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.

项目总结/摘要 认知功能和记忆的缺陷是导致神经退行性疾病的衰弱方面， 长期残疾，给个人及其家庭带来巨大痛苦，并造成重大社会经济代价。 目前，超过1600万美国人患有认知障碍，预计这一数字将持续下去 随着受阿尔茨海默病和相关痴呆症影响的人数预计将增加一倍， 到2060年长时记忆的巩固需要在特定的时间内诱导基因表达， 格局新合成的转录物被翻译并折叠成功能蛋白质，然后被运输到 正确的手机位置这些步骤中的任何一个功能障碍都可能导致记忆障碍， 在疾病条件下，蛋白质表达失调，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Nr 4A亚家族调节基因的特定分子机制 表达来控制长期记忆，以开发治疗AD的治疗工具，我将继续研究， 一个研究机构的独立调查员本建议的总体目标是 确定在记忆形成过程中连接转录调节和蛋白质折叠的机制， 这些过程的中断如何导致阿尔茨海默病的认知障碍。我的中枢 假设是Nr 4A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验证这一点：特异性目标1（K99）：鉴定细胞类型特异性转录因子， 记忆的特征，并使用单细胞鉴定记忆巩固期间Nr 4A的直接基因靶点 RNA测序方法;特异性目标2（K99）：确定Nr 4A靶标的作用，蛋白质折叠 伴侣蛋白Hspa 5在记忆巩固中的作用，并鉴定其下游蛋白质靶点;特异性目标3（R 00）： 确定激活Nr 4A转录因子对小鼠记忆缺陷和基因表达的影响 阿尔茨海默病的模型。该项目提供尖端研究技能培训，包括 单细胞数据的计算分析和记忆研究中的染色质富集。爱荷华州大学 是记忆、计算精神病学、神经退化和分子生物学专家的家园， 协作环境提供了一个理想的环境，在其中获得必要的技能，使我能够 转型为成功的独立研究生涯。因此，在辅导（K99）阶段，我将 参与旨在帮助我成功实现独立的活动，包括科学培训 演示文稿，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领域的尖端技能和专业知识， 生物学，神经变性和行为药理学，以确保强大的技术和 概念基础，开始我的独立实验室调查机制的治疗 老年痴呆症