Cellular therapy for the inner ear

内耳细胞疗法

基本信息

批准号：
7258349
负责人：
Albert Edge
金额：
$ 28.64万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-12 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7258349
关键词：
Acute Address Adult Afferent Neurons Age Animal Model Biological Assay Biological Models Brain Bungarotoxins Candidate Disease Gene Cell Differentiation process Cell Line Cell Therapy Cells Characteristics Chromosome Pairing Cochlea Cochlear nucleus Condition Coupled Development Ear Engraftment Environment Etiology Family Gene Expression Gene Silencing Genetic Gerbils Goals Growth Factor Growth Factor Overexpression Hair Cells Histologic Immunohistochemistry In Vitro Labyrinth Ligands Luciferases Measures Mus Natural regeneration Nature Nerve Nervous system structure Neurodegenerative Disorders Neurons Neuropilin-1 Neuropilins Numbers Organ of Corti Ouabain Parkinson Disease Pathway interactions Process Recovery of Function Reporter Role Sensorineural Hearing Loss Sensory Series Signal Pathway Small Interfering RNA Source Spinal Ganglia Staging Stem cells Synapses System Testing Therapeutic Time Tissues Transplantation Undifferentiated Withdrawal Work axonal guidance cell type design desire embryonic stem cell fetal ganglion cell in vitro Model in vivo in vivo Model inner ear diseases nerve stem cell nerve supply neuron loss neuronal guidance progenitor promoter receptor reconstitution reinnervation relating to nervous system research study response sound spiral ganglion success synaptogenesis transcription factor

项目摘要

DESCRIPTION (provided by applicant): Loss of cochlear neurons and hair cells is a major cause of sensorineural hearing loss. One approach to potential treatments is the transplantation of exogenous progenitor cells. Our strategy for developing cell based therapies for inner ear disorders is to study the reinnervation of a de-afferented organ of Corti. We take this approach because 1) only a single cell type, the spiral ganglion cell, must be replaced to see functional recovery; 2) partial regeneration of damaged tissue by cell replacement has been successful in animal models of other neurodegenerative diseases, such as Parkinson's, suggesting that neuronal circuits in the adult nervous system can be reconstituted if appropriate progenitor cells are introduced and 3) understanding the mechanisms underlying re-formation of neural connections to hair cells in the adult ear is important to any therapeutic approach to sensorineural hearing loss. The Specific Aims comprise four inter-related experiments to probe key variables likely to influence the success of hair cell reinnervation by transplanted neural progenitor cells. In Aim 1 the developmental expression by spiral ganglion neurons of several families of neuronal guidance molecules will be studied by immunohistochemistry. In Aim 2 we use de-afferented cochlear explants to study the reinnervation of hair cells by grafted progenitors, in vitro, by modifying characteristics of the donor cells (e.g. silencing expression of selected guidance molecules or controlling degree of differentiation) or the host environment (e.g. developmental age of the explant or etiology of the initial de-afferentation). In Aim 3 we build on the in vitro results to choose donor cells for in vivo transplantation into a chemically de-afferented gerbil ear, in which the sensory cells are intact but spiral ganglion cells are destroyed. In this model system, success of reinnervation can be assayed both functionally and histologically. In Aim 4 we use a reporter assay to determine conditions needed to bias differentiation of stem cells to a lineage corresponding to sensory neurons by adding specific growth factors in a timed sequence, and by over expressing transcription factors in the pathway to sensory neurons. Clonal cell lines isolated under this Aim will serve as additional donor cell types to be studied in Aims 3 and 4.

描述（由申请人提供）：耳蜗神经元和毛细胞的丧失是感官听力损失的主要原因。潜在治疗的一种方法是外源祖细胞的移植。我们开发基于细胞的内耳疾病疗法的策略是研究Corti脱落器官的加剧。我们采用这种方法是因为1）必须更换单个单元格类型，即螺旋神经节细胞才能看到功能恢复； 2）在其他神经退行性疾病的动物模型（例如帕金森氏病）的动物模型中，部分再生已成功，这表明成人神经系统中的神经元回路可以重新构成适当的祖细胞，并且如果引入了与成年人相结合的机制，则可以将其引入与成年人的损失相结合。该特定目的包括四个相关的实验，以探测可能影响毛细胞通过移植的神经祖细胞重新连接的成功的关键变量。在AIM 1中，将通过免疫组织化学研究几个神经元引导分子的螺旋神经神经元的发育表达。 In Aim 2 we use de-afferented cochlear explants to study the reinnervation of hair cells by grafted progenitors, in vitro, by modifying characteristics of the donor cells (e.g. silencing expression of selected guidance molecules or controlling degree of differentiation) or the host environment (e.g. developmental age of the explant or etiology of the initial de-afferentation).在AIM 3中，我们以体外结果为基础，选择供体细胞以体内移植到化学降低的Gerbil耳朵中，其中感觉细胞完好无损，但螺旋神经节细胞被破坏。在此模型系统中，可以在功能和组织学上分析重新支配的成功。在AIM 4中，我们使用报告基因测定法来确定通过在定时序列中添加特定的生长因子以及在感觉神经元的途径中过度表达转录因子，从而使干细胞分化为对应于感觉神经元的谱系所需的条件。在此目标下分离的克隆细胞系将用作目标3和4中的其他供体细胞类型。