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：
10449333
负责人：
Ulrich Hengst
金额：
$ 40.5万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449333
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 Persons 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.

在阿尔茨海默氏病中，轴突通常是神经元最先受到影响的部分。我们发现，触发局部信号通路导致疾病逆行传播。 β-淀粉样蛋白在几分钟内触发轴突内蛋白质合成，形成独特的转录该复合物的形成和功能是诱导神经变性所必需的。 AD 相关肽寡聚体 Aβ1-42 的反应。人类死后脑组织仅限于 AD 大脑，在此，我们提出这种情况的存在。中枢神经系统中的转录因子复合物是与年龄相关的神经退行性疾病的标志疾病，包括阿尔茨海默病。通过本提案中的实验，我们将研究疾病特异性转录的相关性阿尔茨海默病各种病理表现的复杂因子，我们将研究哪些因子我们将阿尔茨海默病大脑的这些结果与它进行对比。在帕金森病大脑中的发现，以确定通过复合物的信号传导在不同情况下有何不同我们将利用遗传和药理学方法在小鼠身上进行研究。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阻止疾病进展。总之，该研究项目的结果将建立一种神经元反应的新机制我们的结果将为靶向该信号机制并测试该信号提供基本原理。这种方法的可行性。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A systemic cell stress signal confers neuronal resilience toward oxidative stress in a Hedgehog-dependent manner.

DOI：
10.1016/j.celrep.2022.111488
发表时间：
2022-10-18
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Chung, Kyung Min;Kim, Hyunha;Roque, Claudio Gouveia;McCurdy, Ethan P.;Nguyen, Trang T. T.;Siegelin, Markus D.;Huang, Jee-Yeon;Hengst, Ulrich
通讯作者：
Hengst, Ulrich