更新于：2024-09-19

PPP3CB

更新于：2024-09-19

基本信息

别名

Calmodulin-dependent calcineurin A subunit beta isoform、CALNA2、CALNB

+ [7]

简介

Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals (PubMed:19154138, PubMed:25720963, PubMed:32753672, PubMed:26794871). Dephosphorylates TFEB in response to lysosomal Ca(2+) release, resulting in TFEB nuclear translocation and stimulation of lysosomal biogenesis (PubMed:25720963, PubMed:32753672). Dephosphorylates and activates transcription factor NFATC1 (PubMed:19154138). Dephosphorylates and inactivates transcription factor ELK1 (PubMed:19154138). Dephosphorylates DARPP32 (PubMed:19154138). Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB (By similarity). May play a role in skeletal muscle fiber type specification (By similarity).

关联

100 项与 PPP3CB 相关的临床结果

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100 项与 PPP3CB 相关的转化医学

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0 项与 PPP3CB 相关的专利（医药）

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项与 PPP3CB 相关的文献（医药）

2024-06-19·Microbial Genomics

Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysaccharide locus and virulence gene profiles post introduction of pneumococcal conjugate vaccine in Blantyre, Malawi

Article

作者: Swarthout, Todd D ; Kalizang'oma, Akuzike ; Msefula, Jacquline ; Nyirenda, Roseline ; Heyderman, Robert S ; Brown, Comfort ; Bonomali, Farouck ; Chaguza, Chrispin ; Cave, Rory ; French, Neil ; Kwambana-Adams, Brenda ; Mwalukomo, Thandie S ; Kamng'ona, Arox

Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in Malawi in 2011, there has been persistent carriage of vaccine serotype (VT) Streptococcus pneumoniae, despite high vaccine coverage. To determine if there has been a genetic change within the VT capsule polysaccharide (cps) loci since the vaccine’s introduction, we compared 1022 whole-genome-sequenced VT isolates from 1998 to 2019. We identified the clonal expansion of a multidrug-resistant, penicillin non-susceptible serotype 23F GPSC14-ST2059 lineage, a serotype 14 GPSC9-ST782 lineage and a novel serotype 14 sequence type GPSC9-ST18728 lineage. Serotype 23F GPSC14-ST2059 had an I253T mutation within the capsule oligosaccharide repeat unit polymerase Wzy protein, which is predicted in silico to alter the protein pocket cavity. Moreover, serotype 23F GPSC14-ST2059 had SNPs in the DNA binding sites for the cps transcriptional repressors CspR and SpxR. Serotype 14 GPSC9-ST782 harbours a non-truncated version of the large repetitive protein (Lrp), containing a Cna protein B-type domain which is also present in proteins associated with infection and colonisation. These emergent lineages also harboured genes associated with antibiotic resistance, and the promotion of colonisation and infection which were absent in other lineages of the same serotype. Together these data suggest that in addition to serotype replacement, modifications of the capsule locus associated with changes in virulence factor expression and antibiotic resistance may promote vaccine escape. In summary, the study highlights that the persistence of vaccine serotype carriage despite high vaccine coverage in Malawi may be partly caused by expansion of VT lineages post-PCV13 rollout.

2024-06-01·Molecular and Cellular Neuroscience

Protein phosphatases regulate the formation of Müller glia-derived progenitor cells in the chick retina

