Peripheral auditory system deficits and autism-like behaviors

周围听觉系统缺陷和自闭症样行为

• 批准号: 10349592
• 负责人: Hainan Lang
• 金额: $ 19.93万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349592
• 关键词: Abnormal Macrophage; Acoustic Nerve; Address; Age related macular degeneration; Animal Model; Animals; Antibiotics; Arginine; Auditory; Auditory Brainstem Responses; Auditory Perception; Auditory system; Award; Behavior; Behavior Disorders; Brain; CBA/CaJ Mouse; Cells; Child; Cochlea; Collaborations; Communication; Communication impairment; Companions; Complement; Complement 3a; Complement 3d Receptors; Complement Activation; Complement Factor H; Development; Disease; Disease model; Enhancers; Exhibits; FDA approved; Functional disorder; Genes; Goals; Hearing; Hearing problem; Human; Immune; Immune System Diseases; Impairment; Individual; Investigation; K-18 conjugate; Knowledge; Laboratories; Lifestyle-related condition; Link; Macrophage Activation; Measurement; Measures; Medical; Mentors; Mentorship; Microglia; Minocycline; Molecular Profiling; Mus; Muscle Cells; Mutation; National Institute on Deafness and Other Communication Disorders; Nerve Degeneration; Nerve Fibers; Nervous system structure; Neurodevelopmental Disorder; Neuroimmune; Neurons; Pathologic; Pathology; Pathway interactions; Peripheral; Pharmacology; Pharmacotherapy; Physiological; Play; Population; Quality of life; Recovery of Function; Reporting; Research; Research Activity; Research Project Grants; Risk; Role; School Health Services; Scientific Advances and Accomplishments; Sensorineural Hearing Loss; Social Behavior; Social Interaction; Socialization; South Carolina; Symptoms; Syndrome; Testing; Tetracyclines; Therapeutic; Training; Training Activity; Ultrasonics; Universities; Wild Type Mouse; Work; antagonist; auditory processing; autism spectrum disorder; autistic; base; behavioral impairment; behavioral phenotyping; career; common symptom; conditional mutant; demographics; developmental disease; disability; experience; experimental study; functional decline; hearing impairment; human model; human subject; individuals with autism spectrum disorder; inhibitor; innovation; macrophage; medical schools; mouse model; mutant mouse model; neuroimmunology; novel; postnatal; programs; receptor; relating to nervous system; response; social; social communication; tool; treatment strategy; vocalization

SUMMARY Children with hearing loss have an increased risk for developing other disabilities. One commonly associated disability is Autism Spectrum Disorder (ASD), a condition that also includes alterations in the auditory system. Hearing loss might contribute to ASD core symptoms and interfere with communication, social interaction, and overall quality of life. Nearly 1 in 59 children with hearing loss were reported to receive school-based services for ASD. Mutations or deletions in the Myocyte-specific Enhancer Factor 2C (MEF2C) gene have recently been linked to ASD and other neurodevelopmental disorders. A preliminary study conducted in the candidate’s laboratory found that (1) Mef2c is highly expressed in auditory nerve macrophages in postnatal wild type mice, and (2) auditory nerve functional decline and hearing loss occur in a novel mouse model of a syndromic autism disorder, human MEF2C haploinsufficiency syndrome. The overall goal of this NIDCD Research Career Enhancement Award (K18) resubmission is to augment the candidate’s research expertise to study how peripheral auditory system deficits contribute to communication and other social behavior impairments in ASD and other common human developmental disorders. The candidate is an established auditory neuroscientist with more than 20 years of experience in the pathophysiology of the peripheral auditory system and resultant sensorineural hearing loss. With the mentorship of four leading experts from the Medical University of South Carolina and Harvard Medical School, the training plan and research project will provide the opportunity for the candidate to (1) acquire advanced scientific knowledge/research tools in the fields of neuroimmunology, neurodevelopmental disorders, central auditory processing and perception, and communication and social interaction behaviors; and (2) conduct a study to address the novel hypothesis that abnormal macrophage activity resulting from Mef2c deficiency leads to AN functional declines and hearing loss, and that these changes may be associated with abnormalities in higher levels of the nervous system and contribute to communication impairment and other autistic symptoms. These training and research activities will catalyze research collaborations in new directions and establish innovative research programs to study hearing loss and communication impairment in human neurodevelopmental disorders. These investigations will promote a greater understanding of the important role of cochlear macrophage and auditory nerve dysfunction in ASD and other neurodevelopmental disorders, and may reveal a neuro-immune based therapeutic strategy beneficial for this fast growing population.

摘要 听力损失的儿童患其他残疾的风险增加。一个共同的联想 残疾是自闭症谱系障碍(ASD)，也包括听觉系统的改变。 听力损失可能会导致ASD的核心症状，并干扰沟通、社交和 总体生活质量。据报道，近1/59的听力损失儿童接受了校本服务。 对于ASD。最近，心肌细胞特异性增强因子2C(MEF2C)基因的突变或缺失 与自闭症和其他神经发育障碍有关。对候选人进行的一项初步研究 实验室发现(1)MEF2C在出生后野生型小鼠的听神经巨噬细胞中高表达， (2)在一种新的自闭症小鼠模型中出现听神经功能下降和听力损失 人类MEF2C单倍体功能不全综合征。NIDCD研究生涯的总体目标 增强奖(K18)重新提交是为了增强候选人的研究专长，以研究如何 外周听觉系统缺陷导致ASD患者的沟通和其他社会行为障碍 以及其他常见的人类发育障碍。候选人是一位公认的听觉神经学家。 在外周听觉系统的病理生理学方面有20多年的经验 感觉神经性听力损失。在南方医科大学四位顶尖专家的指导下 卡罗莱纳和哈佛医学院的培训计划和研究项目将为 (1)获得神经免疫学领域的先进科学知识/研究工具的候选人； 神经发育障碍、中枢听觉处理和知觉以及交流和社交 相互作用行为；以及(2)进行一项研究，以解决异常巨噬细胞 MEF2C缺乏导致的活动会导致功能下降和听力损失，这些 变化可能与较高水平的神经系统异常有关，并有助于 沟通障碍和其他自闭症症状。这些培训和研究活动将催化 研究新方向的合作，并建立创新的研究计划，以研究听力损失和 人类神经发育障碍中的沟通障碍。这些调查将促进 进一步认识耳蜗巨噬细胞和听神经功能障碍在ASD发病中的重要作用 和其他神经发育障碍，并可能揭示一种基于神经免疫的治疗策略 有益于这一快速增长的人口。