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）：关于干细胞推导及其分化为理想的内耳表型的研究正在迅速发展。但是，实际使用细胞替代疗法来进行听力损失，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。将细胞插入使听觉上皮的细胞层中很复杂，因为上皮形成了汇合且极其紧密的屏障。在这里，我们提出了新的策略，以设计用于在体内听觉上皮中整合外源细胞的方法。挑战包括保持治疗细胞的生命直到插入，在组织中打开缝隙以插入插入，并保持必需的本地细胞完整。我们的总体假设是，可以操纵耳聋以接收和融合干细胞。为了检验这一假设，我们将调查并优化用于暂时性的细胞间连接处的瞬时脱耦，以促进插入外源细胞（AIM 1），测试手段，在Scala培养基中暂时降低钾的浓度，以促进植入细胞的存活，并在植入型细胞的存活中，以保护敏感的和不可或缺的组成部分（在均可及时开放）（在2个中均可在2个均可依次（均可在2）。进入内淋巴而钾水平较低，细胞间连接处开放（AIM 3）。我们提出的工作将提高我们对严重聋哑人的生物学的理解，并促进需要开发需要细胞替代疗法的聋耳的未来疗法。尽管拟议工作的思想和目标是创新的，而且从未尝试过，但专业知识和试剂可用，有望获得成功实验的高可行性。因此，预计这项研究的结果最终将受益于大部分受环境和遗传病因的感官听力损失的患者。