Integrating cells into the auditory epithelium of deaf ears

将细胞整合到聋耳的听觉上皮中

• 批准号: 8394920
• 负责人: YEHOASH RAPHAEL
• 金额: $ 18.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-07 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394920
• 关键词: Address; Adherens Junction; Adverse effects; Apical; Auditory; Biology; Cavia; Cell Culture Techniques; Cell Survival; Cells; Cherry - dietary; Cochlea; Cochlear duct; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Derivation procedure; Development; Diuretics; Ear; Endolymph; Environment; Epithelial; Epithelial Cells; Epithelium; Functional disorder; Furosemide; Future; Genetic Predisposition to Disease; Goals; Grant; Hair Cells; Hearing Impaired Persons; Human; Implant; Injection of therapeutic agent; Intercellular Junctions; Labyrinth; Life; Methods; Modeling; Molecular; Neurons; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Phenotype; Potassium; Procedures; Pump; Reagent; Replacement Therapy; Research; Sensorineural Hearing Loss; Side; Sodium; Stem cells; Supporting Cell; Surface; System; Technology; Testing; Therapeutic; Tight Junctions; Tissues; Translating; Tube; Work; deafness; design; dosage; hearing impairment; improved; in vivo; innovation; insight; novel; novel strategies; research study; seal; spiral ganglion; stem cell technology; stem cell therapy

DESCRIPTION (provided by applicant): Research on derivation of stem cells and their differentiation into desirable inner ear phenotypes is rapidly progressing. However, practical use of cell replacement therapy for hearing loss will depend on the ability to insert these cells into the inner ear and incorporate them into the native tissues. Inserting cells into the layer of cells making the auditory epithelium is complex because the epithelium forms a confluent and extremely tight barrier. Here we propose novel strategies for starting to design methods for integrating exogenous cells in the auditory epithelium of the deaf ear, in vivo. The challenges include keeping the therapeutic cells alive until they are inserted, opening gaps in the tissue to allow insertion, and maintaining essential native cells intact. Our overall hypothesis is that the deaf ear can be manipulated to receive and incorporate stem cells. To test this hypothesis, we will investigate and optimize means for transient decoupling of inter-cellular junctions in order to facilitate insertion of exogenous cells (Aim 1), test means to transiently reduce potassium concentration in the scala media in order to promote survival of implanted cells and to protect sensitive and indispensable components of the cochlea while junctions are open (Aim 2), and test extent of integration of cells inserted into the endolymph while potassium levels are low and intercellular junctions are open (Aim 3). The work we propose will improve our understanding of the biology of the severely deaf cochleae, and facilitate development of future therapies for deaf ears needing cell replacement therapy. While the ideas and goals of the proposed work are innovative and never before attempted, the expertise and reagents are available, promising high feasibility for successful experiments. It is therefore expected that the results of this study will ultimately benefit a large proportion of patients with severe sensorineural hearing loss from environmental and genetic etiologies.

描述（由申请人提供）：关于干细胞的衍生及其分化为所需内耳表型的研究正在迅速进展。然而，细胞替代疗法治疗听力损失的实际应用将取决于将这些细胞插入内耳并将其纳入天然组织的能力。将细胞插入形成听觉上皮的细胞层是复杂的，因为上皮形成汇合且极其紧密的屏障。在这里，我们提出了新的策略，开始设计在体内将外源细胞整合到聋耳听觉上皮细胞中的方法。挑战包括保持治疗细胞存活直到它们被插入、在组织中打开间隙以允许插入，以及保持必需的天然细胞完整。我们的总体假设是，可以操纵聋耳来接收和整合干细胞。为了检验这一假设，我们将研究和优化细胞间连接瞬时解耦的方法，以促进外源细胞的插入（目标 1），测试瞬时降低阶梯介质中钾浓度的方法，以促进植入细胞的存活细胞并在连接打开时保护耳蜗的敏感和不可或缺的成分（目标 2），并在钾水平较低且细胞间连接打开时测试插入内淋巴的细胞的整合程度（目标3）。我们提出的工作将增进我们对重度聋耳蜗生物学的理解，并促进未来针对需要细胞替代疗法的聋耳的治疗方法的开发。虽然拟议工作的想法和目标是创新的并且以前从未尝试过，但专业知识和试剂是可用的，有望成功实验的高度可行性。因此，预计这项研究的结果最终将使大部分因环境和遗传病因而患有严重感音神经性听力损失的患者受益。