G-quadruplex DNA in senescence of the neurovascular unit

神经血管单元衰老中的 G-四链体 DNA

• 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
• 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' s Disease; Alzheimer' 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

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.

项目概要 神经血管单元（NVU）是一种由内皮细胞组成的功能结构，周围有 细胞外基质、神经元、星形胶质细胞和周细胞。 NVU 能够调节局部脑血 流量和营养物质输送到脑组织。随着年龄的增长，NVU 的结构会减弱，这也是 与炎症信号传导和运输缺陷有关。关键的是，目前尚不清楚神经元是如何 星形胶质细胞、周细胞和内皮细胞在NVU中经历衰老，是否存在差异 健康 NVU 衰老与阿尔茨海默病 (AD) NVU 之间的衰老途径。 G-四链体 (G4) 是由四条 DNA 链形成的非规范 DNA 二级结构，其中包含 多次运行鸟嘌呤。 G4s 在 DNA 重组、复制和调节中发挥着重要作用 转录。在我们的数据中，我们证明老年小鼠的大脑样本比普通小鼠含有更多的 G4 年轻的老鼠。我们发现，用小分子 G4 稳定剂治疗的小鼠会出现认知障碍，并且 加速大脑老化。使用异时性联体共生小鼠模型，我们还表明 G4s 的水平 与年龄匹配的异联体小鼠相比，老年联体生物的大脑中的减少，这意味着 再生因子的存在可以逆转 G4 随衰老而升高的情况。老parabiont的作用 对年轻伴侣的影响更为明显（年轻伴侣中有更多的 G4），表明年轻伴侣的强烈负面影响 老化因素。重要的是，在 AD 小鼠模型中，我们证明 G4 在大脑中是稳定的 在淀粉样蛋白沉积发生之前。我们假设这些汇聚的证据表明 衰老机制。因此，拟议研究的主要目标是调查 G4 相关的 NVU、衰老和 AD 中的细胞衰老。在目标 1 中，我们将比较 NVU 中不同细胞类型的 G4。 在目标 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 到神经退行性变。在目标 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，可用于减轻细胞的有害影响 大脑衰老。