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.

项目总结

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.