更新于：2024-05-01

S100A1

S100 calcium binding protein A1

更新于：2024-05-01

基本信息

别名

Protein S100-A1、S-100 protein alpha chain、S-100 protein subunit alpha

+ [5]

简介

Small calcium binding protein that plays important roles in several biological processes such as Ca(2+) homeostasis, chondrocyte biology and cardiomyocyte regulation (PubMed:12804600). In response to an increase in intracellular Ca(2+) levels, binds calcium which triggers conformational changes (PubMed:23351007). These changes allow interactions with specific target proteins and modulate their activity (PubMed:22399290). Regulates a network in cardiomyocytes controlling sarcoplasmic reticulum Ca(2+) cycling and mitochondrial function through interaction with the ryanodine receptors RYR1 and RYR2, sarcoplasmic reticulum Ca(2+)-ATPase/ATP2A2 and mitochondrial F1-ATPase (PubMed:12804600). Facilitates diastolic Ca(2+) dissociation and myofilament mechanics in order to improve relaxation during diastole (PubMed:11717446).

关联

100 项与 S100A1 相关的临床结果

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100 项与 S100A1 相关的转化医学

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0 项与 S100A1 相关的专利（医药）

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项与 S100A1 相关的文献（医药）

2024-01-03·Blood

Single-cell landscape of idiopathic Multicentric Castleman Disease in identical twins.

Article

作者: Jason Yongsheng Chan ; Jui Wan Loh ; Jing Quan Lim ; Herty Liany ; Elizabeth Chun Yong Lee ; Jing Yi Lee ; Bavani Kannan ; Boon Yee Lim ; Zexi Guo ; Kerry May Huifen Lim ; Jeslin Chian Hung Ha ; Cedric Chuan-Young Ng ; Tun Kiat Ko ; Dachuan Huang ; Dominique Yuan Bin Seow ; Chee Leong Cheng ; Sock Hoai Chan ; Joanne Ngeow ; Bin Tean Teh ; Soon Thye Lim ; Choon Kiat Ong

Idiopathic Multicentric Castleman Disease (iMCD) is a rare cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy and organ dysfunction. Here, we present an unusual occurrence of iMCD in identical twins and examined the immune milieu within affected lymphoid organs and the host circulation using multi-omic high-dimensional profiling. Using Stereo-seq spatial transcriptomic profiling, we performed unsupervised spatially-constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. Following a cell segmentation approach, IL-6 pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10X Chromium). Furthermore, single cell sequencing of peripheral blood mononuclear cells revealed an "inflammatory" peripheral monocytosis enriched for the expression of S100A family genes in both twins. In summary, we provided evidence of the putative cell-of-origin of IL-6 signals in iMCD and described a distinct monocytic host immune response phenotype through a unique identical twin model.

2023-12-05·Proceedings of the National Academy of Sciences of the United States of America

Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Article

作者: Lin Jin ; Yunjia Chen ; Suhail Muzaffar ; Chao Li ; Carlos A Mier-Aguilar ; Jasim Khan ; Mahendra P Kashyap ; Shanrun Liu ; Ritesh Srivastava ; Jessy S Deshane ; Tim M Townes ; Boni E Elewski ; Craig A Elmets ; David K Crossman ; Chander Raman ; Mohammad Athar

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49f^high cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.

2023-11-23·Respiratory research

S100A alarmins and thymic stromal lymphopoietin (TSLP) regulation in severe asthma following bronchial thermoplasty.

Article

作者: Pierre-Alexandre Gagnon ; Martin Klein ; John De Vos ; Sabrina Biardel ; Andréanne Côté ; Krystelle Godbout ; Michel Laviolette ; Catherine Laprise ; Said Assou ; Jamila Chakir

RATIONALE:

Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood.

OBJECTIVES:

To assess whether BT affects gene signatures in bronchial epithelial cells (BECs).

METHODS:

In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment.

MEASUREMENTS AND MAIN RESULTS:

Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33.

CONCLUSIONS:

These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.

