雷帕霉素在银屑病治疗中的研究进展

银屑病是一种免疫介导的炎症性皮肤病，已有研究表明PI3K/AKT/mTORC1信号通路在银屑病疾病过程中发挥重要作用。雷帕霉素作为mTORC1抑制剂，可以通过改善银屑病患者角质形成细胞异常功能状态、血管异常增生以及调节Th17细胞免疫功能等机制在银屑病治疗中发挥一定的作用。     

哺乳动物雷帕霉素靶蛋白在脑生理和病理中的作用

哺乳动物雷帕霉素靶蛋白（mTOR）常被用于研究免疫抑制剂药物雷帕霉素的功能和作用机制。作为丝氨酸/苏氨酸激酶,mTOR有两种功能明显不同的复合体--mTORC1和mTORC2,控制诸如蛋白质合成,能量代谢,细胞大小,脂质代谢,自噬,线粒体功能和溶酶体形成等细胞的基本功能。此外,mTOR控制的信号通路还参与调节神经系统的许多生理功能,包括神经系统的发育,突触可塑性,记忆储存和认知功能。因此, mTOR信号通路失调可能与许多神经和精神疾病的发生有关。前期研究表明,抑制mTORC1对癫痫、认知障碍和脑部肿瘤等疾病的治疗有利,而直接或间接刺激mTORC1一方面可促进脑细胞轴突再生和骨髓鞘形成,另一方面该通路可成为治疗抑郁症的靶点之一。     

mTOR信号通路与相关疾病的研究进展

哺乳动物雷帕霉素靶蛋白(mTOR)是一种进化上高度保守的非典型丝氨酸/苏氨酸蛋白激酶,属于磷脂酰肌醇激酶相关激酶家族,主要调控细胞生长、增殖、凋亡和自噬。生理和病理状态下,mTOR信号通路在蛋白质翻译、合成、细胞代谢和应激反应中发挥重要作用。mTOR与特定的接头蛋白形成复合体mTORC1和mTORC2。近年研究表明,mTOR和mTOR信号通路与心血管疾病(高血压和心肌梗死)、葡萄糖和脂质代谢相关疾病(糖尿病)及自身免疫性疾病(多发性硬化症)密切相关。因此,ATP竞争性mTOR激酶抑制剂、PI3K/mTOR双重抑制剂和mTORC1/mTORC2选择性抑制剂及mTOR和mTOR信号通路靶向抑制剂在上述疾病的临床治疗中具有一定的价值。     

AMPK，SIRT1与能量代谢

在调节细胞能量状态的蛋白激酶级联反应中,AMP 激活的蛋白激酶(AMPK) 是其中枢组成部分,AMPK的活性受AMP/ATP比值的调节。沉默信息调节因子2相关酶1（SIRT1）作为一种NAD+依赖的组蛋白去乙酰化酶,同样在调节细胞能量代谢中起着重要作用。AMPK与SIRT1相互起调控作用,阐明AMPK与SIRT1作用的上下游信号通路有可能成为新的治疗代谢疾病作用靶点。     

mTOR调节CD4~+T细胞亚群分化及功能的研究进展

哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)属于磷脂酰肌醇激酶相关激酶蛋白质家族成员,是一种非典型丝氨酸/苏氨酸激酶。mTOR可整合来自营养、能量、生长因子和环境压力对细胞的刺激信号,调节下游蛋白p70S6K和4E-BP1活性而影响细胞生长。CD4+T细胞是一群具有重要免疫调节功能的淋巴细胞,其中不同亚群在机体免疫应答中的作用存在明显差异。近来研究证实,mTOR信号在CD4+T细胞亚群分化发育及功能活性中发挥重要的调节作用。     

NK细胞代谢途径及其功能

NK细胞是固有免疫系统的重要成员,在免疫应答中发挥关键作用。NK细胞激活主要依赖于其表面表达的活化性受体和抑制性受体间的动态平衡。然而,在许多慢性疾病模型中,NK细胞受体表达失衡,导致杀伤活性及细胞因子产生能力降低,处于免疫失活状态。近年许多研究表明,胞内代谢对包括NK细胞在内的免疫细胞至关重要,代谢改变能够通过影响细胞发育、增殖和活性等调节免疫细胞效应功能发挥。鉴于NK细胞强大的抗肿瘤和抗病毒功能及其重要的临床应用价值,深入研究其代谢特征及机制具有重要意义。本文主要从NK细胞的代谢方式及其相关调控通路、代谢对NK细胞发育、记忆和功能的调控作用以及基于代谢的NK细胞疗法进行综述,阐述代谢对NK细胞生物合成、体内稳定及效应功能的重要作用,以及不同慢性疾病模型中NK细胞失活的代谢相关因素,为NK细胞治疗的临床应用提供坚实的研究依据。     

