Translational Hearing Center

转化听力中心

• 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
• 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

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.

项目概要 该生物医学研究卓越中心 (COBRE) 的申请旨在建立转化听证会 该中心由位于市中心的克赖顿大学和男孩镇国家研究医院管理 (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 建立足够数量的学术转化研究人员，开发治疗意图以保存或 从导致听力损失和前庭功能障碍的多种病因中恢复听力和前庭功能 赤字。婴儿和儿童的听力损失会导致听力和口语技能的延迟获得 对于受影响个人的学业成就和最大职业轨迹至关重要。在人口老龄化的背景下， 如果没有适当的康复，听力损失和前庭缺陷会加速衰老和认知能力下降。 目标 1：开发转化听觉和前庭研究的基础设施和专业知识库 COBRE 资金将使中心内的行政核心能够提供独特的、变革性的 为初级研究人员提供将基础科学发现转化为治疗药物的研究环境 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。行政核心将开发药物发现和交付核心，以协调 必要的药物筛选分析和先导化合物衍生物的生产以及将其输送到内部 耳朵和相关的中枢神经通路，以及听觉前庭技术核心来验证 主要候选耳科治疗药物的疗效显着。 目标 2：培养一批关键的受资助研究人员，领导翻译听觉和前庭研究 研究。我们将检查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，其中包括多种方法 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， 通过内部导师的高级调查和生物统计支持来补充他们的专业知识 作为具有转化和临床专业知识的外部研究者作为外部导师。未来的计划要求 继续扩大该中心，包括提交研究性新药申请、安全性和 与克赖顿大学服务的患者群体合作进行功效研究和临床试验 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。底层的 这些听觉缺陷的机制尚不清楚。拟议研究的目标是模拟以下因素的影响 小鼠产前酒精暴露（PAE）为介导神经机制提供基础见解 听觉处理缺陷。鉴于小清蛋白 (PV) 中间神经元在处理 听觉信息，解决 PAE 对初级听觉中 PV 中间神经元的影响非常重要 皮质。目前尚不清楚 PV 中间神经元成熟的改变是否会导致抑制和变化的改变 听觉皮层的网络兴奋导致听觉处理受损。在这里，我们将使用 母亲在整个妊娠期间自愿饮酒的小鼠模型，以检查染色质的改变 PV 中间神经元的可及性、先锋转录因子 Otx2 染色质结合的改变、 中间神经元群体、突触连接性和导致 PV 中间神经元改变的机制 初级听觉皮层的成熟。拟议研究的目标是提供分子基础 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其成熟，从而改变 PV 中间神经元功能， 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，组成一支具有 PAE 专业知识的团队 神经发育、FASD、染色质结构和生物信息学。这些实验室之间的合作使 全面的方法来研究有助于改变 FASD 听觉处理的机制，帮助 提供对听觉处理的分子和神经机制的更深入的了解。这些目标将 揭示 PAE 对听觉皮层影响的染色质基础，并识别基因组位点、转录 因素调节，以及 Otx2 参与这些与 FASD 相对应的改变的程度。所以， 这些发现不仅揭示了 PAE 的新颖机制见解，而且还将为未来奠定基础 在染色质结构、听觉皮层发育以及产前影响领域的合作 酒精暴露。

项目成果

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)
• 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

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.