更新于：2024-05-01

TYROBP

transmembrane immune signaling adaptor TYROBP

更新于：2024-05-01

基本信息

别名

DAP12、DNAX-activation protein 12、KAR-associated protein

+ [7]

简介

Adapter protein which non-covalently associates with activating receptors found on the surface of a variety of immune cells to mediate signaling and cell activation following ligand binding by the receptors (PubMed:9490415, PubMed:9655483, PubMed:10604985). TYROBP is tyrosine-phosphorylated in the ITAM domain following ligand binding by the associated receptors which leads to activation of additional tyrosine kinases and subsequent cell activation (PubMed:9490415). Also has an inhibitory role in some cells (PubMed:21727189). Non-covalently associates with activating receptors of the CD300 family to mediate cell activation (PubMed:15557162, PubMed:16920917, PubMed:17928527, PubMed:26221034). Also mediates cell activation through association with activating receptors of the CD200R family (By similarity). Required for neutrophil activation mediated by integrin (By similarity). Required for the activation of myeloid cells mediated by the CLEC5A/MDL1 receptor (PubMed:10449773). Associates with natural killer (NK) cell receptors such as KIR2DS2 and the KLRD1/KLRC2 heterodimer to mediate NK cell activation (PubMed:9490415, PubMed:9655483, PubMed:23715743). Also enhances trafficking and cell surface expression of NK cell receptors KIR2DS1, KIR2DS2 and KIR2DS4 and ensures their stability at the cell surface (PubMed:23715743). Associates with SIRPB1 to mediate activation of myeloid cells such as monocytes and dendritic cells (PubMed:10604985). Associates with TREM1 to mediate activation of neutrophils and monocytes (PubMed:10799849). Associates with TREM2 on monocyte-derived dendritic cells to mediate up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival (PubMed:11602640). Association with TREM2 mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages (PubMed:18957693). Stabilizes the TREM2 C-terminal fragment (TREM2-CTF) produced by TREM2 ectodomain shedding which suppresses the release of pro-inflammatory cytokines (PubMed:25957402). In microglia, required with TREM2 for phagocytosis of apoptotic neurons (By similarity). Required with ITGAM/CD11B in microglia to control production of microglial superoxide ions which promote the neuronal apoptosis that occurs during brain development (By similarity). Promotes pro-inflammatory responses in microglia following nerve injury which accelerates degeneration of injured neurons (By similarity). Positively regulates the expression of the IRAK3/IRAK-M kinase and IL10 production by liver dendritic cells and inhibits their T cell allostimulatory ability (By similarity). Negatively regulates B cell proliferation (PubMed:21727189). Required for CSF1-mediated osteoclast cytoskeletal organization (By similarity). Positively regulates multinucleation during osteoclast development (By similarity).

关联

100 项与 TYROBP 相关的临床结果

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100 项与 TYROBP 相关的转化医学

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0 项与 TYROBP 相关的专利（医药）

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项与 TYROBP 相关的文献（医药）

2024-02-24·Molecular neurobiology

Transcriptomics and Metabolomics Unveil the Neuroprotection Mechanism of AnGong NiuHuang (AGNH) Pill Against Ischaemic Stroke Injury.

Article

作者: Liangliang Tian ; Guangzhao Cao ; Xiaotong Zhu ; Lihan Wang ; Jingyi Hou ; Yi Zhang ; He Xu ; Lixia Wang ; Shicong Wang ; Chen Zhao ; Hongjun Yang ; Jingjing Zhang

As a famous prescription in China, AnGong NiuHuang (AGNH) pill exerts good neuroprotection for ischaemic stroke (IS), but its mechanism is still unclear. In this study, the neuroprotection of AGNH was evaluated in the rat IS model which were established with the surgery of middle cerebral artery occlusion (MCAO), and the potential mechanism was elucidated by transcriptomic analysis and metabolomic analysis. AGNH treatment obviously decreased the infarct volume and Zea-Longa 5-point neurological deficit scores, improved the survival percentage of rats, regional cerebral blood flow (rCBF), and rat activity distance and activity time. Transcriptomics showed that AGNH exerted its anti-inflammatory effects by affecting the regulatory network including Tyrobp, Syk, Tlr2, Myd88 and Ccl2 as the core. Integrating transcriptomics and metabolomics identified 8 key metabolites regulated by AGNH, including L-histidine, L-serine, L-alanine, fumaric acid, malic acid, and N-(L-arginino) succinate, 1-pyrroline-4-hydroxy-2-carboxylate and 1-methylhistamine in the rats with IS. Additionally, AGNH obviously reduced Tyrobp, Syk, Tlr2, Myd88 and Ccl2 at both the mRNA and protein levels, decreased IL-1β, KC-GRO, IL-13, TNF-α, cleaved caspase 3 and p65 nucleus translocation, but increased IκBα expression. Network pharmacology analysis showed that quercetin, beta-sitosterol, baicalein, naringenin, acacetin, berberine and palmatine may play an important role in protecting against IS. Taken together, this study reveals that AGNH reduced neuroinflammation and protected against IS by inhibiting Tyrobp/Syk and Tlr2/Myd88, as well as NF-κB signalling pathway and regulating multiple metabolites.

