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：放射治疗 (RT) 可导致进行性神经变性和认知障碍 老年患者。老年人放疗后神经退行性变风险增加的原因可能与年龄有关 病理生理机制的相关变化，如辐射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中神经元群体的异质性。 我们假设不同的神经元子集会受到电离辐射（IR）的不同影响。老化 可能会改变这些神经元亚型之间的平衡及其对损伤的反应。常见的衰老现象之一 当细胞逐渐退化并失去其功能时，细胞群中与红外线相关的变化就是衰老。 功能特点。在小鼠 AD 模型中，microRNA (miR) -711 在海马体中表达上调 神经元 DNA 损伤模型以及脑损伤后。我们已经证明 miR-711 促进 IR/DNA 通过下调多个促生存基因的表达来损伤诱导神经元细胞死亡，并诱导 通过 p21 等分子的上调来抑制神经元衰老。 miR-711 还抑制 DNA 修复 机制。该提案的目的是确定神经元亚型及其差异 对 IR 的反应并检查 miR-711 抑制剂对年轻成人的潜在神经保护特性 和老年老鼠。我们的中心假设是 miR-711 抑制可以减少 IR 诱导的神经变性， 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 损伤的敏感性不同，老年小鼠的 DNA 损伤增加。 在这里，我们将使用单个大规模并行单核 RNA-seq、神经行为、组织学和流式细胞仪 细胞计数方法来测试我们的新假设，如以下具体目标所述：目标 1：确定 年轻成年和老年动物中红外线诱导的神经变性驱动机制的差异。我们 假设由于年龄相关，大脑照射会导致老年动物更严重的神经退行性变 神经元亚型的变化及其对 DNA 损伤的易感性。我们将利用 snRNAseq 来评估 衰老和IR对促进神经元亚型神经变性的转录组变化的影响 照射后一周和三个月的人群；将检查红外线引起的认知缺陷 行为评估。目标 2：确定 miR-711 抑制剂对幼年动物受辐射大脑的影响 和老年动物。我们假设 IR 后抑制 miR-711 将减弱神经元细胞死亡， 衰老进程并改善年轻成年小鼠的认知缺陷。 miR-711抑制剂的作用可能 由于神经元亚型的年龄相关变化增加，因此对老年动物特别有益 神经退行性和衰老样反应。