Translational Hearing Center

转化听力中心

基本信息

批准号：
10853798
负责人：
Peter Stephen Steyger
金额：
$ 19.57万
依托单位：
CREIGHTON UNIVERSITY
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：
2021-03-05 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10853798
关键词：
ATAC-seq Academic Medical Centers Academic achievement Acceleration Address Affect Aging Alcohol consumption Alcohols Animal Model Architecture Auditory Auditory area Auditory system Basic Science Behavior Binding Bioinformatics Biological Assay Biometry Cell Density Centers of Research Excellence Child Chromatin Chromatin Structure Clinical Clinical Trials Collaborations Complement Data Development Disease Down-Regulation Drug Delivery Systems Drug Screening Environment Epigenetic Process Equilibrium Etiology Exhibits Extracellular Matrix Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetal alcohol effects Functional disorder Funding Future Gene Expression Genomic Segment Goals Health Health system Hearing Homeodomain Proteins Hospitals Impaired cognition Impairment Individual Infant Infrastructure Institution Interneuron function Interneurons Intervention Investigation Investigational New Drug Application Labyrinth Language Lead Life Measures Mediating Medical center Mentors Modeling Modification Molecular Mus Nebraska Neural Pathways Neuronal Plasticity Neurons Outcome Parvalbumins Peripheral Play Population Pregnancy Production Regulation Rehabilitation therapy Reporting Research Research Personnel Rodent Model Role Signal Transduction Site Stains Synapses Technology Testing Therapeutic Translating Universities aging population alcohol exposure auditory processing base boys career density drug discovery efficacy study efficacy validation experimental study gamma-Aminobutyric Acid genomic locus hearing impairment hearing preservation hearing restoration insight lead candidate molecular marker mouse model neurodevelopment neuromechanism novel patient population programs safety study sensory cortex skills sound transcription factor translational scientist

项目摘要

Project Summary This Center of Biomedical Research Excellence (COBRE) application is to establish the Translational Hearing Center, administered by centrally-located Creighton University, with Boys Town National Research Hospital (BTNRH) and the University of Nebraska Medical Center (UNMC), as institutional partners. Our overall goal is to build a critical mass of academic translational researchers developing therapeutic intentions to preserve or restore hearing and vestibular function from a wide range of etiologies that cause hearing loss and vestibular deficits. Hearing loss in infants and children results in delayed acquisition of listening and spoken language skills critical for academic achievement and maximal career trajectories of affected individuals. In the aging population, hearing loss and vestibular deficits without appropriate rehabilitation accelerates aging and cognitive decline. Aim 1: Develop the infrastructure and expertise base for translational auditory and vestibular research COBRE funding will enable an Administrative Core within the Center to provide a unique, transformational research environment for junior investigators to translate their basic science discoveries into therapeutic strategies that preserve or restore hearing and vestibular function. This will establish a broader nonclinical research program. The Administrative Core will develop a Drug Discovery and Delivery Core that will coordinate necessary drug screen assays and production of derivatives of lead compounds and their delivery to the inner ear and associated central neural pathways, as well as an Auditory Vestibular Technology Core to validate the efficacy of lead candidate ototherapeutics hits. Aim 2: Build a critical mass of funded investigators leading translational auditory and vestibular research. We will examine both peripheral and central mechanisms of hearing loss and vestibular dysfunction, and identify pharmacotherapeutic strategies preserve or restore hearing and vestibular function, with multiple levels of research funding for investigators. We also have an outstanding Mentoring Plan for project leaders, complementing their expertise with senior investigations as Internal Mentors and biostatistical support, as well as outside investigators with translational and clinical expertise as External Mentors. Future plans call for continued expansion of the Center to include submission of Investigational New Drug applications, safety and efficacy studies and clinical trials in partnership with patient populations served by Creighton University’s academic medical center, Catholic Health Initiatives (CHI) Health system, BTNRH and UNMC. Individuals with fetal alcohol spectrum disorders (FASD) exhibit impaired auditory processing. The underlying mechanisms for these auditory deficits are unclear. The goal of the proposed research is to model the effects of prenatal alcohol exposure (PAE) in mice to provide foundational insights into neural mechanisms that mediate auditory processing deficits. Given the important role that parvalbumin (PV) interneurons play in processing of auditory information, it is important to address the impact of PAE on PV interneurons in the primary auditory cortex. It is not known whether altered maturation of PV interneurons contribute to altered inhibition and changes in the network excitation in the auditory cortex resulting in impairments in auditory processing. Here, we will use a mouse model of maternal voluntary alcohol consumption throughout gestation to examine altered chromatin accessibility in PV interneurons, altered chromatin binding of the pioneer transcription factor Otx2, distribution of interneuron populations, synaptic connectivity and mechanisms contributing to altered PV interneuron maturation in the primary auditory cortex. The goal of the proposed studies is to provide a molecular basis for the altered auditory processing observed in FASD. We hypothesize that alterations in the PV interneuron epigenetic modifications could regulate their maturation resulting in altered PV interneuron function that ultimately contribute to auditory processing impairments. These aims bring together labs from vastly different fields to form a team with expertise in PAE neurodevelopment, FASD, chromatin structure, and bioinformatics. Collaboration among these labs enables a comprehensive approach to study mechanisms that contribute to altered auditory processing in FASD, helping to provide greater insight into the molecular and neural mechanisms of auditory processing. These aims will reveal a chromatin basis for the effects of PAE in the auditory cortex, and identify genomic loci, transcription factor regulation, and the degree of Otx2 involvement in these alterations that correspond to FASD. Therefore, not only will these findings reveal novel mechanistic insights into PAE, but will also lay the groundwork for future collaboration in the field of chromatin architecture, development of the auditory cortex, and the impact of prenatal alcohol exposure.

