoplastic processes-end-feet-which contain a large number of vesicles and transporters. We hypothesize the PVMs and ECs are physiologically coupled for control of water and ion movement in the stria vascularis. In this project, we ask if PVMs contribute to the integrity of th BLB. If so, do PVMs control BLB integrity by affecting expression of tight and adherens junction proteins? Is the control mediated by pigment epithelial-derived factor? To test the hypothesis, we established a new primary EC and PVM cell co-culture model which we will use in association with a transgenic mouse model. The transgenic mice encode a diphtheria toxin receptor providing a system for transient depletion of PVMs. In addressing PVM control of BLB integrity, the proposed work will significantly enhance our understanding of the BLB at the cellular and molecular level and may ultimately lead to innovative treatments for BLB dysfunction-related hearing loss.

Public Health Relevance

Disruption of the blood-labyrinth barrier (BLB) has long been considered a major etiologic factor in a variety of hearing disorders;however, the mechanisms that control BLB permeability remain largely unknown. Development of new treatments for BLB-related hearing loss requires a better understanding of BLB physiology. The goal of this program is to advance our physiological understanding of the cochlear BLB and facilitate development of effective drug therapies for BLB dysfunction-related hearing loss.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DC012398-02
Application #
8500225
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$182,875
Indirect Cost
$64,125
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Shi, Xiaorui (2016) Pathophysiology of the cochlear intrastrial fluid-blood barrier (review). Hear Res 338:52-63
Ben Said, Mariem; Grati, M'hamed; Ishimoto, Takahiro et al. (2016) A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60. Hum Genet 135:513-24
Yang, Yuqin; Chen, Fangyi; Karasawa, Takatoshi et al. (2015) Diverse Kir expression contributes to distinct bimodal distribution of resting potentials and vasotone responses of arterioles. PLoS One 10:e0125266
Neng, Lingling; Zhang, Jinhui; Yang, Ju et al. (2015) Structural changes in thestrial blood-labyrinth barrier of aged C57BL/6 mice. Cell Tissue Res 361:685-96
Zhang, Jinhui; Chen, Songlin; Hou, Zhiqiang et al. (2015) Lipopolysaccharide-induced middle ear inflammation disrupts the cochlear intra-strial fluid-blood barrier through down-regulation of tight junction proteins. PLoS One 10:e0122572
Shi, Xiaorui; Zhang, Fei; Urdang, Zachary et al. (2014) Thin and open vessel windows for intra-vital fluorescence imaging of murine cochlear blood flow. Hear Res 313:38-46
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Neng, Lingling; Zhang, Fei; Kachelmeier, Allan et al. (2013) Endothelial cell, pericyte, and perivascular resident macrophage-type melanocyte interactions regulate cochlear intrastrial fluid-blood barrier permeability. J Assoc Res Otolaryngol 14:175-85
Neng, Lingling; Zhang, Wenjing; Hassan, Ahmed et al. (2013) Isolation and culture of endothelial cells, pericytes and perivascular resident macrophage-like melanocytes from the young mouse ear. Nat Protoc 8:709-20

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