2024-02-21·Aging

Single-Cell RNA-seq reveals transcriptomic modulation of Alzheimer's disease by activated protein C.

Article

作者: Mohammad Kasim Fatmi ; Hao Wang ; Lily Slotabec ; Changhong Wen ; Blaise Seale ; Bi Zhao ; Ji Li

Single-Cell RNA sequencing reveals changes in cell population in Alzheimer's disease (AD) model 5xFAD (5x Familial AD mutation) versus wild type (WT) mice. The returned sequencing data was processed through the 10x Genomics CellRanger platform to perform alignment and form corresponding matrix to perform bioinformatic analysis. Alterations in glial cells occurred in 5xFAD versus WT, especially increases in microglia proliferation were profound in 5xFAD. Differential expression testing of glial cells in 5xFAD versus WT revealed gene regulation. Globally, the critical genes implicated in AD progression are upregulated such as Apoe, Ctsb, Trem2, and Tyrobp. Using this differential expression data, GO term enrichment was completed to observe possible biological processes impacted by AD progression. Utilizing anti-inflammatory and cyto-protective recombinant Activated Protein C (APC), we uncover inflammatory processes to be downregulated by APC treatment in addition to recuperation of nervous system processes. Moreover, animal studies demonstrated that administration of recombinant APC significantly attenuated Aβ burden and improved cognitive function of 5xFAD mice. The downregulation of highly expressed AD biomarkers in 5xFAD could provide insight into the mechanisms by which APC administration benefits AD.

2024-02-20·Aging

Comprehensive analysis identifies crucial genes associated with immune cells mediating progression of carotid atherosclerotic plaque.

Article

作者: Zhen Li ; Junhui Liu ; Zhichun Liu ; Xiaonan Zhu ; Rongxin Geng ; Rui Ding ; Haitao Xu ; Shulan Huang

BACKGROUNDS:

Carotid atherosclerosis is prone to rupture and cause ischemic stroke in advanced stages of development. Our research aims to provide markers for the progression of atherosclerosis and potential targets for its treatment.

METHODS:

We performed a thorough analysis using various techniques including DEGs, GO/KEGG, xCell, WGCNA, GSEA, and other methods. The gene expression omnibus datasets GSE28829 and GSE43292 were utilized for this comprehensive analysis. The validation datasets employed in this study consisted of GSE41571 and GSE120521 datasets. Finally, we validated PLEK by immunohistochemistry staining in clinical samples.

RESULTS:

Using the WGCNA technique, we discovered 636 differentially expressed genes (DEGs) and obtained 12 co-expression modules. Additionally, we discovered two modules that were specifically associated with atherosclerotic plaque. A total of 330 genes that were both present in DEGs and WGCNA results were used to create a protein-protein network in Cytoscape. We used four different algorithms to get the top 10 genes and finally got 6 overlapped genes (TYROBP, ITGB2, ITGAM, PLEK, LCP2, CD86), which are identified by GSE41571 and GSE120521 datasets. Interestingly, the area under curves (AUC) of PLEK is 0.833. Besides, we found PLEK is strongly positively correlated with most lymphocytes and myeloid cells, especially monocytes and macrophages, and negatively correlated with most stromal cells (e.g, neurons, myocytes, and fibroblasts). The expression of PLEK were consistent with the immunohistochemistry results.

CONCLUSIONS:

Six genes (TYROBP, ITGB2, ITGAM, PLEK, LCP2, CD86) were found to be connected with carotid atherosclerotic plaques and PLEK may be an important biomarker and a potential therapeutic target.

