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A transcription factor complex specifically induced in neurodegeneration

在神经退行性变中特异性诱导的转录因子复合物

基本信息

批准号：
10207801
负责人：
Ulrich Hengst
金额：
$ 52.01万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207801
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid beta-Protein Appearance Autopsy Axon Binding Brain Brain Diseases Cell Nucleus Cells ChIP-seq Complex Development Disease Disease Progression Etiology Event Future Genes Genetic Genetic Transcription Goals Human Link Mediating Messenger RNA Modeling Molecular Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Parkinson Disease Pathogenicity Pathologic Pathway interactions Peptides Pharmacology Protein Biosynthesis Proteins Reporting Research Research Project Grants Role Sampling Signal Pathway Signal Transduction Specimen Stimulus Testing Transgenic Mice age related neurodegeneration aging brain brain tissue chromatin immunoprecipitation conditional knockout dimer experimental study feasibility testing in vivo insight knockout animal molecular targeted therapies mouse model neuron loss neuronal cell body normal aging novel prevent programs response therapy development transcription factor transcriptome sequencing

项目摘要

In Alzheimer’s disease, axons are frequently the first part of a neuron to be affected. Neurodegenerative stimuli trigger local signaling pathways that cause the retrograde spread of disease. We have found that application of beta-amyloid within minutes triggers the intra-axonal synthesis of proteins that form a unique transcription factor complex. The formation and function of this complex is required for the induction of neurodegeneration in response to the AD-related peptide oligomeric Aβ1-42. The appearance of this transcription factor complex in human postmortem brain tissue is restricted to AD brains. Here, we propose that the presence of this transcription factor complex in the central nervous system is a hallmark of age-related neurodegenerative disorders, including Alzheimer’s disease. With the experiments in this proposal we will investigate the relevance of the disease-specific transcription factor complex for the various pathological manifestations of Alzheimer’s disease, and we will study which genes are up- or downregulated by it. We will contrast these results from Alzheimer’s disease brain with findings in Parkinson’s disease brain, to determine how signaling via the complex differs in distinct neurodegenerative disorders. Using genetic and pharmacological approaches, we will investigate in mouse models of Alzheimer’s disease, whether interference with the disease-specific transcription factor complex slows down or prevents disease progression. Together, the results from this research project will establish a novel mechanism by which neurons react to oligomeric Aβ1-42. Our results will provide the rationale for targeting this signaling mechanism and test the feasibility of such an approach.

在阿尔茨海默病中，轴突通常是神经元的第一部分受到影响。神经退行性刺激触发局部信号通路，导致疾病的逆行传播。我们发现， β-淀粉样蛋白在几分钟内触发轴突内蛋白质的合成，因子复合体这种复合物的形成和功能是诱导神经变性所必需的。对AD相关肽寡聚体Aβ1-42的反应。这种转录因子复合物的出现，人类死后脑组织仅限于AD脑。在这里，我们建议，中枢神经系统中的转录因子复合物是年龄相关性神经退行性疾病的标志。包括阿尔茨海默病在内的疾病。通过本实验，我们将研究疾病特异性转录的相关性，因子复合体的各种病理表现阿尔茨海默病，我们将研究基因的上调或下调。我们将这些结果从阿尔茨海默氏症的大脑与帕金森病大脑中的发现，以确定如何通过复杂的信号不同，神经退行性疾病利用遗传学和药理学方法，我们将在小鼠中进行研究，阿尔茨海默病模型，是否干扰疾病特异性转录因子复合物减缓或预防疾病进展。总之，这项研究项目的结果将建立一种新的机制，寡聚Aβ1-42。我们的研究结果将为靶向这种信号传导机制提供理论基础，并测试这种做法的可行性。