Investigation of TGF-Beta2 in healthy brain ageing

全世界的老年人口正在增加，这对健康和社会经济产生重大影响。大脑衰老与突触丧失、认知能力下降和神经炎症加剧有关。然而，这是在一个范围内发生的：健康的衰老和认知稳定性与较少的神经炎症有关，这种状态在一定程度上可归因于脑内巨噬细胞小胶质细胞的特性。在健康的大脑中，小胶质细胞具有“稳态”转录特征，使其区别于其他巨噬细胞。然而，维持这种状态需要来自大脑微环境的持续指令。在衰老的大脑中，许多“稳态”转录特征基因被下调，这被认为会导致小胶质细胞功能异常和与认知受损相关的神经炎症。我的研究小组目前正在研究促进小胶质细胞稳态的机制，目的是揭示预防有害的年龄相关神经炎症和维持认知功能的方法。我们最近描述了一种研究工具，用于阐明基因转录的非细胞自主控制（Nature Protocols, 2018, PMID: 30250293）。我们发现神经元和星形胶质细胞分泌促进小胶质细胞“稳态”转录特征基因的蛋白质，这些基因通常在衰老的大脑中丢失（Cell Reports, 2021, PMID: 33761343）。作为这项工作的一部分，我们确定了一种蛋白质，我们现在已经发现它可以促进体外小胶质细胞的稳态。这个博士项目的主要目标是描述tgf - β 2在体内衰老大脑中对小胶质细胞功能和神经炎症调节的潜在影响。为了促进这一点，我们开发了一种诱导小鼠TGF-Beta2 KO模型，该模型将允许转化生长因子-Beta2 （TGF-Beta2）对小胶质细胞功能和神经炎症的时空影响与年龄增长的认知能力相关。成像的最新进展（体内2光子（2P）显微镜结合免疫组化/空间转录组学）将允许小胶质细胞的数量/功能和表型在整个生命周期中被定义。将采用小胶质细胞基因特征（qRT-PCR，阵列）和体外炎症状态（吞噬体探针，形态学分析，细胞因子释放）的互补分析。

The population of aged individuals is increasing worldwide, which has significant health and socio-economic implications. Brain aging is associated with synapse loss, cognitive decline, and heightened neuroinflammation. However this occurs on a spectrum: healthy ageing and cognitive stability is associated with less neuroinflammation, a state that is attributable in part, to the properties of microglia, brain-resident macrophages. In a healthy brain, microglia have a "homeostatic" transcriptional signature that distinguishes them from other macrophages. However, maintenance of this requires continued instruction from the brain microenvironment. In the aged brain, many "homeostatic" transcriptional signature genes are downregulated, which is thought to cause aberrant microglial function and neuroinflammation associated with impaired cognition. My research group is currently studying the mechanisms that promote microglial homeostasis with the aim to reveal ways to prevent harmful age-associated neuroinflammation and maintain cognitive function. We recently described a research tool for elucidating non-cell-autonomous control of gene transcription (Nature Protocols, 2018, PMID: 30250293). We found that neurons and astrocytes secrete proteins that promote microglial "homeostatic" transcriptional signature genes which are normally lost in the ageing brain (Cell Reports, 2021, PMID: 33761343). As part of this work, we identified one protein which we have now discovered to promote microglia homeostasis in vitro. The key goal of this PhD project will be to characterise the potential effects of TGF-Beta2 on the modulation of microglial function and neuroinflammation in the ageing brain in vivo. To facilitate this, we have developed an inducible mouse TGF-Beta2 KO model that will allow the spatial and temporal effects of transforming growth factor- Beta2 (TGF-Beta2) on microglial function and neuroinflammation to be defined in relation to cognitive abilities with advancing age. The latest advances in imaging (in vivo 2- photon (2P) microscopy combined with IHC/spatial transcriptomics) would allow microglia numbers/ function and phenotypes to be defined across the lifespan. Complementary analysis of microglia gene signatures (qRT-PCR, array) and inflammatory status in vitro (phagosome probes, morphological analysis, cytokine release) would be employed.