Computational Insights Into the Generation of Endocochlear Potential: Role of Potassium Channels and Tight Junctions
| dc.contributor.advisor | Raphael, Robert M | en_US |
| dc.creator | Garcia Camargo, Lucas | en_US |
| dc.date.accessioned | 2024-05-22T16:25:43Z | en_US |
| dc.date.created | 2024-05 | en_US |
| dc.date.issued | 2024-04-19 | en_US |
| dc.date.submitted | May 2024 | en_US |
| dc.date.updated | 2024-05-22T16:25:43Z | en_US |
| dc.description | EMBARGO NOTE: This item is embargoed until 2025-05-01 | en_US |
| dc.description.abstract | Ion transport and homeostasis is vital to all organ systems in the body. In the auditory system, mechanotransduction by sensory hair cells constantly drains potassium ions from the endolymphatic fluid that bathes hair cell stereocilia. Proper hearing function depends on efficient resupply of these ions through several cochlear spaces that are delineated by tight junctions as well as maintenance of the endocochlear potential in the endolymph. Mutations in the genes responsible for encoding ion channels, transporters and tight junctions are responsible for many cases of hearing loss and auditory dysfunction. The main goal of this study is to understand how the network of ion channels and transporters maintains cochlear ion homeostasis and establishes the endocochlear potential. The model developed in this thesis is able to predict the effect of genetic mutations on the system and for its validation I compare predicted results to previous experimental data in the literature. To accomplish this, I expanded upon the framework of a computational model previously generated by a former student from our group, Dr. Imram Qurashi. The resulting model incorporates biophysical properties of the ion channels, transporters and tight junctions in the various cochlear compartments. The model predicted steady state electrical potentials and ion concentrations consistent with experimental data for both healthy conditions and results from loss-of-function knockout experiments. The sensitivity analysis, demonstrated that the concentrations and potentials were most sensitive to variations in ATP drive from marginal cells. We also found that the endocochlear potential is established by both inward and outward rectifying ion channels (Kir4.1 and Kv) present in the intermediate cells in the syncytium, supporting recent experimental results. The model predicts that the absence of Claudin-11, a tight junction protein between the intrastrial space and perilymph, and the endolymph and perilymph leads to a drop in EP while maintaining a high $K^+$ concentration in the endolymph, as observed in recent experimental results. Notably, the model allowed users to study the pathological state of endolymphatic hydrops, a key feature of Meniere’s disease, by integrating a variable endolymph volume through an osmolar constraint. This computational model serves as a significant step forward in our understanding of cochlear ion homeostasis, the development of auditory pathologies, and the potential for targeted therapeutic interventions. Its ability to simulate the effects of specific ion channel blockades and predict changes in endolymph volume highlights its value as a tool for future research in the realm of inner ear diseases. | en_US |
| dc.embargo.lift | 2025-05-01 | en_US |
| dc.embargo.terms | 2025-05-01 | en_US |
| dc.format.mimetype | application/pdf | en_US |
| dc.identifier.citation | Camargo, Lucas Garcia. Computational Insights Into the Generation of Endocochlear Potential: Role of Potassium Channels and Tight Junctions. (2024). PhD diss., Rice University. https://hdl.handle.net/1911/116194 | en_US |
| dc.identifier.uri | https://hdl.handle.net/1911/116194 | en_US |
| dc.language.iso | eng | en_US |
| dc.rights | Copyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder. | en_US |
| dc.subject | ion transport | en_US |
| dc.subject | endocochlear potential | en_US |
| dc.subject | homeostasis | en_US |
| dc.subject | tight junctions | en_US |
| dc.title | Computational Insights Into the Generation of Endocochlear Potential: Role of Potassium Channels and Tight Junctions | en_US |
| dc.type | Thesis | en_US |
| dc.type.material | Text | en_US |
| thesis.degree.department | Bioengineering | en_US |
| thesis.degree.discipline | Engineering | en_US |
| thesis.degree.grantor | Rice University | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy | en_US |