氨基酸调节mTORC1信号通路的研究进展

氨基酸是合成蛋白质的底物,也可作为信号分子激活哺乳动物雷帕霉素靶蛋白复合体1(mTORC1)。氨基酸调控mTORC1活性的关键步骤是将mTORC1定位于溶酶体表面,Rag GTPase、Ragulator、v-ATPase和SLC38A9等溶酶体相关蛋白及GATOR、Sestrins等胞质蛋白在其中发挥重要的作用。     

气体信号分子硫化氢调节细胞功能的作用与机制

背景：硫化氢作为第3种气体信号分子在细胞功能调节方面的研究越来越多,但是目前对其认识尚存在一些矛盾之处。 目的：总结硫化氢在细胞功能调节方面的作用机制及其研究进展。 方法：应用计算机检索1990至2013年PubMed数据库,以“hydrogen sulfide,gasotransmitter”为检索关键词进行检索,最终纳入54篇相关进行分析。 结果与结论：很多研究证明硫化氢在细胞功能的调节方面起到重要作用,其在细胞功能调节方面的作用机制较为复杂。传统的信号分子(如激素和神经介质)可通过一系列的级联反应来放大信号进行信号转导,但是气体信号分子可通过转录后修饰胞内靶向蛋白而更迅速的影响细胞代谢。大多数研究表明生理浓度下的硫化氢具有抗氧化、抗炎和抗凋亡的作用。但在炎症和凋亡方面的研究,部分研究却得到了不同的结果,也说明硫化氢对于某些细胞功能的调节可能存在双重性,因此对其作用机制的研究有待进一步加强。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

葡萄糖通过mTORC1信号通路调控成纤维细胞增殖

目的 研究葡萄糖对小鼠皮肤成纤维细胞增殖的影响.方法 将小鼠皮肤成纤维细胞培养在含不同浓度葡萄糖的培养基里,用MTT法检测细胞增殖,7-MGTP pulldown实验检测细胞翻译起始情况,Western blot检测mTORC1信号通路分子的活化.结果 与培养基葡萄糖浓度为5.5 mmol/L相比较,当浓度为15 mmol/L时,促进细胞增殖,与7-MGTP结合的翻译起始复合物增加,mTORC1信号通路活化;当25 mmol/L时,抑制细胞增殖,与7-MGTP结合的翻译始复合物减少,mTORC1信号通路中与细胞增殖相关的4EBP1和与细胞生存相关的Akt的磷酸化减弱.结论 葡萄糖通过对mTORC1信号通路的双向调节作用调控成纤维细胞增殖.     

mTOR抑制剂一雷帕霉素对T细胞功能调控的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）作为信号通路的调节分子参与多条重要的信号转导通．路,能形成细胞对多种刺激的应答,mTOR至少存在两种功能性多蛋白复合物形式：mTORCl和mTORC2,其可发挥不同的生物学作用。雷帕霉素作为mTOR的特异性抑制剂可阻断mTOR信号通路信息的传导,调节T细胞的分化、发育、失能以及调节性T细胞（Treg）的增殖和功能,影响生长因子和细胞因子等生物活性物质的分泌,表现出有效的免疫抑制作用。     

mTOR links oncogenic signaling to tumor cell metabolism

As a key regulator of cell growth and proliferation, the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) has been the subject of intense investigation for its role in tumor development and progression. This research has revealed a signaling network of oncogenes and tumor suppressors lying upstream of mTORC1, and oncogenic perturbations to this network result in the aberrant activation of this kinase complex in the majority of human cancers. However, the molecular events downstream of mTORC1 contributing to tumor cell growth and proliferation are just coming to light. In addition to its better-known functions in promoting protein synthesis and suppressing autophagy, mTORC1 has emerged as a key regulator of cellular metabolism. Recent studies have found that mTORC1 activation is sufficient to stimulate an increase in glucose uptake, glycolysis, and de novo lipid biosynthesis, which are considered metabolic hallmarks of cancer, as well as the pentose phosphate pathway. Here, we focus on the molecular mechanisms of metabolic regulation by mTORC1 and the potential consequences for anabolic tumor growth and therapeutic strategies.     

Regulation of T-cell survival and mitochondrial homeostasis by TSC1

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T-cell activation and responses to microbial infection. However, the importance of mTOR regulation in T cells has yet to be explored. The TSC1/TSC2 complex has been shown to inhibit mTORC1 signaling in cell line models. We show here that deletion of TSC1 in the murine T-cell lineage results in a dramatic reduction of the peripheral T-cell pool, correlating with increased cell death. While mTORC1 is constitutively activated, mTORC2 signaling, reflected by Akt phosphorylation and activity, is decreased in TSC1-deficient T cells. Furthermore, TSC1-deficient T cells contain elevated reactive oxygen species (ROS) and exhibit decreased mitochondrial content and membrane potential, which is correlated with the activation of the intrinsic death pathway. Overall, our results demonstrate that TSC1 differentially regulates mTORC1 and mTORC2 activity, promotes T-cell survival, and is critical for normal mitochondrial homeostasis in T cells.     

mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome

Although podocyte damage is known to be responsible for the development of minimal-change disease (MCD), the underlying mechanism remains to be elucidated. Previously, using a rat MCD model, we showed that endoplasmic reticulum (ER) stress in the podocytes was associated with the heavy proteinuric state and another group reported that a mammalian target of rapamycin complex 1 (mTORC1) inhibitor protected against proteinuria. In this study, which utilized a rat MCD model, a combination of immunohistochemistry, dual immunofluorescence and confocal microscopy, western blot analysis, and quantitative real-time RT-PCR revealed co-activation of the unfolded protein response (UPR), which was induced by ER stress, and mTORC1 in glomerular podocytes before the onset of proteinuria and downregulation of nephrin at the post-translational level at the onset of proteinuria. Podocyte culture experiments revealed that mTORC1 activation preceded the UPR that was associated with a marked decrease in the energy charge. The mTORC1 inhibitor everolimus completely inhibited proteinuria through a reduction in both mTORC1 and UPR activity and preserved nephrin expression in the glomerular podocytes. In conclusion, mTORC1 activation may perturb the regulatory system of energy metabolism primarily by promoting energy consumption and inducing the UPR, which underlie proteinuria in MCD.     

Mammalian target of rapamycin complex 1 (mTORC1) signaling in energy balance and obesity

Energy balance is guaranteed by a complex circuitry that in the brain, and in the hypothalamus in particular, integrates and coordinates several types of signals, including hormones and nutrients, so to match energy expenditure to energy needs. Similar to individual cells, the hypothalamus also profits from intracellular pathways known to work as fuel sensors to maintain energy balance. The mammalian target of rapamycin complex 1 (mTORC1) pathway has been recently implicated in such function, due to its ability to integrate nutrient and hormonal signals to control food intake and body weight. This review therefore describes recent advances made in understanding the role of the hypothalamic mTORC1 pathway in energy balance regulation and its possible contribution to the metabolic dysregulation associated with diet-induced obesity.     

NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

The mechanistic target of rapamycin (mTOR) is a central cell growth controller and forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates a wide range of upstream signals, both positive and negative, to regulate cell growth. Although mTORC1 activation by positive signals, such as growth factors and nutrients, has been extensively investigated, the mechanism of mTORC1 regulation by stress signals is less understood. In this study, we identified the Nemo-like kinase (NLK) as an mTORC1 regulator in mediating the osmotic and oxidative stress signals. NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. Cells with Nlk deletion or knock-in of the Raptor S863 phosphorylation mutants are defective in the rapid mTORC1 inhibition upon osmotic stress. Our study reveals a function of NLK in stress-induced mTORC1 modulation and the underlying biochemical mechanism of NLK in mTORC1 inhibition in stress response.     

Metabolomics of the effect of AMPK activation by AICAR on human umbilical vein endothelial cells

AMP-activated protein kinase (AMPK) is a metabolic master switch expressed in a great number of cells and tissues. AMPK is thought to modulate the cellular response to different stresses that increase cellular AMP concentration. The adenosine analog, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) is an AMPK activator used in many studies to assess the effects of AMPK activation on cellular metabolism and function. However, the effect of AICAR on cell metabolism reaches many different pathways and metabolites, some of which do not seem to be fully related to AMPK activation. We have now for the first time used NMR metabolomics on human umbilical vein endothelial cells (HUVEC) for the study of the global metabolic impact of AMPK activation by AICAR. In our study, incubation with AICAR activates AMPK and is associated with, among others, broad metabolic alterations in energy metabolism and phospholipid biosynthesis. Using NMR spectroscopy and metabolic network tools, we analyzed the connections between the different metabolic switches activated by AICAR. Our approach reveals a strong interconnection between different phospholipid precursors and oxidation by-products. Metabolomics profiling is a useful tool for detecting major metabolic alterations, generating new hypotheses and provides some insight about the different molecular correlations in a complex system. The present study shows that AICAR induces metabolic effects in cell metabolism well beyond energy production pathways.     

Metabolic pathways in T cell activation and lineage differentiation

Recent advances in the field of immunometabolism support the concept that fundamental processes in T cell biology, such as TCR-mediated activation and T helper lineage differentiation, are closely linked to changes in the cellular metabolic programs. Although the major task of the intermediate metabolism is to provide the cell with a constant supply of energy and molecular precursors for the production of biomolecules, the dynamic regulation of metabolic pathways also plays an active role in shaping T cell responses. Key metabolic processes such as glycolysis, fatty acid and mitochondrial metabolism are now recognized as crucial players in T cell activation and differentiation, and their modulation can differentially affect the development of T helper cell lineages. In this review, we describe the diverse metabolic processes that T cells engage during their life cycle from naïve towards effector and memory T cells. We consider in particular how the cellular metabolism may actively support the function of T cells in their different states. Moreover, we discuss how molecular regulators such as mTOR or AMPK link environmental changes to adaptations in the cellular metabolism and elucidate the consequences on T cell differentiation and function.