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Mechanisms underlying Tip60 HAT action in neuroprotection of cognitive function

Tip60 HAT 认知功能神经保护作用的机制

基本信息

批准号：
10176606
负责人：
FELICE ELEFANT
金额：
$ 38.84万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176606
关键词：
Address Adult Affinity Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-42 Amyloid beta-Protein Precursor Apoptotic Behavioral Behavioral Assay Binding Biochemical Biological Models Brain Cell Death Chromatin Cognition Cognitive Cognitive deficits Complex DNA Binding Data Set Disease Drosophila Proteins Drug Design Epigenetic Process Gene Expression Gene Targeting Genes Genetic Transcription Goals HDAC2 gene Hippocampus (Brain)Histone Acetylation Histone Deacetylase Human Impaired cognition Impairment Learning Link Mediating Memory Modeling Modification Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurophysiology - biologic function Pathologic Processes Pharmacological Treatment Pilot Projects Process Protein Acetylation Publishing RNA Regulation Research Role Solid Synapses Techniques Testing Therapeutic Therapeutic Intervention base brain tissue cognitive function cognitive process epigenomics fly functional restoration genome-wide genomic locus histone acetyltransferase in vivo insight neural circuit neuropathology neuroprotection novel programs recruit relating to nervous system transcription factor virtual

项目摘要

ABSTRACT Impairment of epigenetic gene control mechanisms in the brain involving reduced histone acetylation levels causes significant cognitive deficits that are a debilitating hallmark of most neurodegenerative disorders, including Alzheimer's disease (AD). Accordingly, of the neural epigenetic modifications identified to date, histone acetylation has been unequivocally linked to facilitating learning and memory by regulating cognition gene expression programs via chromatin packaging control in neurons. Nevertheless, despite the central importance of histone acetylation in higher order brain function, the specific histone acetyltransferases (HATs) that generate these neuroepigenetic marks and their mechanisms of action in neural epigenetic gene control in the brain remain largely unknown. We generated a robust Tip60;APP Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD associated amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to our exciting discovery that Tip60 is critical for cognitive processes based on its role in neural epigenetic gene control and remarkably, promotes neuroprotection for multiple cognitive neural circuits impaired in the brain during early AD associated neurodegenerative progression. Further, our new preliminary studies indicate that Tip60 HAT function in cognitive gene control is impaired in the human AD hippocampus. Our findings have laid a solid groundwork for this proposal and our goal for this project is to identify the mechanisms underlying Tip60 HAT action in neuroprotective gene control using fly and mouse AD models, and to determine how these Tip60 epigenetic processes go awry in the brains of human AD patients. We hypothesize that Tip60 promotes neuroprotection during the AD pathological process by epigenetically reprogramming gene sets in the brain that together protect against synaptic impairment and apoptotic cell death, and thus promote cognitive function. Using a combination of molecular, cellular, biochemical and chromatin based techniques, along with behavioral assays, in Aim 1A we will use our Tip60;APP and Tip60;Aβ42 fly models to identify the full array of Tip60 epigenetic reprogrammed genes, and verify their mammalian Tip60 epigenetic conservation in the mouse brain. In Aim 1B we will test whether these Tip60 neuroprotective genes are epigenetically misregulated in the human AD brain, as we predict. In Aim 2A, we will dissect the transcriptional mechanisms for how Tip60 epigenetically reprograms neuroprotective genes using fly and mouse AD models. In Aim 2B we will test whether these same Tip60 transcriptional regulatory complexes are disrupted in the human AD brain, as we predict. Our studies will provide broad insights into novel Tip60 epigenetic mechanisms underlying human neurodegenerative disorders such as Alzheimer's disease, and new understanding into HAT based drug design for early therapeutic intervention of cognitive deficits.

摘要

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Amyloid-β Peptide Impact on Synaptic Function and Neuroepigenetic Gene Control Reveal New Therapeutic Strategies for Alzheimer's Disease.

DOI：
10.3389/fnmol.2020.577622
发表时间：
2020
期刊：
Frontiers in molecular neuroscience
影响因子：
4.8
作者：
Karisetty BC;Bhatnagar A;Armour EM;Beaver M;Zhang H;Elefant F
通讯作者：
Elefant F

Exploring the Alzheimer's disease neuroepigenome: recent advances and future trends.

DOI：
10.4103/1673-5374.317978
发表时间：
2022-03
期刊：
Neural regeneration research
影响因子：
6.1
作者：
Zhang H;Elefant F
通讯作者：
Elefant F

Tip60 protects against amyloid-β-induced transcriptomic alterations via different modes of action in early versus late stages of neurodegeneration.

DOI：
10.1016/j.mcn.2020.103570
发表时间：
2020-12
期刊：
Molecular and cellular neurosciences
影响因子：
0
作者：
Zhang H;Karisetty BC;Bhatnagar A;Armour EM;Beaver M;Roach TV;Mortazavi S;Mandloi S;Elefant F
通讯作者：
Elefant F