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Investigating the impact of cellular senescence of neuronal progenitor cells and microglia on cellular functionality and behavior

研究神经祖细胞和小胶质细胞的细胞衰老对细胞功能和行为的影响

基本信息

批准号：
269902361
负责人：
Privatdozentin Dr. Susanne A. Wolf
金额：
--
依托单位：
Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/269902361?language=en
关键词：
Investigating impact cellular senescence neuronal

项目摘要

Cellular senescence (CS) is a state of permanent cell-cycle arrest proliferating cells can initiate as a response to stress and damage. Whereas CS in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of CS in the brain. Neuroinflammatory events, gene toxicity or stress could lead to CS in self-renewing brain cells including microglia (MG) and neuronal progenitor cells (NPCs). In recent years it has been demonstrated that microglia play emerging roles in adult hippocampal neurogenesis and their regulation during chronic stress, aging, and neurodegenerative diseases. Stress-induced MG alterations directly regulate certain aspects of cognitive function and emotional regulation. To date, the mechanisms underlying CS in the brain as well as how senescent cells may affect brain function and pathology remain unclear. I here propose 1) to map CS in NPCs and MG in different brain regions utilizing senescent markers and immunohistochemistry in three mouse models of premature aging: maternal inflammation, in utero stress, and induction of cell specific senescence in either NPCs or MG by genetic manipulation. Telomerase activity determines the capacity of self-renewal in cells; thus it can be used in combination with telomere length as a measure of CS in NPCs and in MG. In our previous studies and in our preliminary work we were able to show that telomerase activity decreases and telomere shorten in NPCs derived from mouse models of maternal inflammation and in utero stress. 2) we will here use telomerase activity/telomere length in NPCs and MG freshly isolated out of different brain regions to confirm the senescent phenotype identified by immunohistochemistry in 1). 3) In order to profile senescent brain cells and to identify senescent associated pathways we will subject freshly isolated MG and NPCs to RNA sequencing. The analysis will be done in parallel in all three mouse models of premature aging. 4) In addition we will measure whether cellular functions including phagocytosis, motility and neurogenesis are affected in our mouse models of premature aging. 5) By cross breeding ERCC1 floxed animals with inducible Cre lines driving the promotor for Nestin or Fraktalkine we induce CS in either NPCs or MG respectively. In addition to cellular function and RNA profiling, we will assess behavior. 6) Finally we like to investigate the potential of voluntary exercise to rescue the phenotype of premature aging on a cellular and behavioral level in all three animal models followed by RNA sequencing of NPCs and MG. In a bioinformatics approach we will compare the data obtained from the two cell types in our three models before and after the intervention to identify pathways that could become targets for a therapeutic approach. Moreover we will provide evidence why voluntary exercise is a valuable add on therapy to prevent CS and thus premature aging.

细胞衰老（CS）是一种细胞周期永久停滞的状态，增殖细胞可以作为对应激和损伤的反应而启动。虽然CS在外周组织中已被因果关系与一些年龄相关的病理，很少有人知道CS在大脑中的诱导。神经炎性事件、基因毒性或应激可导致自我更新脑细胞包括小胶质细胞（MG）和神经元祖细胞（NPC）中的CS。近年来研究表明，小胶质细胞在成年海马神经发生及其在慢性应激、衰老和神经退行性疾病中的调节中发挥着重要作用。应激诱导的MG改变直接调节认知功能和情绪调节的某些方面。到目前为止，CS在大脑中的潜在机制以及衰老细胞如何影响大脑功能和病理仍不清楚。我在这里提出1）映射CS在NPC和MG在不同的大脑区域利用衰老标记物和免疫组化在三个小鼠模型的过早老化：母体炎症，在子宫内的压力，和诱导细胞特异性衰老的NPC或MG通过遗传操作。端粒酶活性决定了细胞自我更新的能力;因此，它可以与端粒长度组合使用，作为NPC和MG中CS的量度。在我们以前的研究和我们的初步工作中，我们能够表明，端粒酶活性降低和端粒缩短来自母体炎症和子宫内应激小鼠模型的NPC。2)我们在此将使用从不同脑区域新鲜分离的NPC和MG中的端粒酶活性/端粒长度来确认在1）中通过免疫组织化学鉴定的衰老表型。3)为了分析衰老脑细胞并鉴定衰老相关途径，我们将对新鲜分离的MG和NPC进行RNA测序。将在所有三种早衰小鼠模型中平行进行分析。4)此外，我们将测量细胞功能，包括吞噬作用，运动性和神经发生是否受到影响，在我们的小鼠模型的过早老化。5)通过将ERCC 1 floxed动物与驱动Nestin或Fraktalkine启动子的诱导型Cre系杂交，我们分别在NPC或MG中诱导CS。除了细胞功能和RNA分析，我们还将评估行为。6)最后，我们想研究自愿运动的潜力，以挽救细胞和行为水平上的早衰的表型在所有三个动物模型，然后通过RNA测序的NPC和MG。在生物信息学方法中，我们将比较干预前后从我们三种模型中的两种细胞类型获得的数据，以确定可能成为治疗方法靶点的途径。此外，我们将提供证据，说明为什么自愿运动是预防CS和过早衰老的有价值的附加疗法。