项目摘要这个生物医学研究卓越中心（COBRE）的应用是建立转化听证会中心，由中央位置的克雷顿大学（Creighton University）管理，男孩镇国家研究医院（BTNRH）和内布拉斯加州大学医学中心（UNMC），作为机构合作伙伴。我们的总体目标是建立大量的学术翻译研究人员，发展治疗意图以保存或恢复听力和前庭功能，来自多种病因，导致听力损失和前庭缺陷。婴儿和儿童的听力损失导致听力和口语技能的获取延迟对学术成就和受影响个人的最大职业轨迹至关重要。在老龄化的人口中，听力损失和前庭无适当的康复定义会加速衰老和认知能力下降。目标1：为翻译听觉和前庭研究开发基础架构和专业知识基础毛cr融资将使中心内的行政核心能够提供独特的变革性初级研究人员的研究环境将其基础科学发现转化为治疗保留或恢复听力和前庭功能的策略。这将建立更广泛的非临床研究计划。行政核心将开发出一种药物发现和递送核心，该核心将协调必要的药物筛选分析和铅化合物的衍生物的生产及其递送到内部耳朵和相关的中央神经通路以及听觉前庭技术核心验证铅候选药物的功效。目的2：建立大量资助的研究人员，领先的翻译听觉和前庭研究。我们将检查听力丧失和前庭功能障碍的外围和中心机制，并确定药物治疗策略保留或恢复听力和前庭功能，多个研究人员的研究资金水平。我们还为项目负责人制定了出色的指导计划，通过作为内部导师和生物统计学支持的高级调查来完成他们的专业知识作为外部研究人员，具有翻译和临床专业知识为外部导师。未来计划要求继续扩展该中心，包括提交研究性新药应用，安全性和疗效研究和临床试验与Creighton University的患者人群合作学术医学中心，天主教卫生计划（CHI）卫生系统，BTNRH和UNMC。胎儿酒精谱系障碍（FASD）的个体暴露于听觉处理受损。基础这些听觉缺陷的机制尚不清楚。拟议研究的目的是建模小鼠中的产前酒精暴露（PAE），为介导的神经机制提供基本见解听觉处理缺陷。鉴于白蛋白（PV）中间神经元在处理中发挥的重要作用听觉信息，重要的是要解决PAE对主要听觉中光伏中间神经元的影响皮质。尚不知道PV中神经元的成熟是否有助于改变和变化在听觉皮层中令人兴奋的网络中，导致听觉处理受损。在这里，我们将使用妊娠期间母体自愿饮酒的小鼠模型检查染色质的改变 PV中神经元的可及性，先锋转录因子OTX2的染色质结合改变，分布神经元的种群，突触连通性和导致PV Interneuron改变的机制主要听觉皮层的成熟。拟议的研究的目的是为在FASD中观察到的听觉处理变化。我们假设PV Interneuron中的改变表观遗传修饰可能调节其成熟，从而导致PV中间神经元的功能改变最终有助于听觉处理障碍。这些目标将来自截然不同领域的实验室汇集在一起，以组成一支由PAE专家组成的团队神经发育，FASD，染色质结构和生物信息学。这些实验室之间的协作可以使全面的研究机制的方法有助于改变FASD的听觉处理，从而帮助为了更深入地了解听觉处理的分子和神经机制。这些目标会揭示PAE在听觉皮层中影响的染色质基础，并识别基因组基因座转录因子调节，以及与FASD相对应的这些变化中的OTX2参与程度。所以，这些发现不仅会揭示出对PAE的新型机械见解，而且还将为未来奠定基础染色质体系结构领域的合作，听觉皮层的开发以及产前的影响酒精暴露。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.

DOI：
10.1021/acs.jmedchem.2c00352
发表时间：
2023-01-12
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Bhattarai, Pankaj;Hegde, Pooja;Li, Wei;Prathipati, Pavan Kumar;Stevens, Casey M.;Yang, Lixinhao;Zhou, Hinman;Pandya, Amit;Cunningham, Katie;Grissom, Jenny;Sotelo, Mariaelena Roman;Sowards, Melanie;Calisto, Lilian;Destache, Christopher J.;Rocha-Sanchez, Sonia;Gumbart, James C.;Zgurskaya, Helen I.;Jackson, Mary;North, E. Jeffrey
通讯作者：
North, E. Jeffrey

Local Delivery of Therapeutics to the Cochlea Using Nanoparticles and Other Biomaterials.

DOI：
10.3390/ph15091115
发表时间：
2022-09-07
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
0
作者：
Dash S;Zuo J;Steyger PS
通讯作者：
Steyger PS

Profiling mouse cochlear cell maturation using 10× Genomics single-cell transcriptomics.

DOI：
10.3389/fncel.2022.962106
发表时间：
2022
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
通讯作者：

Innate Immunity to Spiral Ganglion Neuron Loss: A Neuroprotective Role of Fractalkine Signaling in Injured Cochlea.

DOI：
10.3389/fncel.2021.694292
发表时间：
2021
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
Stothert AR;Kaur T
通讯作者：
Kaur T

Molecular and cytological profiling of biological aging of mouse cochlear inner and outer hair cells.

小鼠耳蜗内毛细胞和外毛细胞生物衰老的分子和细胞学分析

DOI：
10.1016/j.celrep.2022.110665
发表时间：
2022-04-12
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Liu, Huizhan;Giffen, Kimberlee P.;Chen, Lei;Henderson, Heidi J.;Cao, Talia A.;Kozeny, Grant A.;Beisel, Kirk W.;Li, Yi;He, David Z.
通讯作者：
He, David Z.