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了重大影响。大脑老化与突触丧失、认知能力下降和神经炎症加剧有关。然而，这种情况发生在一个范围内：健康的老龄化和认知稳定性与较少的神经炎症有关，这种状态部分归因于小胶质细胞，大脑驻留的巨噬细胞的特性。在一个健康的大脑中，小胶质细胞有一个“自我平衡”的转录特征，使它们与其他巨噬细胞区分开来。然而，维持这种状态需要大脑微环境的持续指令。在老年大脑中，许多“稳态”转录特征基因下调，这被认为是导致与认知受损相关的异常小胶质细胞功能和神经炎症的原因。我的研究小组目前正在研究促进小胶质细胞稳态的机制，旨在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用于阐明基因转录的非细胞自主控制的研究工具（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，以促进小胶质细胞在体外的稳态。该博士项目的主要目标是研究TGF-β 2对体内衰老大脑中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，我们已经开发了一种诱导型小鼠TGF-β 2 KO模型，该模型将允许转化生长因子-β 2（TGF-β 2）对小胶质细胞功能和神经炎症的空间和时间效应随着年龄的增长与认知能力相关。成像的最新进展（体内2-光子（2 P）显微镜结合IHC/空间转录组学）将允许在整个生命周期内定义小胶质细胞的数量/功能和表型。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.