项与 TYROBP 相关的新闻（医药）

2024-04-03

·PRNewswire

Verismo Therapeutics Announces Submission of IND Application to the FDA for SynKIR™-310 in Relapsed/Refractory B-cell NHL

Company advances towards their second clinical trial for SynKIR™ platform treating patients with Diffuse Large B Cell Lymphoma and other B-cell Non-Hodgkin Lymphoma subtypes who are relapsed or refractory after standard of care, including CAR T therapies PHILADELPHIA, April 3, 2024 /PRNewswire/ -- Verismo Therapeutics, a clinical-stage CAR T company developing the novel KIR-CAR platform technology, today announced that it has submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for its Phase 1 clinical trial of SynKIR™-310, for the treatment of relapsed/refractory (r/r) B-cell Non-Hodgkin Lymphomas (B-cell NHL), including Diffuse Large B Cell lymphoma (DLBCL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), and Marginal Zone Lymphoma (MZL). The company plans to treat patients who previously received CAR T therapy but who have since relapsed or become refractory to it as well as patients who never received CAR T therapy. Commercially approved CAR T cell therapies have shown impressively high initial response rates in blood cancers. Over time, however, these therapies result in relapse in an estimated 40-50% of patients1. Such relapses are in part due to lack of long-term T cell effector function and persistence. There are currently very limited treatment options for patients with r/r DLBCL who relapse following treatment with commercial CAR T cell therapies. Ongoing clinical investigations into new and/or salvage therapies for these patients have not yet addressed the unmet medical need. SynKIR™-310 relies on Verismo's proprietary CD19 binder (DS191). The binder was developed specifically for the KIR-CAR platform technology to enable treatment of B-cell associated disorders and malignancies. SynKIR™-310 is directed by DS191 to target a similar epitope of CD19 as the commercially approved CAR T therapies, with the added potential to prolong the anti-tumor T cell function and persistence. Verismo's co-founders Dr. Donald Siegel and Dr. Michael Milone are co-inventors of the binder. "Verismo is in a unique position with SynKIR™-310, to address the challenges associated with the current treatment of relapsed/refractory B-cell NHL, including relapse after treatment with commercially approved CAR T therapies," said Dr. Laura Johnson, Chief Scientific Officer of Verismo Therapeutics. "We believe SynKIR™-310, comprised of a split-chain KIR-CAR incorporating our novel DS191 binder, has the potential to prolong T cell anti-tumor function, and improve persistence in patients with aggressive lymphomas, preventing early disease relapse. Initiation of the clinical trial is the culmination of years of focused research and diligent work by the Verismo team." Pending regulatory approval, the company plans to initiate the clinical trial (named CELESTIAL-301) in 2024. This trial will mark the company's second clinical study investigating the KIR-CAR platform technology, which harnesses the power of natural NK cell receptors and aims to shift the paradigm of T cell therapies. Verismo's leading pipeline, SynKIR™-110, is currently undergoing investigation in Phase 1 clinical trial (STAR-101) [NCT05568680] at two sites with plans to open two additional sites in Q2 2024. About the KIR-CAR Platform The KIR-CAR platform is a multi-chain CAR T cell therapy and has been shown in preclinical animal models to be capable of maintaining antitumor T cell activity even in challenging tumor microenvironments. Using NK cell derived KIR and DAP12 split signaling provides a novel combined activation and co-stimulation separate from the usual T cell stimulation pathways. It also enables sustained chimeric receptor expression and improves KIR-CAR T cell long term function. This results in prolonged T cell functional persistence and leads to regression of solid tumors in preclinical models that are resistant to traditional CAR T cell therapies. The KIR-CAR platform is being investigated in combination with many additional emerging technologies to potentially provide the next-generation multimodal targeted immunotherapy for patients in need. About Verismo Therapeutics Verismo Therapeutics is a pioneer in multi-chain KIR-CAR technology, with its first asset SynKIR™-110 currently in a first-in-human Phase 1 clinical trial. Verismo is the only company developing the KIR-CAR platform, using a modified NK cell derived receptor and DAP12 pairing, designed to improve persistence and efficacy against aggressive tumors. The KIR-CAR platform technology was developed specifically for treating advanced solid tumors and B cell associated disorders and malignancies, areas of high unmet medical need. For more information, visit: 1 Blood Adv (2020) 4 (22): 5607-5615; Biol Blood Marrow Transplant (2019) 25(11): e344-e351; Front Pediatr (2024) 11. CONTACT: Raymond Luke; [email protected] SOURCE Verismo Therapeutics

临床1期细胞疗法免疫疗法临床申请

2024-03-07

·BioSpace

Verismo Therapeutics Announces Opening of Second Clinical Site for STAR-101 Phase 1 Trial

