Mechanisms and Consequences of Tau Internalization and Aggregation in the Central Nervous System

中枢神经系统 Tau 内化和聚集的机制和后果

基本信息

批准号：
10459632
负责人：
Jennifer Nicole Rauch
金额：
$ 24.32万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459632
关键词：
Affect Age Aging Alzheimer&apos s Disease Area Astrocytes Biochemistry Brain Brain region CRISPR interference CRISPR-mediated transcriptional activation Cells Cellular Assay Cellular biology Clinical Critical Pathways Data Dementia Disease Disease Marker Disease Progression Gene Targeting Genes Genetic Transcription Homeostasis Human Human Genome Immune Immunologics Knowledge Learning Link Liquid substance Maintenance Mediating Memory Mentors Methodology Methods Microglia Molecular Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neuroimmune Neurons Pathogenesis Pathologic Pathology Pathway interactions Pattern Phase Phenotype Play Process Regulation Research Resolution Role Severities Severity of illness Stress Symptoms System Tauopathies Technology Testing Work cell type experimental study functional genomics gene function in vivo induced pluripotent stem cell insight mouse model neuroinflammation novel novel therapeutic intervention physical state prevent protein aggregation receptor response screening single cell sequencing single-cell RNA sequencing tau Proteins tau aggregation tau mutation uptake

Affect Age Aging Alzheimer&apos s Disease Area Astrocytes Biochemistry Brain Brain region CRISPR interference CRISPR-mediated transcriptional activation Cells Cellular Assay Cellular biology Clinical Critical Pathways Data Dementia Disease Disease Marker Disease Progression Gene Targeting Genes Genetic Transcription Homeostasis Human Human Genome Immune Immunologics Knowledge Learning Link Liquid substance Maintenance Mediating Memory Mentors Methodology Methods Microglia Molecular Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuroglia Neuroimmune Neurons Pathogenesis Pathologic Pathology Pathway interactions Pattern Phase Phenotype Play Process Regulation Research Resolution Role Severities Severity of illness Stress Symptoms System Tauopathies Technology Testing Work cell type experimental study functional genomics gene function in vivo induced pluripotent stem cell insight mouse model neuroinflammation novel novel therapeutic intervention physical state prevent protein aggregation receptor response screening single cell sequencing single-cell RNA sequencing tau Proteins tau aggregation tau mutation uptake

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项目摘要

The aggregation of the protein tau occurs in a range of neurodegenerative diseases, including Alzheimer’s Disease1. The presence of tau aggregates, also known as neurofibrillary tangles (NFTs), is correlated with disease symptoms and clinical severity in patients2. In addition to tau pathology, the ability of innate immune cells in the brain, particularly microglia and astrocytes, to mediate neuroinflammation has been implicated as a significant contributor to Alzheimer’s Disease pathogenesis. Unfortunately, a detailed understanding of how tau aggregation is spurred in the central nervous system (CNS) and how this influences neuroimmune pathways has remained unclear. In the completed K99 phase, we discovered a cellular receptor for tau uptake, LRP1, and developed expertise in single-cell RNA sequencing methods. In the R00 phase, we will expand on the knowledge gained in the K99 mentored phase and focus the research on questions related to microglial tau regulation and cellular influences on tau’s physical state. In the first half of this proposal we will examine the molecular pathways that define microglial recognition of tau and decipher which genes are most critical for this process. In the second half we will leverage our functional genomics expertise to understand pathways critical for de novo aggregation of tau. The novel experimental methods and comprehensive analyses outlined herein will develop our understanding of pathogenic tau regulation. Further, with this mechanistic insight we will be able to envision novel therapeutic strategies for diseases such as Alzheimer’s Disease. Mandelkow, E. M. & Mandelkow, E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med 2, a006247, doi:10.1101/cshperspect.a006247 (2012). Haroutunian, V., Davies, P., Vianna, C., Buxbaum, J. D. & Purohit, D. P. Tau protein abnormalities associated with the progression of alzheimer disease type dementia. Neurobiol Aging 28, 1-7, doi:10.1016/j.neurobiolaging.2005.11.001 (2007).

蛋白质tau的聚集发生在包括阿尔茨海默氏病在内的一系列神经退行性疾病中。 Tau聚集体的存在，也称为神经原纤维缠结（NFTS），与疾病症状和患者的临床严重程度相关。除了tau病理学外，脑中先天免疫细胞（尤其是小胶质细胞和星形胶质细胞）介导神经炎症的能力已被浸入了阿尔茨海默氏病发病机理的重要因素。不幸的是，对中枢神经系统（CNS）如何刺激TAU聚集的详细理解，以及这如何影响神经免疫途径。在完成的K99阶段，我们发现了一个用于Tau摄取，LRP1的细胞接收器，并在单细胞RNA测序方法中开发了专业知识。在R00阶段，我们将扩展K99重要阶段中获得的知识，并将研究重点放在与小胶质细胞调节和细胞对Tau物理状态的影响有关的问题。在本提案的上半年，我们将检查定义tau和decipher的小胶质识别的分子途径哪个基因对此过程最重要。在下半年，我们将利用我们的功能基因组学专业知识来了解对Tau从头聚集至关重要的途径。本文概述的新型实验方法和全面分析将发展我们对致病性TAU调节的理解。此外，有了这种机械洞察力，我们将能够设想诸如阿尔茨海默氏病等疾病的新型治疗策略。 Mandelkow，E。M.和Mandelkow，E。神经原纤维变性中Tau蛋白的生物化学和细胞生物学。冷弹港观点2，A006247，doi：10.1101/cshperspect.A006247（2012）。 Haroutunian，V.，Davies，P.，Vianna，C.，Buxbaum，J。D.＆Purohit，D。P. Tau蛋白质异常与阿尔茨海默氏病型痴呆症的进展相关。 Neurobiol老化28，1-7，doi：10.1016/j.neurobiolaging.2005.11.001（2007）。