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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）的应用是建立翻译听证会中心，由位于市中心的克雷顿大学管理，与男孩镇国家研究医院（BTNRH）和内布拉斯加大学医学中心（UNMC），作为机构合作伙伴。我们的总体目标是建立一个临界质量的学术翻译研究人员发展治疗的意图，以保持或恢复听力和前庭功能，从广泛的病因，造成听力损失和前庭赤字婴儿和儿童的听力损失导致听力和口语技能的延迟获得对受影响个人的学业成就和最大职业轨迹至关重要。在老龄化人口中，听力损失和前庭缺陷而没有适当的康复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建立基础设施和专业知识基础 COBRE的资助将使中心内的行政核心能够提供一个独特的、变革性的初级研究人员将他们的基础科学发现转化为治疗的研究环境保护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。行政核心将制定一个药物发现和交付核心，必要的药物筛选试验和先导化合物衍生物的生产及其向内分泌的递送耳朵和相关的中枢神经通路，以及听觉前庭技术核心，以验证主要候选耳治疗药物的疗效。目标2：建立一个关键质量的资助研究人员领导翻译听觉和前庭 research.我们将研究听力损失和前庭功能障碍的外周和中枢机制，并确定保留或恢复听力和前庭功能的药物治疗策略，研究人员的研究经费水平。我们还为项目负责人制定了出色的指导计划，作为内部导师和生物统计支持，作为具有翻译和临床专业知识的外部研究者作为外部导师。未来计划要求继续扩大中心，包括提交研究性新药申请、安全性和有效性研究和临床试验，与Creighton大学的学术医疗中心，天主教健康倡议（CHI）卫生系统，BTNRH和UNMC。患有胎儿酒精谱系障碍（FASD）的个体表现出听觉处理受损。底层这些听觉缺陷的机制尚不清楚。拟议研究的目标是模拟产前酒精暴露（PAE）的小鼠，以提供基础的见解，神经机制，介导听觉处理缺陷鉴于小清蛋白（PV）中间神经元在处理神经元信号中的重要作用，听觉信息，重要的是要解决PAE对PV中间神经元的影响，在初级听觉皮层目前尚不清楚PV中间神经元的成熟改变是否有助于改变抑制和变化，听觉皮层的网络兴奋导致听觉处理的损伤。在这里，我们将使用在整个妊娠期间，母亲自愿饮酒的小鼠模型，以检查改变的染色质 PV中间神经元的可及性，先驱转录因子Otx 2的染色质结合改变，中间神经元群体、突触连接和有助于改变PV中间神经元的机制初级听觉皮层的成熟。这项研究的目的是为以下方面提供分子基础：在FASD中观察到的听觉处理改变。我们假设PV中间神经元的改变表观遗传修饰可以调节它们的成熟，导致PV中间神经元功能改变，最终导致听觉处理障碍。这些目标将来自不同领域的实验室聚集在一起，形成一个拥有PAE专业知识的团队神经发育，FASD，染色质结构和生物信息学。这些实验室之间的协作使全面的方法来研究有助于改变FASD听觉处理的机制，提供更深入的了解听觉处理的分子和神经机制。这些目标将揭示了PAE在听觉皮层中作用的染色质基础，并确定了基因组位点，转录，因子调节，以及Otx 2参与这些对应于FASD的改变的程度。因此，我们认为，这些发现不仅将揭示对质子加速器效应的新的机理认识，而且还将为未来的研究奠定基础。在染色质结构领域的合作，听觉皮层的发展，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.