生长分化因子11(GDF11)与认知水平相关性及作用机制研究

It is an important proposition to study aging mechanisms and development of new drugs in the life sciences. Previous studies focused on gene damage etc.,In recent years, scientists discovered a protein (growth differentiation factor 11, GDF11) in the blood, which is associated with aging. However, GDF11 is promoting anti-aging or senescence, is still controversial. Our previous study found that,GDF11 indeed may be the aging of neural stem cells tend to be younger at the level of expression profiles. In order to reveal the relationship and its mechanism GDF11 and aging, this project is based on transcriptome analysis and comparative analysis by using Weighted Gene Co-expression Network Analysis of young and old blood lymphocytes of human and monkey. This critical gene, gdf11 is highly enriched in blood samples of young. To observe the effects of neural stem cells and mesenchymal stem cells by adding GDF11 recombinant protein during the stage of pluripotency maintenance, and to study the effects of GDF11 protein by using different age-derived mesenchymal stem cells system differentiate into adipocytes, osteoblasts and chondrocytes. With transcriptome analysis, to elaborate GDF11 for adult stem cells on the level of expression, is to induce younger direction, or induce senescence direction, and the differences between the different age groups for which induction of mesenchymal stem cells differentiation. At the same time, combined with injection of GDF11 recombinant protein in different age mices, to comprehensive assessment of the impact on the cognitive level from the behavior by using Y-maze, novel object recognition, water maze, shading and passive avoidance test. By what mechanism, GDF11 conduct anti-aging or pro-aging effect, this will eventually be answered.

衰老机制的研究与抗衰老新药的研发是生命科学领域中的重要命题。与以往聚焦于基因损伤等的研究不同，近年来科学家开创性的发现血液中的一种蛋白质（生长分化因子11，GDF11）与衰老相关，但GDF11究竟是抗衰老还是促衰老存在争议。我们前期研究发现，GDF11的确可以将衰老的小鼠神经干细胞在表达谱水平上趋向年轻化，为了揭示GDF11与衰老的关系及其作用机制，本项目基于年轻和年老人和猴血液淋巴细胞的转录组结合权重基因共表达分析，找出年轻血液中富集的Gdf11这个枢纽基因。通过GDF11蛋白影响不同衰老程度间充质干细胞的干性维持、及定向成脂, 成骨和成软骨分化, 借助转录组分析，从表达水平上阐述GDF11对成体干细胞是具有向年轻化方向，还是促衰老方向诱导，同时结合小鼠在体注射不同浓度GDF11重组蛋白，通过多种认知行为学实验全面评估对认知水平的影响，为寻找血液中的衰老标记、研发抗衰老药物提供理论依据。

衰老机制的研究与抗衰老新药的研发是生命科学领域中的重要命题。与以往聚焦于基因损伤等的研究不同，近年来科学家开创性的发现血液中的一种蛋白质（生长分化因子11，GDF11）与衰老相关，但GDF11究竟是抗衰老还是促衰老存在争议。通过基于权重基因共表达网络分析（WGCNA），对年轻人 ( 20-30岁)和老年人 (50-60,60-70,70-80,>80岁,以及AD) 外周血淋巴细胞的转录组进行共表达比较后，找到Gdf11这个关键的候选基因。对其在人和非人灵长类外周血中的表达验证的基础上，使用老年小鼠注射GDF11重组蛋白，通过认知行为学实验全面评估对认知水平的影响，并对其各个组织细胞进行高通量测序分析，找出GDF11通过PI3K-AKT-mTOR通路发挥抗衰老作用，并在体外神经干细胞自我更新和定向分化中进行了确认；同时通过GDF11蛋白影响不同衰老程度间充质干细胞的干性维持、及定向成脂和成骨分化, 并借助转录组分析，从表达水平上明确了GDF11的抗衰老作用，最终在间充质干细胞中发现，它与DNA去甲基化酶基因TET2具有双向调节能力，协同发挥抗衰老作用。并且发现了一个非常好的衰老标记物：GDF11启动子区域，2个DNA甲基化位点。