Single cell analysis of mitotic regeneration in the mouse vestibular system

小鼠前庭系统有丝分裂再生的单细胞分析

基本信息

批准号：
10700828
负责人：
Taha A Jan
金额：
$ 18.83万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700828
关键词：
Ablation Acceleration Adopted Affect Auditory Award Basic Science Behavior Bioinformatics Biological Biology Cell Lineage Cell Maintenance Cell Proliferation Cell division Cells Clinical Data Decision Making Development Epithelium Equilibrium Event Faculty Functional disorder Funding Gene Expression Profile Genes Genetic Goals Grant Hair Cells Hearing Hearing problem Heterogeneity Homeostasis Human In Vitro Individual Injury Knowledge LGR5 gene Labyrinth Lead Learning Location Maintenance Mammals Mentors Mitosis Mitotic Modeling Molecular Mus Natural regeneration Neonatal Olfactory Pathways Operative Surgical Procedures Organ Otolaryngology Otology Pathway interactions Patients Persons Physicians Population Proliferating Regenerative Medicine Research Scientist Sensorineural Hearing Loss Sensory Sensory Disorders Signal Transduction Skin Somatosensory Cortex Supporting Cell Surgeon System Techniques Technology Therapeutic Tissues Training Training Programs Utricle structure Work beta catenin biomarker identification body system cell behavior equilibration disorder experimental study hair cell regeneration hearing impairment hearing restoration in silico in vivo in vivo Model injured insight interest medical schools member mouse genetics mouse model neonatal injury neonatal mice overexpression permanent hearing loss progenitor programs regeneration following injury regenerative regenerative therapy self-renewal single cell analysis single-cell RNA sequencing skills small molecule spatiotemporal stem stem cells tissue regeneration transcription factor transmission process undergraduate student

项目摘要

PROJECT SUMMARY (ABSTRACT) Sensorineural hearing loss and vestibular dysfunction are most common sensory disorders affecting millions worldwide 1–3. Auditory and vestibular functions require mechanosensitive hair cells, with hair cell loss leading to permanent hearing loss and disabling vestibular dysfunction/hypofunction. Recently, the neonatal mouse utricle, one of five vestibular organs that relies on hair cells to detect linear acceleration, was shown to harbor robust numbers of progenitor cells 6,7. However, while the existence of both mitotic and non-mitotic mechanisms in mammals is now clear, we currently lack understanding of the timing, location, and mechanisms of cell fate decisions. In other systems, like the skin, it is known that fate decisions are made downstream of stem cells and their transit amplifying populations, but we do not yet know the fates of these putative populations in the inner ear 39. A central regulator of tissue homeostasis and stem cell maintenance across many organs is the Wnt pathway 8, and this signaling cascade is upregulated in the inner ear 12. I hypothesize that following injury, mitotic regeneration leads to different cell lineages in the neonatal utricular sensory epithelium, and that Wnt activation directs more supporting cells to adopt the mitotic cell lineage. Gaining an in-depth understanding of the sequence of events that drive mitotic regeneration post injury will reveal potential approaches to regenerate hair cells and supporting cells, with the ultimate goal of restoring hearing and balance functions. As a surgeon-scientist with a passion for treating patients with hearing and balance disorders, I am well equipped to tackle the scientific questions outlined. My interests in the basic sciences stem from my undergraduate years working on the genetics and development of the somatosensory cortex and studying the olfactory system. During medical school, I saw the lack of therapies of patients with permanent hearing loss as an opportunity, working on hair cell regeneration under the tutelage of renowned scientists, including Dr. Stefan Heller and Dr. Roel Nusse (Jan et al., 2013, Development). As a resident in otolaryngology, I focused on gaining the clinical and surgical expertise to treat patients and had the opportunity to continue basic science research with a focus on hearing loss under Dr. Konstantina Stankovic. In order to gain advanced surgical skills and learn state of the art techniques to study inner ear regeneration, I completed the T32 funded Clinician Scientist Training Program in Otology & Neurotology. This program further allowed me to collect preliminary data and chart my goals for this proposal as a new faculty member at UCSF. While I have extensive training in inner ear biology, my knowledge is lacking in advanced mouse genetics, new single cell RNAseq technologies, and advanced bioinformatics. Under the guidance of renowned stem cell physician-scientist Dr. Ophir Klein as my mentor at UCSF, and expert inner ear surgeon-scientist, Dr. Alan Cheng as my co-mentor at Stanford, I am confident this award will prepare me for scientific independence through the R01 grant mechanism.

项目概要（摘要）感音神经性听力损失和前庭功能障碍是最常见的感觉障碍全球数百万人 1–3 听觉和前庭功能需要机械敏感的毛细胞，但毛细胞会丢失。最近，新生儿出现永久性听力损失和前庭功能障碍/功能减退。小鼠椭圆囊是依赖毛细胞检测线性加速度的五个前庭器官之一，被证明可以拥有大量的祖细胞 6,7 然而，同时存在有丝分裂和非有丝分裂。哺乳动物的机制现已清楚，但我们目前缺乏对时间、地点和机制的了解在其他系统中，例如皮肤，众所周知，命运决定是在细胞命运决定的下游做出的。干细胞及其转运扩增群体，但我们还不知道这些假定群体的命运在内耳 39. 许多器官的组织稳态和干细胞维持的中央调节器是 Wnt 通路 8，并且该信号级联在内耳 12 中上调。受伤后我帮助了这一点，有丝分裂再生导致新生儿椭圆囊感觉上皮细胞谱系不同，并且 Wnt 激活引导更多支持细胞采用有丝分裂细胞谱系。损伤后驱动有丝分裂再生的事件顺序将揭示潜在的再生方法毛细胞和支持细胞，最终目标是恢复听力和平衡功能。作为一名热衷于治疗听力和平衡障碍患者的外科医生科学家，我很好我对基础科学的兴趣源于我的能力，能够解决所概述的科学问题。本科期间致力于体感皮层的遗传学和发育并研究在医学院期间，我发现永久性听力损失患者缺乏治疗。一个机会，在包括 Stefan 博士在内的著名科学家的指导下致力于毛细胞再生 Heller 和 Roel Nusse 博士（Jan 等人，2013 年，发展）作为耳鼻喉科住院医师，我专注于获得知识。治疗患者的临床和外科专业知识，并有机会继续基础科学研究在康斯坦蒂娜·斯坦科维奇 (Konstantina Stankovic) 博士的指导下，重点关注听力损失，以获得先进的手术技能和学习。研究内耳再生的最先进技术，我完成了 T32 资助的临床科学家培训耳科和神经耳科项目进一步使我能够收集初步数据并绘制图表。作为加州大学旧金山分校的新教员，我的目标是内耳生物学方面的广泛培训，我缺乏先进的小鼠遗传学、新的单细胞 RNAseq 技术和先进的知识在著名干细胞医师科学家 Ophir Klein 博士（作为我的导师）的指导下。加州大学旧金山分校 (UCSF) 以及内耳外科医生专家 Alan Cheng 博士作为我在斯坦福大学的共同导师，我对此充满信心该奖项将使我通过 R01 资助机制为科学独立做好准备。