更新于：2024-09-19

RTN4R

更新于：2024-09-19

基本信息

别名

NgR、Nogo receptor、Nogo receptor 1

+ [5]

简介

Receptor for RTN4, OMG and MAG (PubMed:12037567, PubMed:12068310, PubMed:12426574, PubMed:12089450, PubMed:16712417, PubMed:18411262, PubMed:12839991, PubMed:19052207). Functions as receptor for the sialylated gangliosides GT1b and GM1 (PubMed:18411262). Besides, functions as receptor for chondroitin sulfate proteoglycans (By similarity). Can also bind heparin (By similarity). Intracellular signaling cascades are triggered via the coreceptor NGFR (PubMed:12426574). Signaling mediates activation of Rho and downstream reorganization of the actin cytoskeleton (PubMed:16712417, PubMed:22325200). Mediates axonal growth inhibition (PubMed:12839991, PubMed:19052207, PubMed:28892071). Plays a role in regulating axon regeneration and neuronal plasticity in the adult central nervous system. Plays a role in postnatal brain development. Required for normal axon migration across the brain midline and normal formation of the corpus callosum. Protects motoneurons against apoptosis; protection against apoptosis is probably mediated via interaction with MAG. Acts in conjunction with RTN4 and LINGO1 in regulating neuronal precursor cell motility during cortical development. Like other family members, plays a role in restricting the number dendritic spines and the number of synapses that are formed during brain development (PubMed:22325200).

关联

项与 RTN4R 相关的药物

NEP1-40

靶点

RTN4R x p75NTR

作用机制

RTN4R拮抗剂 [+1]

在研机构-

原研机构

Yale University

在研适应症-

非在研适应症

脑损伤 [+5]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RTN4R 相关的临床结果

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100 项与 RTN4R 相关的转化医学

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0 项与 RTN4R 相关的专利（医药）

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763

项与 RTN4R 相关的文献（医药）

2024-11-01·Plant Science

Effects of LAZY family genes on shoot gravitropism in Lotus japonicus

Article

作者: Wu, Guojiang ; Song, Shusi ; Xu, Shaoming ; Jiang, Huawu ; Chen, Yaping

Plant architecture is an important agronomic trait to determine the biomass and sward structure of forage grass. The IGT family plays a pivotal role in plant gravitropism, encompassing both the gravitropic response and the modulation of plant architecture. We have previously shown that LjLAZY3, one of the IGT genes, plays a distinct role in root gravitropism in L. japonicus. However, the function of LAZY proteins on shoot gravitropism in this species is poorly understood. In this study, we identified nine IGT genes in the L. japonicus genome, which have been categorized into four clades based on the phylogenetic relationships of IGT proteins from 18 legumes: LAZY1, NGR (NEGATIVE GRAVITROPIC RESPONSE OF ROOTS), IGT-LIKE, and TAC1. We found that LAZY genes in the first three clades have demonstrated distinct role for modulating plant gravitropism in L. japonicus with specific impacts as follows. Mutation of the LAZY1 gene, LjLAZY1, defected the gravitropic response of hypocotyl without impacting the main stem's branch angle. In contrast, the overexpression of the NGR gene, LjLAZY3, substantially modulated the shoot's gravitropism, leading to narrower lateral branch angles. Additionally, it enhanced the shoots' gravitropic response. The overexpression of another NGR gene, LjLAZY4, specifically reduced the main stem's branch angle and decreased plant stature without affecting the shoot gravitropic response. The phenotype of IGT-LIKE gene LjLAZY2 overexpression is identical to that of LjLAZY4. While overexpression of the IGT-LIKE gene LjLAZY5 did not induce any observable changes in branch angle, plant height, or gravitropic response. Furthermore, the LjLAZYs were selectively interacted with different BRXL and RLD proteins, which should the important factor to determine their different functions in controlling organ architecture in L. japonicus. Our results deepen understanding of the LjLAZY family and its potential for plant architecture improvement in L. japonicus.