项与 S100A1 相关的新闻（医药）

2022-12-01

·生物制药小编

BMS终止历时七年基因疗法合作，AAV治心衰要被放弃？

上周批准的B型血友病基因疗法Hemgenix（350万美元，约合2500万元）又又又一次刷新了史上最贵药物的世界纪录。而正当CSL Behring和uniQure正在为Hemgenix的成功获批而欣喜之时，uniQure却在一份11月28日向美国证券交易委员会披露的文件中表示，百时美施贵宝（BMS）方面做出决定，将在2023年2月21日终止与uniQure方面已经维持了7年，价值10亿美元，以充血性心力衰竭为方向的基因治疗战略合作。不过，在提交的文件中，uniQure没有透露BMS选择终止协议的原因。这项合作最初始于2015年，那时的合作最初集中在一项基因S100A1上，这是一种钙结合蛋白，S100A1是心脏功能的主要调节因子，可通过SERCA2a、PLN、RyR2等多种途径发挥其调控钙循环的功能，在充血性心力衰竭模型中显示出恢复大部分心脏功能的潜力。而通过递送S100A1-AAV有治疗心力衰竭疾病的潜力。随后双方在2020年对协议设计的付款事宜，合作项目，排他性问题进行了修订，从现在来看，这些合作项目总共涉及了uniQure管线中未披露的四个项目。BMS的放弃虽然未曾说明原因，但也一定程度上打出了一个“问号”：采用基因治疗递送心脏来治疗心衰这件事本身可行吗？基因治疗治心衰的尝试目前基因治疗递送至心衰的主要靶点有：肌质网钙离子ATP酶2a（SERCA2a），腺苷酸环化酶 6（AC6），基质细胞衍生因子1（SDF-1）和S100A1等等，其中进入人体临床且采用AAV的仅有SERCA2a，在安全性方面基因治疗似乎与安慰剂并无差异，但在有效性方面这些基因疗法似乎都遇到了阻碍。以SERCA2a为例，使用AAV治疗心脏的临床开始于Roger J. Hajjar博士领导的使用AAV1递送SERCA2a。（又名MYDICAR）SERCA2a基因过表达可增强肌浆网钙泵逆浓度梯度重新摄取心肌细胞内钙离子，从而改善心肌高钙环境。在广泛小动物，大动物，体外的临床实验中，AAV1-SERCA2a均证明了AAV1改善了心肌收缩性。然而，2007年在患者中开展的I/II a期试验CUPID却并不如人意。尽管早期试验证明有临床事件减少，但2015年随后发布的临床数据表明，AAV1/SERCA2a在测试剂量下并未改善心力衰竭和射血分数降低患者的临床进程，临床也随之终止。这一失败导致了开发MYDICAR的Celladon公司因此一蹶不振，裁员80%，最后不得不选择与Eiger公司合并，而后MYDICAR也遭到“雪藏”。而对于AAV临床失败的原因，研究人员也有对此的解释，在他们检查了不幸死亡或接受心脏移植的受试者的心脏后发现，在分析的组织中几乎没有发现病毒载体基因组，这表明基因转导有缺陷，而不是转基因功能无效，这一结果表明，递送问题仍然是AAV的首要需要解决的问题。以AC6为例，2016年Hammond等人报道了Ad5.hAC6（研发代码RT-100）在心衰患者中的安全性和有效性数据，但其结果并不理想。虽然在心力衰竭患者中冠状动脉内递送Ad5.hAC6似乎是安全的，（基因治疗组和安慰剂组患者均有出现不良事件，其中不良事件指住院或死亡，但两组之间并没有统计学上差异。）但在一些关键指标上Ad5.hAC6的有效性似乎并不足以证明自己。同患者基因治疗组与安慰剂组比较，患者的运动耐量无显著差异。而评价心衰的重要指标射血分数（EF值）在4周时较安慰剂组上升(P<0. 04)，但在12周时EF值又无统计学差异(P = 0. 16)。在住院率方面，基因治疗组患者的住院率为9. 5%，而安慰剂组的住院率为28.6%(P = 0.1)。这些结果似乎表明Ad5（腺病毒）在心脏内递送具有持久性问题，研究人员也在发表论文中认为需要III期临床试验进行摸索。然而，可惜的是，进行该治疗的公司Renova Therapeutics在2019年时以重新评估RT-100的临床开发计划和战略为由撤回了III期临床，从该公司官网也并无后续太多关于RT-100的信息了。以SDF-1为例，表达SDF-1蛋白JVS-100有别于上述两种基因治疗方法，是通过质粒进行治疗的基因疗法。虽然安斯泰来在2018年时与Juventas Therapeutics公司就JVS-100达成了合作协定，然而，JVS-100的I期临床和II临床的数据差异似乎较大，I期临床展现出了6至12个月各项指标的改善，但在II期临床中，15mg 30mg JVS-100以及安慰剂组三组患者的上述指标并没有展现出统计学差异，但是对于心脏功能极差的患者(EF<26% )，在治疗的12个月时其EF值的增加量与安慰剂组比较具有统计学差异，这表明JVS-100由于其机制是通过通过促进心肌细胞的修复达到改善心功能的目的，因此对于心功能更差的患者SDF-1的效果可能更好。而目前，Juventas Therapeutics官网Pipeline上已经没有JVS-100的任何开发计划。小编总结总体而言，BMS终止合作的做法完全在意料之中，两家公司选择合作的2015年本就不是心衰AAV治疗的好时间，毕竟MYDICAR就是那段时间暂停的，隔了7年时间再选择停止，可能是为这没有意义的长跑划下了一个句号。参考来源：https://clinicaltrials.gov/ct2/show/NCT00534703?term=SERCA2a+AAV&draw=2&rank=1Hammond HK, Penny WF, Traverse JH, Henry TD, Watkins MW, Yancy CW, Sweis RN, Adler ED, Patel AN, Murray DR, Ross RS, Bhargava V, Maisel A, Barnard DD, Lai NC, Dalton ND, Lee ML, Narayan SM, Blanchard DG, Gao MH. Intracoronary Gene Transfer of Adenylyl Cyclase 6 in Patients With Heart Failure: A Randomized Clinical Trial. JAMA Cardiol. 2016 May 1;1(2):163-71. doi: 10.1001/jamacardio.2016.0008. PMID: 27437887; PMCID: PMC5535743. 内容来源于网络，如有侵权，请联系删除。

