Developing novel stem cell-based epigenetic approaches to treat hearing loss

开发基于干细胞的新型表观遗传学方法来治疗听力损失

• 批准号: 10038743
• 负责人: Zhengqing Hu
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038743
• 关键词: Adult; Affect; Aging; Auditory; Auditory system; Azacitidine; Biological; Brain Stem; Caregivers; Caring; Cell Differentiation process; Cell Line; Cell Lineage; Cells; Cellular Mechanotransduction; Clinical; Coculture Techniques; DNA; DNA Methylation; DNA Methylation Regulation; DNA Methyltransferase Inhibitor; DNA Sequence; Data; Deoxycytidine; Department of Defense; Diagnosis; Electrophysiology (science); Epigenetic Process; Epithelial; Epithelial Cells; Exhibits; Family; Functional disorder; Future; Gene Expression; Gene Proteins; Genes; Genomic DNA; Goals; Hair Cells; Health; Hearing; Heritability; Human; In Vitro; Ion Channel; Labyrinth; Medical; Medical center; Methylation; Military Personnel; Mus; Natural regeneration; Neurons; Noise; Pattern; Phenotype; Pilot Projects; Potassium; Proteins; Quality of life; RNA; Reporting; Role; Safety; Science; Sensory Hair; Signal Transduction; Stem Cell Research; Supporting Cell; Synapses; System; Testing; Tinnitus; Transplantation; Traumatic Brain Injury; United States Department of Veterans Affairs; United States Food and Drug Administration; Utricle structure; Veterans; Work; base; clinical application; deaf; demethylation; experience; hearing impairment; hearing restoration; improved; in vivo; inhibitor/antagonist; inner ear development; inner ear diseases; innovation; mechanotransduction; military service; military veteran; novel; novel strategies; permanent hearing loss; receptor; service member; sound; spiral ganglion; stem; stem cell based approach; stem cell technology; stem cells; success; synaptogenesis; welfare

Project Summary Auditory hair cells are mechanotransduction receptors that convey sound signals to the brainstem via spiral ganglion neurons (SGNs). However, hair cells are vulnerable to a number of insults, including noise, blast, aging, and traumatic brain injury. Adult mammalian hair cell loss is usually irreversible, causing permanent hearing loss and other inner ear disorders. Currently, there are no biological approaches to replenish human hair cells. The long-term goal of this project is to use stem cell-based approaches to regenerate the damaged auditory system to treat hearing loss and other inner ear disorders. In this proposal, we will generate human sensory hair cells and rebuild hair cell-SGN connections using a stem cell-based epigenetic approach. We have identified human utricle epithelia-derived prosensory-like cells (HUCs) that exhibit features of prosensory cells. We found that HUCs demonstrated genomic DNA methylation in a pilot study. We applied the DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-aza) to HUCs and found that treated HUCs expressed hair cell genes and proteins. Therefore, in this proposal we hypothesize that the DNMT inhibitor 5- aza induces HUCs to differentiate into new functional hair cells that can replace damaged hair cells and form synapses with auditory neurons. To test this hypothesis, three specific aims are proposed: Specific Aim 1: Define the induction of HUCs into sensory hair cells by 5-aza. Specific Aim 2: Investigate the integration and synapse formation of 5-aza-treated HUCs in vitro. Specific Aim 3: Determine the survival, differentiation, integration, and function of 5-aza-treated HUCs in vivo. In this proposal, we will generate human sensory hair cells and rebuild hair cell-neuron connections using a stem cell-based epigenetic approach. The advantage of an epigenetic approach is that expression and phenotype of gene are heritably changed, whereas their DNA sequences remain constant. The long-term aims of this work are (a) to discover and explore innovative regeneration approaches to improve the health and welfare of military personnel and veterans with hearing disturbances, and (b) to accelerate the transition of stem cell technologies into new standards of care to treat hearing loss and other inner ear disorders. Success of this work will significantly promote the research of stem cell-based hearing regeneration, which will potentially affect the state of medical science in today’s battlefield experience on function, wellness, and overall quality of life for veterans as well as their caregivers and families.

项目概要 听觉毛细胞是机械传导受体，通过螺旋将声音信号传递到脑干 然而，毛细胞很容易受到多种损伤，包括噪音、爆炸、 衰老和创伤性脑损伤通常是不可逆转的，导致永久性的哺乳动物毛细胞损失。 目前，还没有生物方法来补充人类的听力损失和其他内耳疾病。 该项目的长期目标是使用基于干细胞的方法来再生受损的毛细胞。 治疗听力损失和其他内耳疾病的听觉系统在这项提案中，我们将生成人类。 感觉毛细胞并使用基于干细胞的表观遗传方法重建毛细胞-SGN 连接。 我们已经鉴定出人类椭圆囊上皮来源的原感觉样细胞（HUC），其表现出以下特征： 我们在一项试点研究中发现 HUC 表现出基因组 DNA 甲基化。 DNA甲基转移酶（DNMT）抑制剂5-氮杂胞苷（5-aza）作用于HUC，发现处理过的HUC 因此，在本提案中，我们追求 DNMT 抑制剂 5-。 aza 诱导 HUC 分化为新的功能性毛细胞，可以替代受损的毛细胞并形成 为了检验这一假设，提出了三个具体目标： 具体目标 1：定义 5-aza 将 HUC 诱导为感觉毛细胞。 具体目标 2：在体外研究 5-aza 处理的 HUC 的整合和突触形成。 具体目标 3：确定 5-aza 处理的 HUC 体内的存活、分化、整合和功能。 在这个提案中，我们将生成人类感觉毛细胞并使用 基于干细胞的表观遗传方法的优点是表达和表达。 基因的表型会发生遗传性改变，而其 DNA 序列则保持不变。 这项工作的重点是 (a) 发现和探索创新的再生方法，以改善健康和 有听力障碍的军事人员和退伍军人的福利，以及 (b) 加速过渡 干细胞技术成功应用于治疗听力损失和其他内耳疾病的新护理标准。 这项工作将显着促进基于干细胞的听力再生研究，这将 潜在地影响当今医学科学在功能、健康和整体体验方面的战场经验 退伍军人及其护理人员和家人的生活质量。