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

项目摘要 从流行病学研究中可以很好地建立听力损失和痴呆症之间的联系;然而， 听力损失和痴呆症之间的因果关系尚不清楚。建议的主要目标 研究是使用共同基金数据集来调查与听力相关的常见基因突变 功能障碍和认知缺陷。拟议的研究扩大了父母补助金的范围， 在三种特定的小鼠模型中表征听力损失的行为和生理轨迹， 基因突变导致大脑病理学模仿阿尔茨海默氏症和相关痴呆症的某些方面 （ADRD）在人类。虽然这些模型对于研究特定的生物学行为的潜在贡献是有用的， 在听觉功能障碍的预定病理轨迹，他们不足以概括人类 痴呆，这可能是由一系列机制引起的，并显示出不同的认知行为表型。 识别使一个人易患听力障碍和痴呆症的遗传因素对预防和治疗听力障碍至关重要。 开发更有效的动物模型并探索生物医学治疗的潜在靶向机制。 我们假设，与正常小鼠相比， 对于那些没有听力障碍的人来说。我们的研究将通过两个具体目标来解决这一知识差距 他们使用共同基金的数据来研究听力与基因型和表型之间的关系， 功能障碍和认知缺陷：1）分析听力表型和认知-情绪之间的相关性 敲除小鼠表型分析程序（KOMP 2）的数据中的行为表型，以确定常见的 遗传机制，以及2）将目标1中鉴定的感兴趣基因与目标1中公开可用的数据进行比较。 人类生物分子图谱计划（HuBMAP）和其他公开可用的数据库，以确定 人类组织表达这些基因，并且已知哪些基因在外周和中枢表达 听觉系统此外，我们将量化听力障碍、认知缺陷和 焦虑恐惧或压力表型我们将把性别作为一个生物学变量来确定听力 在KOMP 2数据集中，具有认知表型的功能障碍在男性或女性中更普遍。这项工作 将为未来的研究提供信息，将听力障碍的轨迹与认知缺陷联系起来，包括 ADRD，并为未来研究新的治疗干预措施的临床前研究提供潜在的目标。

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.