更新于：2024-09-19

TRAP1

更新于：2024-09-19

基本信息

别名

Heat shock protein 75 kDa, mitochondrial、HSP 75、HSP75

+ [7]

简介

Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.

关联

项与 TRAP1 相关的药物

ACU-D3

靶点

TRAP1

作用机制

TRAP1拮抗剂

在研机构

Accuitis, Inc.

原研机构

Accuitis, Inc.

在研适应症

黑色素瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

SH-491

靶点

CTSK x MMP9 x TRAP1

作用机制

CTSK抑制剂 [+2]

在研机构

华东师范大学

原研机构

华东师范大学

在研适应症

骨质疏松症

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TRAP1 相关的临床结果

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100 项与 TRAP1 相关的转化医学

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0 项与 TRAP1 相关的专利（医药）

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1,102

项与 TRAP1 相关的文献（医药）

2024-08-08·Nature

In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution

Article

作者: Khandekar, Ameya ; Kretz, Jonas A ; Ellis, Stephanie J ; Duré, Clara ; Lee, Minkyoung ; Baghai Sain, Simona ; Bernasconi, Martino ; Valdivia-Francia, Fabiola ; Hyams, Katie ; Pohly, Marcel ; Ghoshdastider, Umesh ; Ficht, Xenia ; Forny, Merima ; Renz, Peter F ; Ormiston, Mark ; Moor, Andreas E ; Sendoel, Ataman

AbstractThe tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1–3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial–mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.

2024-08-01·European Journal of Pharmacology

Porphyrin derivatives inhibit tumor necrosis factor α-induced gene expression and reduce the expression and increase the cross-linked forms of cellular components of the nuclear factor κB signaling pathway

Article

作者: Sasaki, Saki ; Kataoka, Takao ; Osada, Hiroyuki ; Morimoto, Kyoko ; Tamura, Ryuichi ; Baba, Kosuke ; Vu, Nhat Thi ; Vu, Quy Van ; Hirano, Hiroyuki

The transcription factor nuclear factor κB (NF-κB) is activated by proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and Toll-like receptor (TLR) ligands. Screening of NPDepo chemical libraries identified porphyrin derivatives as anti-inflammatory compounds that strongly inhibited the up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression induced by TNF-α, interleukin-1α, the TLR3 ligand, and TLR4 ligand in human umbilical vein endothelial cells. In the present study, the mechanisms of action of porphyrin derivatives were further elucidated using human lung adenocarcinoma A549 cells. Porphyrin derivatives, i.e., dimethyl-2,7,12,18-tetramethyl-3,8-di(1-methoxyethyl)-21H,23H-porphine-13,17-dipropionate (1) and pheophorbide a (2), inhibited TNF-α-induced ICAM-1 expression and decreased the TNF-α-induced transcription of ICAM-1, vascular cell adhesion molecule-1, and E-selectin genes. 1 and 2 reduced the expression of the NF-κB subunit RelA protein for 1 h, which was not rescued by the inhibition of proteasome- and lysosome-dependent protein degradation. In addition, 1 and 2 decreased the expression of multiple components of the TNF receptor 1 complex, and this was accompanied by the appearance of their cross-linked forms. As common components of the NF-κB signaling pathway, 1 and 2 also cross-linked the α, β, and γ subunits of the inhibitor of NF-κB kinase complex and the NF-κB subunits RelA and p50. Cellular protein synthesis was prevented by 2, but not by 1. Therefore, the present results indicate that porphyrin derivative 1 reduced the expression and increased the cross-linked forms of cellular components required for the NF-κB signaling pathway without affecting global protein synthesis.

2024-08-01·Journal of Cellular Physiology

The miR‐29‐3p family suppresses inflammatory osteolysis

Article

作者: Shin, Bongjin ; Karki, Sangita ; Hrdlicka, Henry C ; Delany, Anne M ; Lee, Sun-Kyeong ; Fraser, Brianna

AbstractOsteoclasts are the cells primarily responsible for inflammation‐induced bone loss, as is particularly seen in rheumatoid arthritis. Increasing evidence suggests that osteoclasts formed under homeostatic versus inflammatory conditions may differ in phenotype. While microRNA‐29‐3p family members (miR‐29a‐3p, miR‐29b‐3p, miR‐29c‐3p) promote the function of RANKL‐induced osteoclasts, the role of miR‐29‐3p during inflammatory TNF‐α‐induced osteoclastogenesis is unknown. We used bulk RNA‐seq, histology, qRT‐PCR, reporter assays, and western blot analysis to examine bone marrow monocytic cell cultures and tissue from male mice in which the function of miR‐29‐3p family members was decreased by expression of a miR‐29‐3p tough decoy (TuD) competitive inhibitor in the myeloid lineage (LysM‐cre). We found that RANKL‐treated monocytic cells expressing the miR‐29‐3p TuD developed a hypercytokinemia/proinflammatory gene expression profile in vitro, which is associated with macrophages. These data support the concept that miR‐29‐3p suppresses macrophage lineage commitment and may have anti‐inflammatory effects. In correlation, when miR‐29‐3p activity was decreased, TNF‐α‐induced osteoclast formation was accentuated in an in vivo model of localized osteolysis and in a cell‐autonomous manner in vitro. Further, miR‐29‐3p targets mouse TNF receptor 1 (TNFR1/Tnfrsf1a), an evolutionarily conserved regulatory mechanism, which likely contributes to the increased TNF‐α signaling sensitivity observed in the miR‐29‐3p decoy cells. Whereas our previous studies demonstrated that the miR‐29‐3p family promotes RANKL‐induced bone resorption, the present work shows that miR‐29‐3p dampens TNF‐α‐induced osteoclastogenesis, indicating that miR‐29‐3p has pleiotropic effects in bone homeostasis and inflammatory osteolysis. Our data supports the concept that the knockdown of miR‐29‐3p activity could prime myeloid cells to respond to an inflammatory challenge and potentially shift lineage commitment toward macrophage, making the miR‐29‐3p family a potential therapeutic target for modulating inflammatory response.

