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G-quadruplex DNA in senescence of the neurovascular unit

神经血管单元衰老中的 G-四链体 DNA

基本信息

批准号：
10044252
负责人：
Sean P Marrelli
金额：
$ 156万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10044252
关键词：
Abbreviations Affect Age Aging Algorithms Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid deposition Animals Area Artificial Intelligence Astrocytes Binding Proteins Blood Circulation Brain Brain Diseases Brain region CXC chemokine receptor 3 CXCL10 gene Cell Aging Cell physiology Cells Cerebellum Cerebrovascular Circulation Chromatin Cognitive deficits Cytoplasmic Granules DNA DNA Damage DNA Sequence DNA biosynthesis Data Development Diffusion Disease Endothelial Cells Exhibits Extracellular Matrix Frontotemporal Dementia G-Quartets Gene Expression Gene Expression Alteration Genes Genetic Recombination Genetic Transcription Glucose Goals Guanine Health Hippocampus (Brain)Human Impaired cognition In Vitro Inflammation Inflammatory Interneurons Lateral Location Machine Learning Malignant Neoplasms Metabolic Metabolism Mitotic Mus Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nutrient Parabiosis Pathogenesis Pathway interactions Pericytes Peripheral Phenotype Play Proteins Regulation Role Running Sampling Shapes Signal Transduction Stretching Structure Techniques Tg2576 Tight Junctions Transcriptional Regulation Water age related aged aging brain blood-brain barrier permeabilization brain tissue cell type chemokine chromatin remodeling dentate gyrus effective therapy frontal lobe hippocampal pyramidal neuron mouse model negative affect neurovascular unit normal aging novel oxidation prevent quadruplex DNA senescence small molecule

项目摘要

Project Summary The neurovascular unit (NVU) is a functional structure that consists of endothelial cells, surrounded by an extracellular matrix, neurons, astrocytes, and pericytes. The NVU enables regulation of regional cerebral blood flow and nutrient delivery to the brain tissue. With aging, a structural weakening of the NVU occurs, which is also associated with inflammatory signaling and transport deficiencies. Critically, it is not clear how neurons, astrocytes, pericytes, and endothelial cells undergo senescence in the NVU, and whether there are differences in senescence pathways between healthy NVU aging and NVU in Alzheimer's diseases (AD). The G-quadruplex (G4) is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G4s play important roles in DNA recombination, replication, and regulation of transcription. In our data, we demonstrated that brain samples from aged mice contain more G4s than that of young mice. We showed that mice treated with a small-molecule G4 stabilizer develop cognitive impairment and accelerated brain aging. Using a heterochronic parabiosis mouse model, we also showed that the levels of G4s are decreased in the brain of old parabiont, compared to the age-matched iso-parabiotic mice, implicating presence of rejuvenating factors that can reverse the elevation of G4s with aging. The effect of the old parabiont on the young partner is more pronounced (more G4s in the young), suggesting a strong negative influence of aging factors. Importantly, in a mouse model of AD, we demonstrated that G4s are stabilized in the brains, well before the deposition of amyloid occurs. We hypothesize that these converging lines of evidence point at а mechanism of senescence. Thus, the primary objective of the proposed studies is to investigate G4-associated cellular senescence in the NVU, in aging and AD. In Aim 1, we will compare G4s across cell types in the NVU. In Aim 2, we will determine whether G4s preferentially accumulate in the NVUs of brain regions most vulnerable to neurodegeneration. In Aim 3, we will investigate how a peripheral factor, CXCL10, contributes to NVU's G4 senescence. G4s might be a novel pathway that can be targeted to mitigate the detrimental effects of cellular senescence in the brain.

项目总结