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

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。RT后老年人神经退行性变风险增加的原因可能涉及年龄- 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凋亡。 衰老/神经变性。最近的研究表明，在大脑中的神经元群体的异质性。 我们假设不同的神经元亚群将受到电离辐射（IR）的不同影响。老化 可能改变这些神经元亚型之间的平衡及其对损伤的反应。一种常见的衰老 细胞群中与IR相关的变化是衰老，当细胞逐渐退化并失去其功能时， 功能特性在小鼠AD模型中，microRNA（miR）-711在海马中上调， 神经元DNA损伤模型和脑损伤后。我们已经证明miR-711促进IR/DNA 通过下调多个促存活基因的表达诱导损伤诱导的神经细胞死亡， 神经元衰老通过分子如p21的上调。miR-711还抑制DNA修复 机制等本提案的目的是确定神经元亚型及其 IR的反应，并检查miR-711抑制剂的潜在神经保护特性， 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抑制的益处显著 增加在老年小鼠由于不同的神经元亚型易感性IR诱导的DNA损伤。 在这里，我们将使用单一的大规模并行单核RNA-seq，神经行为，组织学和血流 细胞计数方法来测试我们的新假设，如以下具体目标所概述：目标1： 在非成年和老年动物中驱动IR诱导的神经变性的机制的差异。我们 假设脑照射将导致老年动物由于年龄相关的更严重的神经变性， 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学变化的影响 照射后1周和3个月的人群;将检查IR诱导的认知缺陷 行为评估目的2：确定miR-711抑制剂在幼年动物辐射脑中的作用 老年动物我们假设IR后抑制miR-711将减弱神经元细胞死亡， 衰老进程和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， 神经退行性和衰老样反应。

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.