Understanding the molecular mechanism of memory from single-cell gene expression to protein folding

从单细胞基因表达到蛋白质折叠理解记忆的分子机制

• 批准号: 10392436
• 负责人: Snehajyoti Chatterjee
• 金额: $ 13.25万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392436
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; American; Attention; Autopsy; Award; Behavioral; Cells; Chromatin; Cognitive deficits; Computer Analysis; Data; Dementia; Disease; Dominant-Negative Mutation; Dorsal; Ensure; Exhibits; Family; Foundations; Functional disorder; Future; GRP78 gene; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Genomic Segment; Goals; Grant; Hippocampus (Brain); Home; Human; Impaired cognition; Individual; Institution; Interview; Iowa; Label; Laboratories; Lead; Learning; Link; Location; Memory; Memory Loss; Memory impairment; Mentors; Molecular; Molecular Biology; Molecular Chaperones; Mus; NR4A1 gene; NR4A2 gene; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathologic; Pathway interactions; Pattern; Peer Review; Persons; Pharmacology; Phase; Play; Population; Preparation; Process; Protein Biosynthesis; Proteins; Proteomics; Psychiatry; RNA; Regulation; Research; Research Personnel; Resolution; Role; Running; Sampling; Tauopathies; Technology; Testing; Therapeutic; Time; Training; Transcript; Transcriptional Regulation; Transgenes; Transgenic Mice; Translating; Universities; Viral; Work; World Health Organization; Writing; aged; base; behavioral pharmacology; career; cell type; cognitive function; collaborative environment; cost; design; differential expression; disability; enhancing factor; experimental study; gene induction; genetic manipulation; insight; long term memory; memory consolidation; memory process; mouse model; mutant; overexpression; protein folding; protein function; single cell analysis; single-cell RNA sequencing; skills; socioeconomics; spatial memory; tau Proteins; tau aggregation; therapeutic target; tool; trafficking; transcription factor; transcriptomics

Project Summary / Abstract Deficits in cognitive function and memory are a debilitating aspect of neurodegenerative disease resulting in long-term disability, enormous suffering to individuals and their families, and significant socioeconomic cost. Currently, more than 16 million Americans live with cognitive impairment, and this number is expected to continue rising as the number of individuals affected by Alzheimer's disease and related dementias is predicted to double by 2060. Long-term memory consolidation requires the induction of gene expression in a specific temporal pattern. Newly synthesized transcripts are translated and folded into functional proteins and then trafficked to the correct cellular location. Dysfunction in any of these steps can lead to memory impairment and may be dysregulated in disease conditions, although the precise mechanisms by which this occurs are unclear. My long- term goal is to determine the specific molecular mechanisms through which the Nr4A sub-family regulates gene expression to control long-term memory in order to develop therapeutic tools to treat AD, which I will pursue as an independent investigator at a research-focused institution. The overall objective of this proposal is to determine the mechanisms that link transcriptional regulation and protein folding during memory formation and how the disruption of these processes contributes to cognitive impairment in Alzheimer's disease. My central hypothesis is that Nr4A regulates genes in specific cell types to facilitate protein folding and memory formation. I will test this through the following three aims: Specific Aim 1 (K99): identify cell-type specific transcriptional signatures of memory and identify direct gene targets of Nr4A during memory consolidation using a single-cell RNA sequencing approach; Specific Aim 2 (K99): determine the role of an Nr4A target, the protein folding chaperone Hspa5, in memory consolidation and identify its downstream protein targets; Specific Aim 3 (R00): determine the effect of activating Nr4A transcription factors on memory deficits and gene expression in a mouse model of Alzheimer's disease. This project provides training in cutting-edge research skills, including computational analysis of single cell data and chromatin enrichment in memory research. The University of Iowa is home to experts on memory, computational psychiatry, neurodegeneration, and molecular biology, and the collaborative environment provides an ideal setting in which to obtain the necessary skills that will allow me to transition into a successful independent research career. As such, during the mentored (K99) phase, I will engage in activities designed to prepare me to successfully achieve independence, including training in scientific presentations, laboratory management skills, grant writing tools, scientific peer-review, and interview/application preparation. Collectively, this award will provide me with the cutting-edge skills and expertise in molecular biology, neurodegeneration and behavioral pharmacology necessary to ensure a strong technical and conceptual foundation to start my independent laboratory investigating mechanisms for the treatment of Alzheimer's disease.

项目概要/摘要 认知功能和记忆缺陷是神经退行性疾病的一个令人衰弱的方面，导致 长期残疾，给个人及其家庭带来巨大痛苦，以及巨大的社会经济成本。 目前，超过 1600 万美国人患有认知障碍，并且这一数字预计将持续下去 随着阿尔茨海默氏病和相关痴呆症患者数量预计将增加一倍，这一数字也在上升 到 2060 年。长期记忆巩固需要在特定时间诱导基因表达 图案。新合成的转录物被翻译并折叠成功能蛋白，然后被运输到 正确的蜂窝位置。这些步骤中任何一个的功能障碍都可能导致记忆障碍，并可能 在疾病条件下失调，尽管发生这种情况的确切机制尚不清楚。我的长- 长期目标是确定 Nr4A 亚家族调节基因的具体分子机制 控制长期记忆的表达，以开发治疗 AD 的治疗工具，我将以此为目标 以研究为重点的机构的独立调查员。该提案的总体目标是 确定记忆形成过程中转录调控和蛋白质折叠之间的联系机制 这些过程的破坏如何导致阿尔茨海默病的认知障碍。我的中央 假设 Nr4A 调节特定细胞类型中的基因以促进蛋白质折叠和记忆形成。 我将通过以下三个目标来测试这一点： 具体目标 1 (K99)：识别细胞类型特异性转录 使用单细胞在记忆巩固过程中识别记忆特征并识别 Nr4A 的直接基因目标 RNA测序方法；具体目标 2 (K99)：确定 Nr4A 靶标的作用，即蛋白质折叠 伴侣 Hspa5，参与记忆巩固并确定其下游蛋白质靶标；具体目标 3 (R00)： 确定激活 Nr4A 转录因子对小鼠记忆缺陷和基因表达的影响 阿尔茨海默病模型。该项目提供尖端研究技能的培训，包括 记忆研究中单细胞数据和染色质富集的计算分析。爱荷华大学 是记忆、计算精神病学、神经退行性疾病和分子生物学专家的所在地 协作环境提供了一个理想的环境，让我能够获得必要的技能 过渡到成功的独立研究生涯。因此，在指导（K99）阶段，我将 参加旨在帮助我成功实现独立的活动，包括科学培训 演示、实验室管理技能、资助写作工具、科学同行评审和面试/申请 准备。总的来说，这个奖项将为我提供分子生物学方面的尖端技能和专业知识 生物学、神经退行性变和行为药理学是确保强大的技术和能力所必需的 启动我的独立实验室研究治疗机制的概念基础 阿尔茨海默病。