Clinical-stage CAR-T company is actively recruiting patients to evaluate SynKIR™-110, a new treatment candidate for ovarian cancer, mesothelioma, and cholangiocarcinoma PHILADELPHIA, March 7, 2024 /PRNewswire/ -- Verismo Therapeutics, a clinical-stage CAR-T company developing the novel KIR-CAR platform technology, today announced that it has activated a second clinical site for its STAR-101 Phase 1 clinical trial at The University of Texas MD Anderson Cancer Center. STAR-101 is a multi-center clinical trial designed to evaluate Verismo Therapeutic's lead candidate, SynKIR™-110, for the treatment of mesothelin-overexpressing ovarian cancer, malignant pleural mesothelioma, and cholangiocarcinoma. "This milestone marks the steady progress towards our goal of bringing SynKIR™-110 to as many patients as possible," said Dr. Bryan Kim, Co-Founder and CEO of Verismo Therapeutics. "We are grateful for the opportunity to work with Dr. Mehmet Altan at MD Anderson to bring us closer to that goal." Verismo achieved clearance from the FDA to initiate this multi-center clinical trial for SynKIR™-110 and has partnered with the Hospital of the University of Pennsylvania as the first clinical site. Verismo has previously announced that SynKIR™-110 received Orphan Drug Designation and Fast Track Designation for the treatment of mesothelin-expressing mesotheliomas. For more information about the STAR-101 clinical trial, please visit ClinicalTrials.gov NCT05568680. About the KIR-CAR Platform The KIR-CAR platform is a dual-chain CAR T cell therapy and has been shown in preclinical animal models to be capable of maintaining antitumor T cell activity even in challenging solid tumor environments. DAP12 acts as a novel costimulatory molecule for T cells using additional T cell stimulating pathways, further sustaining chimeric receptor expression and improving KIR-CAR T cell functional persistence. This continued T cell function and persistence can lead to ongoing regression of solid tumors in preclinical models, including those resistant to traditional CAR T cell therapies. The KIR-CAR platform is being investigated in combination with many additional emerging technologies, such as in vivo gene engineering, advanced cell manufacturing and reprogramming, combinational therapies, and even allogeneic cellular therapies to potentially provide the next-generation multimodal targeted immunotherapy for patients in need. About Verismo Therapeutics Verismo Therapeutics is a pioneer in dual-chain KIR-CAR technology, with its first asset SynKIR™-110 under investigation in a first-in-human clinical trial. Verismo is the only company developing the KIR-CAR platform, a modified NK-like receptor designed to improve persistence and efficacy against aggressive solid tumors. The KIR-CAR platform technology was developed specifically for advanced solid tumors, an area of high unmet medical need. For more information, visit: CONTACT: Raymond Luke, raymond.luke@verismotherapeutics.com