项与 TRAP1 相关的新闻（医药）

2022-09-15

·生物谷

iScience：科学家有望开发出一种能有效抵御人类遗传性神经性疾病的潜在疗法

来自西奈山Icahn医学院等机构的科学家们通过研究逆转了人类细胞和小鼠机体中称为溶酶体贮存紊乱疾病的的多种严重威胁生命的遗传性神经变性疾病所产生的影响效应。目前大量研究都揭示了溶酶体和线粒体功能障碍或许参与到了多种神经退行性疾病的病理学过程中，比如阿尔兹海默病和帕金森疾病。近日，一篇发表在国际杂志iScience上题为“Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction”的研究报告中，来自西奈山Icahn医学院等机构的科学家们通过研究逆转了人类细胞和小鼠机体中称为溶酶体贮存紊乱疾病（LSDs，lysosomal storage disorders）的多种严重威胁生命的遗传性神经变性疾病所产生的影响效应。研究者表示，我们能通过所识别出的增加TRAP1活性的新型化合物来恢复线粒体和溶酶体的合适功能，TRAP1蛋白能帮助细胞中的线粒体正常发挥功能。LSDs的主要特征为遗传缺陷，其能使得细胞中的溶酶体无法分解并循环脂肪、糖类和蛋白质等，从而就会导致包括机体肝脏和大脑在内的器官发生堆积，这就会引发线粒体的功能异常，从而导致这些器官进一步损伤。长期以来，研究人员一直在寻找能影响溶酶体的药物，从而就能尝试影响溶酶体贮存紊乱疾病，这或许就是治疗这些疾病的新方法，增加TRAP1的活性或许就能促进线粒体蛋白质的折叠，并促进细胞的合适平衡，这些一流的分子就会激活线粒体中的TRAP1，并能减少LSDs中的储存。相关研究数据表明，线粒体中的TRAP1或许能作为影响机体中枢神经系统的多种疾病的潜在新型治疗性靶点，研究者发现，TRAP1或许就会启动线粒体和溶酶体之间的串扰，其对于恢复机体内部的细胞平衡至关重要。令人惊讶的是，当TRAP1激活时，其就会开启一系列级联事件从而恢复LSDs中正常的溶酶体功能，导致每种溶酶体疾病的缺陷或许仍然会存在，但这种串扰或许就会绕过遗传缺陷。科学家有望开发出一种能有效抵御人类遗传性神经性疾病的潜在疗法。图片来源： Ioannou Lab, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai 研究人员表明，增加尼曼匹克症C1型（Niemann-Pick disease，一类LSD）患者机体细胞中的TRAP1的水平或许就会纠正脂质储存障碍并能恢复正常的胆固醇水平，此外，增加来自其它LSDs患者（比如Fabry疾病患者）细胞中的TRAP1的活性或许就能纠正其各自的脂肪储存；尼曼匹克症C1型是一种能影响患者机体代谢细胞中脂肪能力的罕见遗传性疾病。文章中，研究人员开发了一种检测手段，其能测定化合物对尼曼匹克症C1型患者机体的影响效应，随后他们联合研究将这种测试与一种高通量筛选设施一起使用，从而快速筛选出了成千上万种化合物。研究者发现，激活TRAP1的化合物或能让线粒体再次正常工作，并能重新启动溶酶体的循环能力，并帮助减少溶酶体和细胞中的脂肪，随后研究者化学性地改良了似乎能发挥最好效果的化合物，并对其进行了进一步测试。研究者表示，这一研究发现对于拥有相似发病原因的其它神经退行性疾病也具有非常重要的意义，比如帕金森疾病、肌萎缩性侧所硬化症和阿尔兹海默病等。研究人员希望能进一步理解这些化合物是如何逆转LSDs中的特征，这或许有助于帮助开发潜在的药物疗法，下一步他们计划继续完善这些化合物并分析其在多种模型中的效应，包括影响更为常见的神经性疾病的能力等，比如阿尔兹海默病和帕金森疾病等。综上，本文研究结果表明，TRAP1参与到了溶酶体-线粒体的串扰过程中从而就能维持细胞的平衡，并可能会代表一种针对多种疾病的潜在治疗性靶点。（生物谷Bioon.com）原始出处： Fannie W. Chen，Joanna P. Davies，Raul Calvo, et al. Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction, iScience (2022). DOI: 10.1016/j.isci.2022.104941