Role of aging-dependent changes in neuronal sub-types in development of radiotherapy-induced cognitive decline in the elderly population

神经元亚型的衰老依赖性变化在老年人放疗引起的认知能力下降中的作用

• 批准号: 10468224
• 负责人: BOGDAN ADRIAN STOICA
• 金额: $ 15.45万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468224
• 关键词: Affect; Age; Aging; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animals; Apoptosis; Apoptotic; Astrocytes; Attenuated; Automobile Driving; Behavior assessment; Brain; Brain Injuries; Cell Aging; Cell Nucleus; Cells; Characteristics; Chronic; Cognitive deficits; Cranial Irradiation; DNA Damage; DNA Repair; Data; Development; Elderly; Equilibrium; Female; Flow Cytometry; Foundations; Gene Expression; Gene Expression Profile; Genes; Glioblastoma; Heterogeneity; Hippocampus (Brain); Histologic; Impaired cognition; Incidence; Ionizing radiation; Lead; Malignant neoplasm of brain; Methods; MicroRNAs; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neuroglia; Neurologic Dysfunctions; Neurons; Normal tissue morphology; Outcome; Pathologic Processes; Pathway interactions; Patients; Population; Predisposition; Process; Property; Publishing; Quality of life; Radiation; Radiation Induced DNA Damage; Radiation exposure; Radiation therapy; Resolution; Risk; Role; Testing; Therapeutic; Time; Traumatic Brain Injury; Untranslated RNA; Up-Regulation; Vascular Endothelial Cell; age effect; age group; age related; aged; aging population; antagonist; attenuation; base; brain cell; cell type; improved; inhibitor; irradiation; juvenile animal; male; mitochondrial dysfunction; neurobehavioral; neuron apoptosis; neuron loss; novel; older patient; progressive neurodegeneration; radiation effect; radiation response; response; response to injury; senescence; sex; side effect; tool; transcriptome; transcriptome sequencing; transcriptomics; treatment effect; tumor; young adult

Project Summary: Radiotherapy (RT) can result in progressive neurodegeneration and cognitive impairment in elderly patients. The cause for increased risk of neurodegeneration in the elderly after RT may involve age- related changes in pathophysiological mechanisms such as irradiation-induced neuronal cell death and neuronal senescence/neurodegeneration. Recent studies demonstrated heterogeneity of neuronal population in the brain. We hypothesize that distinct subsets of neurons will be differentially affected by ionizing radiation (IR). Aging may alter the balance among such neuronal subtypes and their responses to injury. One of the common aging and IR-related changes in cell populations is senescence when cells gradually degenerate and lose their functional characteristics. microRNA (miR) -711 is upregulated in the hippocampus in a mouse AD model, in neuronal DNA-damage models, and after brain injury. We have demonstrated that miR-711 promotes IR/DNA damage-induced neuronal cell death by down-regulating expression of multiple pro-survival genes and induces neuronal senescence through up-regulation of molecules such as p21. miR-711 also inhibits DNA repair mechanisms. The objective of this proposal is to determine the differences in neuronal subtypes and their responses to IR and examine the potential neuroprotective properties of a miR-711 inhibitor in both young-adult and aged mice. Our central hypothesis is that miR-711 inhibition can reduce IR-induced neurodegeneration and limit long-term cognitive dysfunction; the induction of miR-711 and benefits of miR-711 inhibition are significantly increased in the aged mice due to differences in neuronal subtype susceptibility to IR-induced DNA damage. Here, we will use single massively parallel single-nucleus RNA-seq, neurobehavioral, histological and flow cytometry approaches to test our novel hypotheses as outlined in following specific aims: Aim 1: Determine the differences in mechanisms driving the IR-induced neurodegeneration in young-adult and aged animals. We hypothesize that brain irradiation will cause more severe neurodegeneration in aged animals due to age-related changes in subtypes of neurons and their susceptibility to DNA damage. We will utilize snRNAseq to assess the effects of aging and IR on transcriptomic changes promoting neurodegeneration in sub-types of neuronal populations at one week and three months post-irradiation; IR-induced cognitive deficits will be examined behavioral assessments. Aim 2: Determine the effect of miR-711 inhibitor in the irradiated brain of young animals and aged animals. We hypothesize that inhibition of miR-711 after IR will attenuate neuronal cell death and senescence progression and improve cognitive deficits in young adult mice. The effects of miR-711 inhibitor may be particularly beneficial in aged animals due to age-related changes in neuronal subtypes that increase neurodegenerative and senescence-like responses.

项目摘要：放疗（RT）可以导致进行性神经变性和认知障碍 老年患者。 RT后老年人神经退行性风险增加的原因可能涉及年龄 病理生理机制的相关变化，例如辐照诱导的神经元细胞死亡和神经元 衰老/神经变性。最近的研究表明，大脑神经元种群的异质性。 我们假设神经元的不同子集将受到电离辐射（IR）的差异影响。老化 可能会改变这种神经元亚型之间的平衡及其对损伤的反应。普通衰老之一 当细胞逐渐退化并失去其细胞时，细胞群体与IR相关的变化是衰老 功能特征。 microRNA（mir）-711在鼠标AD模型的海马中上调，在 神经元DNA破坏模型，脑损伤后。我们已经证明miR-711促进了IR/DNA 损伤诱导的神经元细胞死亡通过多个生存基因的下调表达并诱导 神经元衰老通过分子（例如p21）的上调。 miR-711还抑制DNA修复 机制。该提议的目的是确定神经元亚型及其的差异 对IR的反应并检查MiR-711抑制剂在两个年轻成年中的潜在神经保护特性 和老鼠。我们的核心假设是miR-711抑制可以减少IR诱导的神经退行性变性和 限制长期认知功能障碍； miR-711的诱导和miR-711抑制的益处显着 由于神经元亚型对IR诱导的DNA损伤的敏感性差异，老年小鼠的增加。 在这里，我们将使用单一平行的单核RNA-seq，神经行为，组织学和流动 细胞仪方法测试我们的新假设，如以下特定目的所述：目标1：确定 驱动IR引起的年轻人和老年动物的神经变性的机制差异。我们 假设脑照射会因年龄相关而导致老年动物的更严重的神经变性 神经元亚型的变化及其对DNA损伤的敏感性。我们将利用SNRNASEQ评估 衰老和IR对促进神经元亚型神经退行性变化的影响 辐照后一个星期零三个月的人口； IR引起的认知缺陷将检查 行为评估。目标2：确定miR-711抑制剂在幼小动物的辐照大脑中的作用 和老年动物。我们假设IR后对miR-711的抑制作用会减弱神经元细胞死亡和 衰老进展并改善年轻成年小鼠的认知缺陷。 miR-711抑制剂的影响可能 由于与年龄相关的神经元亚型的变化，对老年动物特别有益 神经退行性和类似衰老的反应。