Cell cycle re-entry in the aging adult brain

 描述（由申请人提供）：与衰老相关的认知能力下降具有严重的公共卫生和经济后果，随着美国老年人比例的上升，这种后果将增加。到目前为止，几乎没有有效的治疗方法来解决这个问题，部分原因是根本原因仍然不清楚。老年哺乳动物大脑表现出细胞周期失调的证据，并且已经提出大脑中有丝分裂后细胞的异常细胞周期重新进入是神经变性的原因和结果。大部分关于衰老大脑中细胞周期再进入的研究都局限于相关研究，这是由于难以获得衰老样本、测量细胞周期再进入的不一致性以及难以在哺乳动物模型系统中操纵衰老过程中大脑中特异性的细胞周期调节剂。我们观察到果蝇的大脑表现出与年龄相关的细胞周期再进入的证据，本项目旨在建立果蝇作为一个遗传上易于处理和快速老化的模型系统，以研究和操纵衰老大脑中的细胞周期再进入。在目标1中，我们建立了在正常生理老化条件下，老年果蝇脑细胞周期重新进入的时间和地点。在目标2中，我们确定了操纵大脑中细胞周期重新进入衰老表型的生物学结果。本研究的成功完成将建立一个新的遗传学上易于处理的模型系统，以研究衰老与脑细胞周期重入的关系，并解决脑细胞周期重入与行为衰退随年龄的因果关系。这项研究可能为通过靶向细胞周期机制治疗衰老相关的神经功能衰退提供新的途径。这项研究的长期未来方向将包括填补将大脑中的衰老和细胞周期失调联系起来的分子细节。

 DESCRIPTION (provided by applicant): Aging-associated cognitive decline has serious public health and economic consequences, which will increase as the percentage of aged Americans rises. Thus far there is little effective treatment to combat this problem, in part because the underlying causes remain unclear. The aged mammalian brain exhibits evidence of cell cycle de-regulation and aberrant cell cycle re-entry of postmitotic cells in the brain has been proposed to be both a cause and a consequence of neurodegeneration. Most of the research on cell cycle re-entry in the aging brain has been limited to correlative studies due to difficulty in obtaining aged samples, inconsistencies in measuring cell cycle re-entry and difficulty in manipulating cell cycle regulators specifically in the brain during aging in mammalian model systems. We have observed that the brain of the fruit fly Drosophila melanogaster exhibits evidence of age-associated cell cycle re-entry and this project seeks to establish Drosophila as a genetically tractable and quickly aging model system to study and manipulate cell cycle re-entry in the aging brain. In Aim 1, we establish when and where cell cycle re-entry occurs in the aged fly brain, under normal physiological aging conditions. In Aim 2, we determine the biological outcomes of manipulating cell cycle re-entry in the brain on aging phenotypes. Successful completion of the proposed work will establish a new genetically tractable model system to study the relationship of aging and cell cycle re-entry in the brain and resolve the cause-effect relationship of cell cycle re-entry in the brain and behavioral decline with age. This research may indicate new avenues to treat aging related neural decline by targeting cell cycle machinery. Longer-term future directions for this research will include filling in the molecular details that link aging and cell cycle de-regulation in the brain.