免疫疗法细胞疗法孤儿药快速通道临床1期

2023-12-13

·药研网

NKp30——癌症免疫治疗的前瞻性靶点

自然杀伤 (NK) 细胞是先天免疫系统的重要组成部分,具有细胞毒性和免疫调节双重功能。 NK细胞的免疫活性是由大量的细胞表面受体介导的，这些受体识别不同的配体并介导不同的信号通路。在目前已知的四种天然细胞毒性受体（NCR）中，三种在NK细胞中组成型表达（NKp30、NKp46和NKp80），而NKp44仅存在于活化的NK细胞表面。这些受体与其配体的结合向细胞传递强烈的激活信号。NCR 的信号转导通过相关蛋白 DAP12、NKp44 中的 ITAM 基序、NKp30 和 NKp46 中的 FcεRIγ 和 CD3δ 进行（图1）。 NKp30 的质量为 30 kDa，包含一个138 个氨基酸长的Ig 样胞外结构域、一个 19 个氨基酸的跨膜 (TM) 结构域和一个 33 个氨基酸的胞质尾。 NKp30的胞外域包含Ig样折叠，通过短柄结构域与跨膜α螺旋（红色）连接。Ig 样结构域由8个β链组成，形成两个反向平行的β片层（黄色），通过Cys39和Cys108之间的二硫键连接（图2）。胞外结构域包含两个参与配体结合的N连接糖基化的潜在位点。 TM结构域包含带正电荷的精氨酸残基，与ITAM接头分子CD3ζ和FCεRIγ的 TM 结构域中带负电荷的天冬氨酸结合。这也是其他 NK 细胞激活受体的共同特征。 NKp30在几乎所有人类的NK细胞上都有表达，是免疫球蛋白超家族的I型跨膜激活受体。NKp30 介导的反应由特定配体（例如肿瘤细胞衍生的B7-H6）的结合触发，并引发细胞毒性介质TNF-α、IFN-γ、穿孔素和颗粒酶的分泌。当NKp30与激动剂抗体或配体结合后，会将强烈的激活信号转导给细胞，该NCR的信号转导通过NKp30中的FcεRIγ和CD3ζ的ITAM基序发生（图3）。NKp30激活可诱导NK细胞的细胞毒作用和细胞因子分泌功能，在抗肿瘤、抗病毒和抗寄生虫感染中发挥着重要的作用。 NKp30 受体可能与多种配体类型结合。痘病毒血凝素 (HA)，与NKp30结合充当拮抗剂；人巨细胞病毒外皮蛋白 pp65 (HCMV pp65) 也能够阻断 NKp30 参与的触发信号；恶性疟原虫红细胞膜蛋白1 (PfEMP-1) 被鉴定为 NKp30 和 NKp46 的强激活配体，一旦结合，就会导致受感染细胞裂解。配体BAT3 BAT3（HLA-B 相关转录物 3，也称为 BAG6、BCL2 相关 athanogene 6）是一种蛋白质伴侣，肿瘤细胞响应应激信号而过度表达。BAT3 促进黑色素瘤患者外泌体介导的转移，并已被确定为肝细胞癌、肠胃间质瘤、非小细胞肺癌患者的预后生物标志物。配体B7-H6 NKp30配体B7-H6在正常组织和细胞中几乎不表达或低表达，当细胞发生癌变或感染时，B7-H6分子表达上调。与其他 B7 家族蛋白不同，在稳态条件下，B7-H6 不会在正常人体组织中表达，但在炎性应激下会被诱导表达。相应地，B7-H6 已被证明会在各种不同的肿瘤组织上表达。B7-H6 会与自然杀伤细胞上的 NKp30 激活受体结合，诱导细胞毒性，从而促进抗肿瘤免疫应答。与此相对的是，研究还显示可溶性 B7-H6（可由 ADAM 介导的胞外域脱落产生）与某些癌症中的 NKp30 表达减少和自然杀伤细胞功能障碍相关,这表明B7-H6 在某些条件下可能负向调节免疫应答。此外,在利用人乳腺癌或神经胶质瘤细胞系开展的研究中发现，B7-H6 可促进肿瘤细胞增殖并抑制细胞凋亡，这进一步表明 B7-H6 可能参与了肿瘤发生。同样，B7-H6 在人卵巢癌中的高水平表达与肿瘤进展和转移呈正相关。目前，布局NKp30的企业并不多，且多处于临床前开发阶段，主要集中于抗体药物研发。另外，NKp30已在嵌合抗原受体 T 细胞 (CAR-T) 疗法中也得到了探索！吉满生物科技（上海）有限公司，是位于上海浦东的一家以创新为驱动的工程化细胞系研发公司，基于自有的国内最大报告基因平台、慢病毒平台以及最迅速的药研网资讯平台，目前已构建出700余株现货单克隆细胞系产品，覆盖ROR1/DLL3/SLC39A6/TROP2/BCMA/BDCA/TREM2……200余新药热门靶点，其中有100余靶点开发有对应luciferase reporter方法，更有国内独家/首家CCR8, BDCA, TREM2和GAPR等luciferase的assay平台。数据展示 H_NKp30 Reporter Jurkat Cell Line(Genomeditech/GM-C29776)使用两种NKP30抗体包被激活验证结果 H_NKP30 CHO-K1 Cell Line（Genomeditech/GM-C29749）使用Anti-NKP30 hIgG1 Antibody(BGA-1833)（Genomeditech/GM-49311AB）流式验证结果 H_NKP30 HEK-293 Cell Line（Genomeditech/GM-C30360）使用Anti-NKP30 hIgG1 Antibody(BGA-1833)（Genomeditech/GM-49311AB）流式验证结果 Cynomolgus_NKP30 CHO-K1 Cell Line（Genomeditech/GM-C33009）使用Anti-NKP30 hIgG1 Antibody(BGA-1833)（Genomeditech/GM-49311AB）流式验证结果吉满生物助力药物研发，紧随前沿靶点资讯，储备几百株现货细胞，覆盖GPCR、细胞因子、免疫检查点、TAA等多领域近200余个靶点。参考资料：【1】doi: 10.1111/bph.15222【2】https://en.wikipedia.org/wiki/NCR3 内容来源于网络，如有侵权，请联系删除。