Article

作者: Crider, Andrew ; Kelly, Lisa E ; El-Hodiri, Heithem M ; Fischer, Andy J

Different kinase-dependent cell signaling pathways are known to play important roles in glia-mediated neuroprotection and reprogramming of Müller glia (MG) into Müller glia-derived progenitor cells (MGPCs) in the retina. However, very little is known about the phosphatases that regulate kinase-dependent signaling in MG. Using single-cell RNA-sequencing (scRNA-seq) databases, we investigated patterns of expression of Dual Specificity Phosphatases (DUSP1/6) and other protein phosphatases in normal and damaged chick retinas. We found that DUSP1, DUSP6, PPP3CB, PPP3R1 and PPPM1A/B/D/E/G are widely expressed by many types of retinal neurons and are dynamically expressed by MG and MGPCs in retinas during the process of reprogramming. We find that inhibition of DUSP1/6 and PP2C phosphatases enhances the formation of proliferating MGPCs in damaged retinas and in retinas treated with insulin and FGF2 in the absence of damage. By contrast, inhibition of PP2B phosphatases suppressed the formation of proliferating MGPCs, but increased numbers of proliferating MGPCs in undamaged retinas treated with insulin and FGF2. In damaged retinas, inhibition of DUSP1/6 increased levels of pERK1/2 and cFos in MG whereas inhibition of PP2B's decreased levels of pStat3 and pS6 in MG. Analyses of scRNA-seq libraries identified numerous differentially activated gene modules in MG in damaged retinas versus MG in retinas treated with insulin+FGF2 suggesting significant differences in kinase-dependent signaling pathways that converge on the formation of MGPCs. Inhibition of phosphatases had no significant effects upon numbers of dying cells in damaged retinas. We conclude that the activity of different protein phosphatases acting through retinal neurons and MG "fine-tune" the cell signaling responses of MG in damaged retinas and during the reprogramming of MG into MGPCs.

2024-05-01·Molecular Psychiatry

Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics

Article

作者: Hill, M D ; Wolf, S K ; Dainton, H D ; Roseberry, K ; Niculescu, A B ; Gill, S S ; Le-Niculescu, H ; Kurian, S M ; Murray, O K ; MacKie, O ; Shekhar, A ; Bhagar, R

