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 老年病人。老年人放疗后神经变性风险增加的原因可能与年龄有关。 相关的病理生理机制的变化，如辐射诱导的神经细胞死亡和神经元 衰老/神经变性。最近的研究表明，大脑中神经元数量的异质性。 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。老龄化 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。常见的老龄化之一 而与IR相关的细胞群的变化是当细胞逐渐退化并失去 功能特征。在小鼠AD模型中，microRNA(MiR)-711在海马区上调 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 损伤通过下调多种促生存基因和诱导物的表达诱导神经细胞死亡 神经元通过上调p21等分子的表达而衰老。MIR-711还抑制DNA修复 机械装置。这项建议的目的是确定神经元亚型的差异和它们的 青年和成人对IR的反应以及miR-711抑制剂潜在的神经保护特性 和衰老的小鼠。我们的中心假设是miR-711抑制可以减少IR诱导的神经变性和 限制长期认知功能障碍；miR-711的诱导和miR-711抑制的好处显著 在衰老小鼠中，由于神经元亚型对IR诱导的DNA损伤的敏感性不同而增加。 在这里，我们将使用单个大规模平行的单核rna-seq、神经行为、组织学和Flow。 通过细胞学方法来检验我们的新假设，具体目标如下：目标1：确定 幼年-成年和老年动物IR诱导的神经变性机制的差异。我们 假设脑照射将由于年龄相关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损伤的敏感性。我们将利用SnRNAseq来评估 衰老和IR对促进神经元亚型变性的转录改变的影响 照射后一周和三个月的人群；IR引起的认知障碍将被检查 行为评估。目的2：检测miR-711抑制剂对幼年动物受照脑组织的影响 和年迈的动物。我们推测，抑制IR后miR-711将减轻神经细胞死亡和 年轻成年小鼠的衰老进程和改善认知缺陷。MiR-711抑制剂的作用可能 在老年动物中尤其有益，因为与年龄相关的神经元亚型变化增加 神经退行性和衰老性反应。

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.