Behavioral and physiological measurements of hearing in mouse models of Alzheimer's Disease

阿尔茨海默病小鼠模型听力的行为和生理测量

• 批准号: 10878437
• 负责人: MICHEAL L DENT
• 金额: $ 16.94万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10878437
• 关键词: Acoustics; Affect; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Model; Anxiety; Area; Attention; Auditory Brainstem Responses; Auditory system; Behavioral; Biological; Blood Vessels; Brain; Brain Pathology; Central Nervous System; Characteristics; Cognition; Cognitive; Cognitive deficits; DNA Sequence Alteration; Data; Data Set; Dementia; Emotional; Female; Fright; Functional disorder; Funding; Future; Gene Expression Regulation; Gene Mutation; Genes; Genetic; Genotype; Goals; Hearing; Human; Human BioMolecular Atlas Program; Impaired cognition; Individual; Investigation; Knockout Mice; Knowledge; Link; Metabolic dysfunction; Metabolism; Modality; Modeling; Mus; Nerve Degeneration; Neurons; Pathologic; Peripheral; Peripheral Nervous System; Persons; Phenotype; Physiological; Physiology; Prevalence; Research; Sensory; Startle Reaction; Stress; Visual; Work; behavioral phenotyping; data repository; epidemiology study; genetic risk factor; hearing impairment; hearing loss treatment; hearing measurement; human tissue; interest; male; mouse model; neural; novel therapeutic intervention; parent grant; preclinical study; prevent; programs; sex; sound; targeted treatment

Project Summary A link between hearing loss and dementia is well established from epidemiological studies; however, whether or not there is a causal link between hearing loss and dementia is unclear. The primary goal of the proposed research is to use Common Fund datasets to investigate common genetic mutations associated with hearing dysfunction and cognitive deficits. The proposed research extends the scope of the parent grant which focuses on characterizing the behavioral and physiological trajectory of hearing loss in three specific mouse models with gene mutations that result in brain pathologies mimicking certain aspects of Alzheimer’s and related dementias (ADRD) in humans. While these models are useful for investigating the potential contribution of specific predetermined pathological trajectories in hearing dysfunction, they do not adequately recapitulate human dementias, which may arise from a host of mechanisms and display varying cognitive-behavioral phenotypes. Identification of genetic factors that predispose a person to both hearing dysfunction and dementia is critical for developing more valid animal models and probing potential mechanisms to target with biomedical treatments. We hypothesize that abnormal cognition will be more prevalent in KO mice with hearing dysfunction compared to those without hearing dysfunction. Our research will address this knowledge gap through two Specific Aims that use Common Fund data to investigate additional genotype-phenotype relationships between hearing dysfunction and cognitive deficits: 1) Analyze correlations between hearing phenotypes and cognitive-emotional behavioral phenotypes in data from the Knockout Mouse Phenotyping Program (KOMP2) to identify common genetic mechanisms, and 2) Compare genes of interest identified in Aim 1 against publicly available data in the Human BioMolecular Atlas Program (HuBMAP) and other publicly available data repositories to determine which human tissues express these genes and which genes are known to be expressed in the peripheral and central auditory systems. Additionally, we will quantify the co-occurrence of hearing dysfunction, cognitive deficits, and anxiety, fear, or stress phenotypes. We will consider sex as a biological variable to determine if hearing dysfunction with cognitive phenotypes are more prevalent in males or females in the KOMP2 dataset. This work will inform future investigations linking the trajectory of hearing dysfunction with cognitive deficits, including ADRD, and provide potential targets for future preclinical studies investigating novel therapeutic interventions.

项目摘要 从流行病学研究中，听力损失与痴呆症之间的联系得到了很好的建立。但是，是否或 听力损失和痴呆症之间没有因果关系。提议的主要目标 研究是使用共同基金数据集研究与听力相关的常见遗传突变 功能障碍和认知缺陷。拟议的研究扩展了父母赠款的范围 在表征三种特定鼠标模型中听力损失的行为和身体轨迹时 导致大脑病理学的基因突变模仿阿尔茨海默氏症和相关痴呆症的某些方面 （ADRD）在人类中。尽管这些模型可用于研究特定的潜在贡献 在听力功能障碍中，预定的病理轨迹，它们不能充分概括人类 痴呆症可能是由多种机制引起的，并且表现出不同的认知行为表型。 识别使人易于听到功能障碍和痴呆症的遗传因素至关重要 开发更有效的动物模型并探测潜在的机制，以使用生物医学治疗靶向。 我们假设在听力功能障碍的KO小鼠中，异常认知将更加普遍 对于那些没有听到功能障碍的人。我们的研究将通过两个具体目标解决这一知识差距 使用常见的基金数据来研究听力之间的其他基因型 - 表型关系 功能障碍和认知缺陷：1）分析听力表型与认知情感的相关性 敲除鼠标表型程序（KOMP2）的数据中的行为表型以识别常见 遗传机制和2）比较AIM 1中鉴定的感兴趣基因与在 人类生物分子图集计划（Hubmap）和其他公开可用的数据存储库来确定哪个 人体组织表达这些基因，哪些基因在外围和中央表达 听觉系统。此外，我们将量化听力功能障碍，认知缺陷和 焦虑，恐惧或压力表型。我们将性视为确定听力是否的生物变量 在KOMP2数据集中，男性或女性的认知表型功能障碍更为普​​遍。这项工作 将为未来的调查提供有关听力功能障碍与认知缺陷的轨迹的调查，包括 ADRD，并为未来研究新治疗干预措施的临床前研究提供了潜在的靶标。