2024-06-01·Neuroscience Bulletin

Three-phase Enriched Environment Improves Post-stroke Gait Dysfunction via Facilitating Neuronal Plasticity in the Bilateral Sensorimotor Cortex: A Multimodal MRI/PET Analysis in Rats

Article

作者: Lu, Yun ; Zhao, Hui ; Lei, Jianfeng ; Li, Mingcong ; Zhuang, Yuming ; Nie, Binbin ; Lin, Ziyue ; Zhao, Yuanyuan

The three-phase Enriched Environment (EE) paradigm has been shown to promote post-stroke functional improvement, but the neuronal mechanisms are still unclear. In this study, we applied a multimodal neuroimaging protocol combining magnetic resonance imaging (MRI) and positron emission tomography (PET) to examine the effects of post-ischemic EE treatment on structural and functional neuroplasticity in the bilateral sensorimotor cortex. Rats were subjected to permanent middle cerebral artery occlusion. The motor function of the rats was examined using the DigiGait test. MRI was applied to investigate the EE-induced structural modifications of the bilateral sensorimotor cortex. [¹⁸F]-fluorodeoxyglucose PET was used to detect glucose metabolism. Blood oxygen level-dependent (BOLD)-functional MRI (fMRI) was used to identify the regional brain activity and functional connectivity (FC). In addition, the expression of neuroplasticity-related signaling pathways including neurotrophic factors (BDNF/CREB), axonal guidance proteins (Robo1/Slit2), and axonal growth-inhibitory proteins (NogoA/NgR) as well as downstream proteins (RhoA/ROCK) in the bilateral sensorimotor cortex were measured by Western blots. Our results showed the three-phase EE improved the walking ability. Structural T2 mapping imaging and diffusion tensor imaging demonstrated that EE benefited structure integrity in the bilateral sensorimotor cortex. PET-MRI fused images showed improved glucose metabolism in the corresponding regions after EE intervention. Specifically, the BOLD-based amplitude of low-frequency fluctuations showed that EE increased spontaneous activity in the bilateral motor cortex and ipsilateral sensory cortex. In addition, FC results showed increased sensorimotor connectivity in the ipsilateral hemisphere and increased interhemispheric motor cortical connectivity and motor cortical-thalamic connectivity following EE intervention. In addition, a strong correlation was found between increased functional connectivity and improved motor performance of limbs. Specifically, EE regulated the expression of neuroplasticity-related signaling, involving BDNF/CREB, Slit2/Robo1, as well as the axonal growth-inhibitory pathways Nogo-A/Nogo receptor and RhoA/ROCK in the bilateral sensorimotor cortex. Our results indicated that the three-phase enriched environment paradigm enhances neuronal plasticity of the bilateral sensorimotor cortex and consequently ameliorates post-stroke gait deficits. These findings might provide some new clues for the development of EE and thus facilitate the clinical translation of EE.

2024-05-01·Current Molecular Medicine

siRNA Mediated Downregulation of RhoA Expression Reduces Oxidative Induced Apoptosis in Retinal Ganglion Cells

Article

作者: Liu, Qian ; Liu, Changgeng ; Lei, Bo

Backgrounds:Glaucoma is the second leading cause of blindness. Apoptosis of retinal ganglion cells (RGCs) is an important mechanism of glaucomatous optic injury. Rho kinase expression is significantly increased in apoptotic RGCs. This study aimed to investigate the role of RhoA, a Rho GTPase, on the survival of RGCs and further to explore its potential therapeutic applications.Methods:RGCs were treated with siRhoA for 24 hours in vitro. Knockdown of RhoA was confirmed with quantitative RT-PCR. Oxidative stress was induced by treating the RGCs with 200 μM of H2O2 for 1 hour, and apoptosis of RGCs was quantified with TUNEL assay in situ, and with flow cytometry. The mRNA expression levels of RhoA, Nogo receptor, caspase 3 and Bcl-2 were evaluated by quantitative RT-PCR, and the protein levels of RhoA, ROCK1, ROCK2, Nogo receptor, caspase 3 and Bcl-2 were evaluated by Western blot. We found siRhoA treatment efficiently downregulated the expression of RhoA in RGCs and protected against H2O2-induced injury in RGCs in vitro. Apoptosis of RGC cells under oxidative stress was quantified in situ using TUNEL assay and confirmed with flow cytometry (FCM).Results:With the knockdown of RhoA, the expression of ROCK1, ROCK2, Nogo Receptor, Casepase-3 were decreased, while the expression of Bcl-2 was increased in both mRNA and protein level. Our data indicated that siRhoA prevented H2O2-induced apoptosis in RGC cells by modulating the RhoA/ROCK pathway.Conclusion:The results suggested that siRhoA may exert potentially effective neuroprotection for RGCs by reducing injury.

