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

• 批准号: 10416080
• 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
• 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/10416080
• 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; Development; Epithelial; 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; 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; undergraduate student

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.

项目总结（摘要）