Disease Models & Mechanisms最新文献_第2页

Comparative transcriptomic analysis of articular cartilage of post-traumatic osteoarthritis models. 创伤后骨关节炎小鼠模型关节软骨的转录组比较分析

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-21 DOI: 10.1242/dmm.050583

Sophie J Gilbert, Jamie Soul, Yao Hao, Hua Lin, Katarzyna A Piróg, Jonathan Coxhead, Krutik Patel, Matt J Barter, David A Young, Emma J Blain

{"title":"Comparative transcriptomic analysis of articular cartilage of post-traumatic osteoarthritis models.","authors":"Sophie J Gilbert, Jamie Soul, Yao Hao, Hua Lin, Katarzyna A Piróg, Jonathan Coxhead, Krutik Patel, Matt J Barter, David A Young, Emma J Blain","doi":"10.1242/dmm.050583","DOIUrl":"10.1242/dmm.050583","url":null,"abstract":"Animal models of post-traumatic osteoarthritis (PTOA) recapitulate the pathological changes observed in human PTOA. Here, skeletally mature C57Bl6 mice were subjected to either rapid-onset non-surgical mechanical rupture of the anterior cruciate ligament (ACL) or to surgical destabilisation of the medial meniscus (DMM). Transcriptome profiling of micro-dissected cartilage at day 7 or day 42 following ACL or DMM procedure, respectively, showed that the two models were comparable and highly correlative. Gene ontology (GO) enrichment analysis identified similarly enriched pathways that were overrepresented by anabolic terms. To address the transcriptome changes more completely in the ACL model, we also performed small RNA sequencing, describing the first microRNA profile of this model. miR-199-5p was amongst the most abundant, yet differentially expressed, microRNAs, and its inhibition in primary human chondrocytes led to a transcriptome response that was comparable to that observed in both human 'OA damaged vs intact cartilage' and murine DMM cartilage datasets. We also experimentally verified CELSR1, GIT1, ECE1 and SOS2 as novel miR-199-5p targets. Together, these data support the use of the ACL rupture model as a non-invasive companion to the DMM model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNA sequencing reveals molecular mechanisms of endometriosis lesion development in mice. RNA 测序揭示了小鼠模型中子宫内膜异位症病变发展的新分子机制。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-23 DOI: 10.1242/dmm.050566

Kavita Panir, John E Schjenken, James Breen, Hon Yeung Chan, Erin Greaves, Sarah A Robertson, M Louise Hull

{"title":"RNA sequencing reveals molecular mechanisms of endometriosis lesion development in mice.","authors":"Kavita Panir, John E Schjenken, James Breen, Hon Yeung Chan, Erin Greaves, Sarah A Robertson, M Louise Hull","doi":"10.1242/dmm.050566","DOIUrl":"10.1242/dmm.050566","url":null,"abstract":"Understanding of molecular mechanisms contributing to the pathophysiology of endometriosis, and upstream drivers of lesion formation, remains limited. Using a C57Bl/6 mouse model in which decidualized endometrial tissue is injected subcutaneously in the abdomen of recipient mice, we generated a comprehensive profile of gene expression in decidualized endometrial tissue (n=4), and in endometriosis-like lesions at Day 7 (n=4) and Day 14 (n=4) of formation. High-throughput mRNA sequencing allowed identification of genes and pathways involved in the initiation and progression of endometriosis-like lesions. We observed distinct patterns of gene expression with substantial differences between the lesions and the decidualized endometrium that remained stable across the two lesion timepoints, and showed similarity to transcriptional changes implicated in human endometriosis lesion formation. Pathway enrichment analysis revealed several immune and inflammatory response-associated canonical pathways, multiple potential upstream regulators, and involvement of genes not previously implicated in endometriosis pathogenesis, including IRF2BP2 and ZBTB10, suggesting novel roles in disease progression. Collectively, the provided data will be a useful resource to inform research on the molecular mechanisms contributing to endometriosis-like lesion development in this mouse model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11524442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Immunometabolism and mitochondria in inflammatory bowel disease: a role for therapeutic intervention? 炎症性肠病中的免疫代谢和线粒体：治疗干预的作用？

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-10-01 Epub Date: 2024-10-17 DOI: 10.1242/dmm.050895

Claire E Adams, Duncan G Rutherford, Gareth R Jones, Gwo-Tzer Ho

引用次数: 0

A prioritization tool for cilia-associated genes and their in vivo resources unveil new avenues for ciliopathy research. 纤毛相关基因优先排序工具及其体内资源为纤毛病研究开辟了新途径。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-12 DOI: 10.1242/dmm.052000

Robert E Van Sciver,Tamara Caspary

引用次数: 0

Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve. GATA6-CXCR7 信号缺陷导致主动脉瓣双瓣。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-10 DOI: 10.1242/dmm.050934