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

项与 PPP3CB 相关的新闻（医药）

2023-02-06

·生物谷

STTT：突破！川大/首医大团队发现自闭症谱系障碍的新风险基因，抗炎药和催产素类似物是潜在干预方案

该研究发现了一个新的ASD风险基因SCGN，而且发现SCGN的缺失会破坏催产素信号，并异常激活炎症，最终导致导致类似自闭症的行为、损害大脑发育，而催产素和抗炎药物或可以减弱由SCGN缺失引起的ASD相每年的4月2日，是世界“自闭症儿童关爱日”，这是一群被称为“来自星星的孩子”：世界在他们面前，也不在他们面前，世界倒映在他们眼里，他们却什么都看不见，就像天上的星星，独居在自己的世界里。自闭症谱系障碍（ASD）是一组以交流和社会互动障碍为特征的异质神经发育疾病，包括自闭症、阿斯伯格综合征、不典型自闭症以及儿童瓦解性精神障碍。2021年，美国疾病控制与预防中心（CDC）发布的报告显示：每44名8岁儿童中就有一名（2.3%）被确认患有ASD[1]。 ASD患者主要表现为沟通和社会互动障碍，以及重复或受限的感觉运动行为。除了这些核心症状外，可能还会出现发育迟缓、智力障碍、焦虑、抑郁、胃肠道和免疫系统疾病等。鉴于ASD的临床特征异质性，一直没有针对这种疾病的有效治疗方法，现有的ASD治疗药物不仅效果不佳，而且还会产生巨大的副作用，因此进一步了解ASD的发病机制对于开发新的治疗策略是必不可少的。近日，由四川大学贾大、张小虎、莫显明，以及首都医科大学李巍共同领衔的研究团队，在Signal Transduction and Targeted Therapy在线发表了最新研究成果。在这项研究中，他们发现突触传递的调节因子促泌素（SCGN）是ASD的一个新的风险基因，SCGN缺失通过破坏激活大脑中的促炎反应和催产素信号导致自闭症行为，而用消炎药和催产素类似物治疗SCGN缺失的动物则可以纠正自闭症行为[2]。文章首页截图为了识别潜在的ASD风险基因，研究人员首先对ASD先证者（对ASD遗传性状进行家系调查时，其家系中第一个被确诊的那个人）及其父母进行了全外显子组测序，在参与研究的168例病例中，有2例确定存在SCGN突变（ASD0010和ASD0014）。这两名患者都表现出典型的ASD核心特征，包括通过CABS、ABC和CARS评分衡量的沟通和社交缺陷。此外，根据Gesell发育量表，这两名SCGN突变的ASD患者还表现出严重的发育迟缓。 SCGN的突变与ASD有关接下来研究人员使用CRISPR/Cas9基因编辑技术，生成了scgn基因缺失的斑马鱼模型，以确定scgn基因在社会行为和神经元发育中的作用。结果发现相比于scgn+/−、scgn−/−基因型的斑马鱼，scgn+/+基因型的斑马鱼的社交持续时间明显更长，表现出更强的社会凝聚力，也就是说scgn基因纯合或杂合缺失会导致斑马鱼的自闭症样行为。此外，研究人员还观察到scgn基因缺失损坏斑马鱼的大脑发育，与scgn+/+胚胎相比，scgn−/−胚胎的头部尺寸显著减小，反映斑马鱼大脑发育的的眼长和眼距也体现出类似的结果：与scgn+/+组相比，scgn−/−胚胎表现出明显更小的眼睛，眼睛之间的距离更短。 scgn缺失损害斑马鱼的神经元发育那么scgn缺失是如何导致ASD的呢？为了回答这个问题，研究人员使用RNA-seq比较了scgn+/+和scgn−/−的斑马鱼大脑和小鼠下丘脑的基因表达谱差异。基因集富集分析（GSEA）显示，两者的差异表达基因（DEGs）主要富集在神经递质受体活性等通路。有趣的是，在炎症和先天免疫反应信号等多种免疫调节通路中也有富集。为了进一步证实上述观察结果，研究人员进行定量RT-PCR比较了scgn缺失小鼠模型中免疫相关的多个基因的表达，结果发现scgn缺失导致促炎基因IL-6和TNF的上调。ELISA结果也表明，scgn−/−小鼠中IL-6和IL-1β蛋白水平升高。也就是说，scgn基因缺失会改变免疫反应，导致异常炎症。 scgn缺失会改变免疫反应由于scgn蛋白通常调节激素分泌，因此研究人员进一步比较了scgn+/+和scgn−/−小鼠的血清代谢组学差异。综合代谢组学和转录组分析的结果，研究人员发现，scgn缺失导致催产素信号和神经活性配体-受体相互作用通路中断，影响催产素通路中许多基因如Oxt、Ppp3cb和Plcb3的表达。此外，与年龄匹配的scgn+/+组相比，scgn+/−和scgn−/−斑马鱼大脑中的催产素mRNA和蛋白质水平均显著降低，scgn+/−和scgn−/−斑马鱼的血清催产素水平相对于scgn+/+对照组降低了31%。总之，这些数据表明，scgn的功能缺失导致斑马鱼和小鼠催产素减少。 scgn缺失影响催产素分泌那么抗炎药物的使用和催产素的补充是否可以挽救scgn缺失导致的异常炎症和神经元发育障碍呢？研究人员于是选择了两种抗炎药物地塞米松和阿司匹林，以及一种半衰期延长的催产素合成物卡贝催产素处理ASD动物模型。可以看到，0.5μM或1μM卡贝催产素处理1天后，scgn+/−和scgn−/−斑马鱼胚胎的IL-1β的表达明显减弱，其表达与未处理对照组相似，抗炎药地塞米松和阿司匹林处理也强烈降低了scgn+/−和scgn−/−斑马鱼中IL-1β的表达。此外，scgn缺失所导致的ASD表型也可以被上述三种药物改善，其中高剂量的卡贝催产素和阿司匹林表现出最显著的改善效果，1μM的卡贝催产素处理使近2/3的scgn−/−斑马鱼的社会互动恢复到正常对照的水平，而10μM阿司匹林处理则可以使1/3-1/2的斑马鱼的社会互动恢复到正常对照组水平。催产素类似物、抗炎药物可拮抗斑马鱼scgn缺失导致的ASD 总的来说，该研究发现了一个新的ASD风险基因SCGN，而且发现SCGN的缺失会破坏催产素信号，并异常激活炎症，最终导致导致类似自闭症的行为、损害大脑发育，而催产素和抗炎药物或可以减弱由SCGN缺失引起的ASD相关缺陷。上述研究提示，催产素和抗炎药物是SCGN缺乏患者的潜在治疗方法，在精准医疗时代，这些机制的阐明将有助于开发针对ASD的个性化治疗手段，拓宽目前有限的ASD治疗干预方法的选择。同时，这一研究成果也提示根据ASD患者的具体发病机制来提供不同的治疗手段是至关重要的，这可以极大地提高治疗的成功率。参考文献： [1] Jiang, Chen-Chen et al. “Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications.” Signal transduction and targeted therapy vol. 7,1 229. 11 Jul. 2022 [2] Liu, Zhe et al. “SCGN deficiency is a risk factor for autism spectrum disorder.” Signal transduction and targeted therapy vol. 8,1 3. 2 Jan. 2023