基因疗法引进/卖出

2022-11-29

·BioSpace

BMS Terminates 2015 Gene Therapy Pact with uniQure

Courtesy nitpicker/Shutterstock Bristol Myers Squibb is terminating a seven-year-old gene therapy collaboration to develop potential treatments for congestive heart failure with uniQure N.V. valued at $1 billion. The collaboration, first forged in 2015 and then amended in 2020, will quietly expire on Feb. 21, 2023, uniQure revealed in a filing with the U.S. Securities and Exchange Commission. Headquartered in Amsterdam, uniQure announced BMS opted to end the collaboration rather than extend it or change agreed-upon targets, which had been an option based on the most recent modification of the contract. In the filing, uniQure did not disclose why the pharma giant opted to end the agreement. uniQure noted it would not be liable for any payments to BMS for early termination of the project, something that had been built into the agreement. The company did not disclose any penalties or payments owed by BMS. uniQure said the original investor agreement struck in 2015 remains in force. Tom Malone, senior director of corporate communications at uniQure, told BioSpace the assets that were part of the collaboration with BMS were all early-stage and belong to the larger pharmaceutical company. The 2015 compact was slated to expire by Dec. 1, 2023. Malone said uniQure is of the belief that BMS determined it could not effectively develop those targets in the remaining time. However, he noted that his team is not privy to BMS’s internal evaluations of its programs and does not know the exact reason for their decision to terminate the agreement now. BMS and uniQure first inked their partnership in 2015. The collaboration initially centered on uniQure's S100A1, a calcium sensor that showed potential to restore much of the heart's function in congestive heart failure models. S100A1 is a master regulator of cardiac function. The companies planned to deliver to the target via adeno-associated virus (AAV) gene therapy. A Blip in an Otherwise Strong Season The end of the developmental partnership with BMS comes one week after another uniQure partner posted a regulatory win for a hemophilia B gene therapy. Last week, the FDA approved Hemgenix (etranacogene dezaparvovec-drlb), a one-time gene therapy developed for adults with hemophilia B, the first-such gene therapy approved for the rare clotting disorder. Also this month, the Data Safety Monitoring Board overseeing the Phase Ib/II trial of uniQure's experimental gene therapy for Huntington's disease recommended that patient enrollment in the higher-dose cohort could resume. Enrolment in this cohort was paused in August following reports of suspected unexpected severe adverse reactions in three patients. The company reported that the issues had been resolved. The Phase Ib/II trial is assessing AMT-130, the first-ever AAV gene therapy for Huntington's to enter clinical testing. Data from the U.S. portion of the study is expected to be announced in the second quarter of 2023.

基因疗法上市批准引进/卖出临床研究