项与 RTN4R 相关的新闻（医药）

2023-12-23

·今日头条

首次！“双向调控”策略——抑制肿瘤免疫逃逸！山大齐鲁联合郑大发文

本文为转化医学网原创，转载请注明出处作者：Sophia 导读：低水平的肿瘤免疫原性和免疫检查点依赖性抑制引起的肿瘤免疫逃逸限制了免疫治疗效果。近日，山东大学齐鲁医学院学者联合郑州大学人民医院学者在期刊《Advanced Science》上发表题为“Nano-Regulator Inhibits Tumor Immune Escape via the “Two-Way Regulation” Epigenetic Therapy Strategy”的研究论文，研究结果表明，纳米调节因子CG-J/ZL可以上调TAAs的表达以增强T细胞浸润，下调PD-L1的表达以改善T细胞对肿瘤细胞的识别，代表了一种有前途的改善抗肿瘤免疫应答的策略。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202305275 研究背景 01 免疫疗法是治疗肿瘤最有效的方法之一。然而，大多数患者没有从免疫治疗中获益，免疫治疗的总缓解率仅为10%-35%。免疫编辑理论指出，免疫逃逸是免疫治疗的最大障碍，包括肿瘤免疫原性水平低和免疫检查点依赖性抑制，导致T细胞瘤内浸润不足和T细胞对肿瘤细胞的识别不足。表观遗传调控是肿瘤免疫逃逸的重要原因。DNA 甲基化是主要的表观遗传调控之一，通过在控制基因表达的 DNA 甲基转移酶（DNMT）的催化下向 DNA 中添加甲基（CH3）基团而发生。据报道，肿瘤相关抗原（TAAs）启动子区域存在DNA高甲基化，通过降低TAAs表达导致肿瘤免疫原性水平低，从而降低抗原呈递细胞（APC）向T细胞呈递抗原的能力。因此，抑制肿瘤细胞的DNA高甲基化有望直接上调TAAs的表达，从而增加肿瘤免疫原性并增强T细胞的瘤内浸润。肿瘤细胞除了通过表观遗传调控DNA高甲基化来抑制肿瘤抗原表达外，还可以调节组蛋白乙酰化机制来控制免疫检查点的表达。程序性死亡-1（PD-1）是一种主要在T细胞上表达的受体，可降低免疫反应。肿瘤细胞表面表达大量程序性细胞死亡1配体1（PD-L1），通过与T细胞上的PD-1受体结合，帮助肿瘤细胞逃避免疫监视。因此，抑制肿瘤细胞中PD-L1的表达是阻断PD-1/PD-L1的有效手段，从而重新激活T细胞以杀死肿瘤。PD-L1由位于9p24.1染色体上的CD274基因编码，9p24.1染色质结构和性质的变化直接影响PD-L1的表达。溴结构域和额外末端结构域（BET）蛋白家族是组蛋白乙酰化的表观遗传读取器，可以调节基因转录。