Cell type specific vulnerability to aging

细胞类型特定的衰老脆弱性

• 批准号: 10737185
• 负责人: PATRICK O KANOLD
• 金额: $ 243.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737185
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animals; Auditory; Auditory area; Auditory system; Bar Codes; Behavior; Behavioral; Brain; CDH23 gene; Cell Nucleus; Cells; Central Auditory Diseases; Central Nervous System; Communication; Data; Dementia; Disease Progression; Functional disorder; Gene Expression; Genetic Transcription; Goals; Hearing; Hearing problem; Human; Image; Impaired cognition; Intervention; Knowledge; Link; Measurement; Modality; Molecular; Molecular Profiling; Multiplexed Analysis of Projections by Sequencing; Mus; Neurons; Peripheral; Physiological; Presbycusis; Prevention strategy; Procedures; Process; Public Health; Resolution; Risk; Role; Series; Social isolation; Societies; Testing; Therapeutic; Training; Work; age related; aged; auditory pathway; cell type; cognitive function; experimental study; gene function; hearing impairment; human disease; in situ sequencing; in vivo; life-long learning; mild cognitive impairment; multimodality; neuroimaging; next generation; normal aging; prevent; tau Proteins; transcriptome sequencing; transcriptomics; translational potential; two-photon

Project Summary: Cognitive decline is an already significant and increasing public health issue. Multiple factors contribute to cognitive decline. In particular, hearing is central to human communication and age-related hearing loss (ARHL, presbycusis) by itself is a common ailment due to age-related changes along the auditory pathway. Both hearing loss and aging are associated with cognitive decline, increasing the risk for Alzheimer's disease (AD). In many cases of presbycusis peripheral function is normal, pointing to a large role of central auditory system dysfunctions. However, the age-related changes in the central nervous system that underlie these functional deficits are largely unknown due to the functional and molecular complexity of central circuits. This lack of knowledge precludes targeted interventions. We hypothesize that the key changes in normal aging and AD in the central nervous system is the dedifferentiation of neurons, that is the loss of their functional, transcriptional, and connectional identities, and that this dedifferentiation occurs more rapidly in AD. We test this hypothesis by a series of molecular and cellular neuro-imaging experiments in both aged animals and an AD model, which explores the molecular, connectomic, and physiological correlates of ARHL and identifies precisely which auditory cortical circuits are impacted by aging. Based on preliminary data showing that lifelong auditory training can prevent at least some of the age-related changes in A1, we then develop therapeutic strategies through plasticity induced by engagement of cognitive functions. To achieve our goals, we integrate at the level of single cells across large scale single-nucleus RNAseq, spatially resolved STARmap in situ sequencing, next-generation barcode-based connectomics, and in vivo 2-photon imaging. We also use training procedures to reverse some of the age-related changes.

项目摘要：认知能力下降是一个已经很重要的公共卫生问题。 多种因素导致认知能力下降。特别是，听力是人类的核心 沟通和与年龄有关的听力损失（ARHL，长期）本身就是一种常见的疾病 由于沿听觉途径与年龄相关的变化。听力损失和衰老都是 与认知能力下降有关，增加了阿尔茨海默氏病（AD）的风险。许多人 长期外围功能的病例正常，表明中央听觉的重要作用 系统功能障碍。但是，中枢神经系统中与年龄相关的变化 这些功能缺陷的基础在很大程度上是由于功能和分子而未知的 中央电路的复杂性。缺乏知识排除了针对性的干预措施。我们 假设中枢神经系统中正常衰老和AD的关键变化是 神经元的去分化，即失去其功能，转录和连接 身份，这种去分化在AD中更快地发生。 我们通过一系列分子和细胞神经成像实验检验了这一假设 在老年动物和AD模型中，探讨了分子，连接组和 ARHL的生理相关性，并准确识别哪些听觉皮层电路是 受衰老的影响。基于初步数据，表明终身听觉训练可以预防 至少有一些与年龄相关的A1变化，然后我们通过 认知功能的参与引起的可塑性。为了实现我们的目标，我们整合 大规模单核RNASEQ的单细胞水平，空间分辨的阶段 原位测序，下一代条形码的连接组和体内2光子成像。 我们还使用培训程序来扭转一些与年龄有关的变化。