生物类似药基因疗法

2022-07-07

·BioSpace

Insilico's AI Identifies Potential New Therapeutic Targets for ALS

The quest to develop a new treatment approach to amyotrophic lateral sclerosis (ALS) may soon be shortened due to the discovery of new potential therapeutic targets by Insilico Medicine. Using a proprietary AI-driven target discovery engine called PandaOmics, New York-based Insilico found genes that could serve as potential targets for new therapeutics. Insilico’s research is being conducted in collaboration with Answer ALS, a global research project aimed at finding new therapies and a potential cure for ALS. The AI-driven discovery engine analyzed expression profiles of central nervous system samples from public datasets and direct iPSC-derived motor neurons (diMN) from Answer ALS. As a result, the study identified 17 high-confidence and 11 novel therapeutic targets. These targets were further validated in a model that mimics the most common genetic cause of ALS. Insilico said eight unreported genes, including KCNB2, KCNS3, ADRA2B, NR3C1, P2RY14, PPP3CB, PTPRC and RARA strongly “rescue neurodegeneration through their suppression.” The findings from this study were published in Frontiers in Aging Neuroscience. “The results of this collaborative research effort show what is possible when we bring together human expertise with AI tools to discover new targets for diseases where there is a high unmet need,” Alex Zhavoronkov, founder and CEO of Insilico said in a statement. “This is only the beginning.” ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disease that negatively affects neurons in the brain and the spinal cord. Patients with ALS rapidly lose the ability to control muscle movement. That eventually leads to total paralysis and then death. It is estimated that approximately 12,000 to 15,000 Americans have ALS, with about 5,000 to 6,000 new cases diagnosed annually. Currently available drugs, including Riluzole and Mitsubishi Tanabe’s Radicava, do not halt or reverse the loss of function in ALS patients. Feng Ren, co-CEO and chief scientific officer of Insilico, said the new targets for therapeutics demonstrate the power of the PandaOmics platform. “It is impressive that around 70% (18 out of 28) targets identified by AI were validated in a preclinical animal model. We are working with collaborators to progress some targets toward clinical trials for ALS. At the same time, we are also further expanding the utilization of PandaOmics to discover novel targets for other disease areas including oncology, immunology and fibrosis,” Ren said in a statement. Insilico did not announce its plans for the data’s use, but there are likely a number of companies that may opt to approach these potential ALS targets. Several companies, such as Amylyx Pharmaceuticals, NeuroSense and QurAlis are working on potential treatments for this devastating disease. Amylyx's ALS asset, AMX0035, authorized for use in Canada, will be revisited by a U.S. Food and Drug Administration Advistory Committee to re-evaluate the drug candidate following the publication of additional clinical data.