溴结构域蛋白4（BRD4）， BET蛋白家族成员，主要参与PD-L1的表达，PD-L1可与CD274启动子和增强子区域的乙酰化组蛋白H3K27Ac结合，促进PD-L1的表达。因此，使用BDD4抑制剂可以有效阻断PD-1/PD-L1免疫检查点，从而重新激活免疫效应细胞对肿瘤细胞的杀伤。研究设计 02 基于表观遗传调控对肿瘤免疫逃逸的显著影响，首次提出了一种“双向调控”表观遗传治疗策略，通过整合的纳米调节因子抑制肿瘤免疫逃逸，上调TAAs表达以提高免疫原性，下调PD-L1表达阻断PD-1/PD-L1免疫检查点。为了设计纳米调节剂，将DNMT抑制剂zebularine（Zeb）和BRD4抑制剂JQ1通过静电相互作用与缩合的Toll样受体9（TLR9）激动剂CpG[33-36]（G-J/ZL）共同加载到阳离子脂质体中，然后在G-J/ZL表面包覆靶向配体天冬酰胺-甘氨酸-精氨酸（NGR）修饰的电荷逆转材料羧甲基壳聚糖（CMCS），构建核壳结构CG-J/ZL。在NGR的介导下，CG-J/ZL可以靶向肿瘤组织，并在酸性TME下触发拆解。Zeb通过抑制DNA甲基转移酶，有效上调肿瘤表面的TAAs，从而增强肿瘤免疫原性，提高免疫识别能力。JQ1可抑制PD-L1表达，阻断免疫检查点阻断;CpG 作为 TLR9 激动剂，可以促进树突状细胞（DC）成熟，从而与 Zeb 合作促进 T 细胞的活化。此外，CpG可以“唤醒”肿瘤相关巨噬细胞（TAM），并重新激活TAM杀死肿瘤细胞的能力。研究结果 03 本研究成功构建了纳米调节剂CG-J/ZL，表征了CG-J/ZL的理化性质和pH响应性分解，考察了CG-J/ZL的肿瘤蓄积能力和共递送能力，评价了CG-J/ZL的“双向调控”能力，包括TAAs表达上调和PD-L1表达下调。此外，还评估了T细胞、DC、TAM、细胞毒性T淋巴细胞（CTL）和细胞因子分泌的肿瘤内浸润。我们进一步将PD-1单克隆抗体与纳米调节因子CG-J/ZL联合使用，以评估其抗肿瘤作用和抗转移功效。综上所述， CG-J/ZL可以上调TAAs表达以增强T细胞浸润，下调PD-L1表达以改善T细胞对肿瘤细胞的识别，从而抑制肿瘤免疫逃逸，这为改善抗肿瘤免疫应答提供了一种有前途的策略（图1）。图1：集成纳米调节因子通过“双向调节”表观遗传治疗策略抑制肿瘤免疫逃逸的示意图。参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/10.1002/advs.202305275 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 北京｜12月19日-20日 ▶第四届单细胞测序技术应用研讨会暨单细胞&空间组学研讨会（日程稍后公布）点击对应文字查看详情

