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

项目摘要 流行病学研究很好地确定了听力损失和痴呆症之间的联系；然而，无论或 目前还不清楚听力损失和痴呆症之间是否存在因果关系。建议的主要目标是 这项研究将使用共同基金的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。拟议的研究扩大了家长资助的范围，重点是 三种特定的小鼠听力损失模型的行为和生理轨迹特征 导致类似阿尔茨海默氏症和相关痴呆某些方面的脑部病理的基因突变 (ADRD)在人类身上。虽然这些模型对于研究特定的 听力障碍的预定病理轨迹，它们不能充分概括人类 痴呆症可能由多种机制引起，表现出不同的认知-行为表型。 识别易患听力障碍和痴呆症的遗传因素对 开发更有效的动物模型，探索以生物医学治疗为靶点的潜在机制。 我们假设，与听力障碍相比，认知异常在KO小鼠中更普遍 给那些没有听力障碍的人。我们的研究将通过两个具体目标来解决这一知识差距 使用共同基金的数据来调查听力之间的其他基因-表型关系 功能障碍与认知缺陷：1)分析听力表型与认知情绪的相关性 来自基因敲除小鼠表型程序(KOMP2)的数据中的行为表型以识别共同的 遗传机制，以及2)将目标1中确定的感兴趣基因与 人类生物分子图谱计划(HuBMAP)和其他公开可用的数据存储库，以确定 人类组织表达这些基因，已知哪些基因在外周和中央表达 听觉系统。此外，我们将量化听力障碍、认知障碍和 焦虑、恐惧或压力表型。我们将把性别作为一个生物变量来确定是否听力 在KOMP2数据集中，具有认知表型的功能障碍在男性或女性中更为普遍。这部作品 将为未来将听力障碍与认知障碍联系起来的研究提供信息，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靶点。

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.