Rebeca Piñeiro-Sabarís,Donal MacGrogan,José Luis de la Pompa

{"title":"Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve.","authors":"Rebeca Piñeiro-Sabarís,Donal MacGrogan,José Luis de la Pompa","doi":"10.1242/dmm.050934","DOIUrl":"https://doi.org/10.1242/dmm.050934","url":null,"abstract":"The cardiac outflow tract (OFT) transiently links the ventricles to the aortic sac and forms the arterial valves. Abnormalities in these valves, such as bicuspid aortic valve (BAV), are common congenital anomalies. GATA6-inactivating variants cause cardiac OFT defects and BAV, but their mechanisms are unclear. We generated Gata6STOP/+ mice using CRISPR-Cas9, which show highly penetrant BAV (70%) and membranous ventricular septal defects (43%). These mice exhibited decreased proliferation and increased ISL1-positive progenitor cells in the OFT, indicating abnormal cardiovascular differentiation. Gata6 deletion with the Mef2cCre driver line recapitulated Gata6STOP/+ phenotypes, indicating a cell-autonomous role for Gata6 in the second heart field. Gata6STOP/+ mice showed reduced OFT length and caliber, associated with deficient cardiac neural crest cell contribution, which may cause valvulo-septal defects. RNA-sequencing analysis showed depletion in pathways related to cell proliferation and migration, highlighting Cxcr7 (also known as Ackr3) as a candidate gene. Reduced mesenchymal cell migration and invasion were observed in Gata6STOP/+ OFT tissue. CXCR7 agonists reduced mesenchymal cell migration and increased invasion in wild-type but not in Gata6STOP/+ explants, indicating the GATA6-dependent role of CXCR7 in OFT development and its potential link to BAV.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

eEF1α2 is required for actin cytoskeleton homeostasis in the aging muscle. eEF1α2 是老化肌肉肌动蛋白细胞骨架平衡所必需的。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-08-29 DOI: 10.1242/dmm.050729

Hidetaka Katow, Hyung Don Ryoo

{"title":"eEF1α2 is required for actin cytoskeleton homeostasis in the aging muscle.","authors":"Hidetaka Katow, Hyung Don Ryoo","doi":"10.1242/dmm.050729","DOIUrl":"10.1242/dmm.050729","url":null,"abstract":"The translation elongation factor eEF1α (eukaryotic elongation factor 1α) mediates mRNA translation by delivering aminoacyl-tRNAs to ribosomes. eEF1α also has other reported roles, including the regulation of actin dynamics. However, these distinct roles of eEF1α are often challenging to uncouple and remain poorly understood in aging metazoan tissues. The genomes of mammals and Drosophila encode two eEF1α paralogs, with eEF1α1 expressed ubiquitously and eEF1α2 expression more limited to neurons and muscle cells. Here, we report that eEF1α2 plays a unique role in maintaining myofibril homeostasis during aging in Drosophila. Specifically, we generated an eEF1α2 null allele, which was viable and showed two distinct muscle phenotypes. In young flies, the mutants had thinner myofibrils in indirect flight muscles that could be rescued by expressing eEF1α1. With aging, the muscles of the mutant flies began showing abnormal distribution of actin and myosin in muscles, but without a change in actin and myosin protein levels. This age-related phenotype could not be rescued by eEF1α1 overexpression. These findings support an unconventional role of Drosophila eEF1α2 in age-related homeostasis of muscle myofibers.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11381931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment. 代谢涟漪效应--解读癌症中的脂质代谢如何与肿瘤微环境相互作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-16 DOI: 10.1242/dmm.050814

Patrick B Jonker, Alexander Muir

{"title":"Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.","authors":"Patrick B Jonker, Alexander Muir","doi":"10.1242/dmm.050814","DOIUrl":"10.1242/dmm.050814","url":null,"abstract":"Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142281733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Axolotl mandible regeneration occurs through mechanical gap closure and a shared regenerative program with the limb. Axolotl 下颌骨的再生是通过机械缝隙闭合和与肢体共享再生程序实现的。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-27 DOI: 10.1242/dmm.050743

Julia Kramer, Rita Aires, Sean D Keeley, Tom Alexander Schröder, Günter Lauer, Tatiana Sandoval-Guzmán

{"title":"Axolotl mandible regeneration occurs through mechanical gap closure and a shared regenerative program with the limb.","authors":"Julia Kramer, Rita Aires, Sean D Keeley, Tom Alexander Schröder, Günter Lauer, Tatiana Sandoval-Guzmán","doi":"10.1242/dmm.050743","DOIUrl":"10.1242/dmm.050743","url":null,"abstract":"The mandible plays an essential part in human life and, thus, defects in this structure can dramatically impair the quality of life in patients. Axolotls, unlike humans, are capable of regenerating their lower jaws; however, the underlying mechanisms and their similarities to those in limb regeneration are unknown. In this work, we used morphological, histological and transcriptomic approaches to analyze the regeneration of lateral resection defects in the axolotl mandible. We found that this structure can regenerate all missing tissues in 90 days through gap minimization, blastema formation and, finally, tissue growth, differentiation and integration. Moreover, transcriptomic comparisons of regenerating mandibles and limbs showed that they share molecular phases of regeneration, that these similarities peak during blastema stages and that mandible regeneration occurs at a slower pace. Altogether, our study demonstrates the existence of a shared regenerative program used in two different regenerating body structures with different embryonic origins in the axolotl and contributes to our understanding of the minimum requirements for a successful regeneration in vertebrates, bringing us closer to understand similar lesions in human mandibles.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Supporting the evolution of infectious disease research. 支持传染病研究的发展。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-10-01 DOI: 10.1242/dmm.052112

Kirsty Hooper

引用次数: 0

Preclinical evaluation of targeted therapies for central nervous system metastases. 中枢神经系统转移瘤靶向疗法的临床前评估。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1242/dmm.050836

Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar

{"title":"Preclinical evaluation of targeted therapies for central nervous system metastases.","authors":"Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar","doi":"10.1242/dmm.050836","DOIUrl":"10.1242/dmm.050836","url":null,"abstract":"The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood-brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0