免疫疗法

2023-05-03

·生物制品圈

山东大学齐鲁医院张娜、刘永军团队发现重塑肿瘤免疫抑制微环境以提高肿瘤治疗效果的关键策略

导读：靶向肿瘤免疫抑制微环境是免疫治疗中的关键策略。然而，肿瘤淋巴结（LN）免疫微环境（TLIME）在肿瘤免疫顺势淤滞中的关键作用往往被忽视。近日，药学院张娜、刘永军团队在重塑肿瘤—淋巴结免疫微环境提高肿瘤治疗效果方面取得新进展，并在国际期刊《Nature Communications》杂志上发表了题为“Temperature Sensitive Liposome Based Cancer Nanomedicine Enables Tumour Lymph Node Immune Microenvironment Remodeling”的研究论文，突出了TLIME在免疫治疗中的关键作用，并为在癌症免疫治疗中将LN靶向与免疫检查点阻断相结合提供了原理证明。https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-38014-6研究背景 01 免疫疗法通过利用宿主免疫系统识别和杀死肿瘤细胞，彻底改变了抗肿瘤疗法。肿瘤微环境通过循环和淋巴系统与周围免疫细胞相互作用，显著影响抗肿瘤免疫应答和临床疗效，重塑免疫抑制肿瘤微环境已被广泛用于增强免疫治疗;然而，免疫疗法的效果仍有待提高。逆转肿瘤免疫抑制微环境策略已经被广泛用于增强肿瘤免疫治疗效果，肿瘤—淋巴结免疫微环境也受到越来越多的关注。肿瘤引流淋巴结作为肿瘤相关免疫细胞的“大本营”，其微环境能够显著影响免疫细胞的存活和功能，进而影响肿瘤免疫治疗效果。然而，目前尚缺乏逆转肿瘤引流淋巴结免疫抑制微环境的有效手段，迫切需要开发一种能够同时调控肿瘤—淋巴结免疫微环境的新型递药系统，以增强肿瘤免疫治疗效果。研究进展 02 研究人员开发了一种策略来重塑被抑制的TLIME，并同时动员TLIME中的T细胞和NK细胞以达到最佳功效。他们精心构建了脂质纳米诱导剂，通过对pH敏感NGR和基质金属蛋白酶780（MMP1）响应性白细胞介素（IL）-1（NGR/IL-2-IR2/15-MT-Lip，NIL-IM-Lip）的修饰，将光热剂IR15和IDO780抑制剂1-MT共加载到温度敏感脂质体中，以精确靶向肿瘤组织并按预期定向到LN。然后，优化了NIL-IM-Lip对LNs积累的粒径和胆固醇比，有效的TLIME重塑需要有效的肿瘤和LNs积累的药物。为了保证NIL-IM-Lip的肿瘤积累和LNs指导特性，pH敏感靶向DSPE-酰基腙键-PEG5000-NGR （DSPE-HyD-PEG5000-NGR）用于在肿瘤微环境中提供肿瘤特异性靶向和快速拆卸，以满足LN分配的需求。然后，为共活化CTLs和NK细胞，选择光热剂IR780触发光热疗法诱导ICD效应，利用IL-15促进免疫细胞的杀伤能力。考虑到IR780和IL-15靶细胞的不同，MMP2敏感接头DSPE-PEG2000-MMP2 敏感肽马来酰亚胺（DSPE-PEG2000以-MMP2敏感型pep-Mal）为接头，修饰NIL-IM-Lip表面的IL-15，实现异型细胞递送，与MMP15酶一起在肿瘤微环境中释放IL-2，加强CTL和NK细胞的共活化。此外，选择IDO1抑制剂1-MT来缓解TLIME中的Treg抑制并逆转免疫抑制TLIME。1-MT还同时消除了光热疗法诱导的IDO1过表达。最后，为了增强抗肿瘤疗效，减少对正常组织的毒副作用，设计了光控释放和时空特异性释放，以温度敏感脂质物质1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱（DPPC）为载体组分，实现药物的彻底特异性释放。纳米诱导剂重塑肿瘤—淋巴结免疫微环境，同时激活T细胞和NK细胞，有效提升肿瘤免疫治疗效果在这里，纳米调节诱导剂NIL-IM-Lip被设计用于靶向肿瘤和LN，以重塑TLIME并增强CTL和NK细胞的抗肿瘤作用。与抗PD-1治疗联合使用后，NIL-IM-Lip可有效抑制冷热肿瘤（B16F10和CT26模型）的肿瘤生长。纳米调节诱导剂提供了一个平台，可以向肿瘤和LN提供递送，并能够针对热肿瘤和冷肿瘤进行强大的抗肿瘤免疫治疗，同时重塑抑制性TLIME，从而为进一步的应用铺平道路。研究意义 03 综上，研究结果表明，NIL-IM-Lip联合PD-1抗体在热肿瘤（B16F10模型）和冷肿瘤（CT26模型）中均显示了良好的抗肿瘤效果。该论文的研究结果凸显了肿瘤—淋巴结免疫微环境调控在肿瘤免疫治疗中的关键作用，论文制备的纳米诱导剂和免疫检查点抑制剂联用在模型动物上获得满意治疗效果，展现出了广阔的临床应用前景。参考资料：https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-023-38014-6

免疫疗法