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.

项目摘要神经血管单元（NVU）是由内皮细胞组成的功能结构，周围是细胞外基质，神经元，星形胶质细胞和周细胞。 NVU可以调节区域脑血流向脑组织的流量和养分递送。随着衰老，发生NVU的结构削弱，这也是与炎症信号传导和运输缺陷有关。至关重要的是，尚不清楚神经元如何星形胶质细胞，周细胞和内皮细胞在NVU中经历着感应，以及是否存在差异在阿尔茨海默氏病（AD）中，健康的NVU衰老与NVU之间的敏感途径中。 G-四链体（G4）是一种非典型的DNA二级结构，由四个含DNA链形成多次鸟嘌呤。 G4在DNA重组，复制和调节中起重要作用转录。在我们的数据中，我们证明了来自老年小鼠的脑样本的G4比年轻的老鼠。我们表明，用小分子G4稳定剂治疗的小鼠会出现认知障碍和加速大脑衰老。使用异核抛物性小鼠模型，我们还显示了G4S的水平与年龄匹配的同核小鼠相比具有恢复活力的因素，可以随着衰老的衰老而逆转G4的升高。旧派托比昂的效果在年轻的伴侣上更为明显（年轻的G4），这表明老化因素。重要的是，在AD的小鼠模型中，我们证明了G4在大脑中稳定，很好在淀粉样蛋白沉积之前。我们假设这些融合的证据线指向感应机制。这是拟议研究的主要目的是研究与G4相关的 NVU，衰老和AD中的细胞感应。在AIM 1中，我们将比较NVU中细胞类型的G4S。在AIM 2中，我们将确定G4是否优先积聚在最脆弱的大脑区域的NVU中到神经变性。在AIM 3中，我们将研究外围因素CXCL10如何促进NVU的G4 衰老。 G4S可能是一种新的途径，可以针对减轻细胞的有害影响大脑衰老。