Disease Models & Mechanisms最新文献_第6页

The role of the International Society for Stem Cell Research (ISSCR) guidelines in disease modeling. 国际干细胞研究学会（ISSCR）指南在疾病建模中的作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-08 DOI: 10.1242/dmm.050947

Cody Juguilon, Joseph C Wu

引用次数: 0

Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences. 桥小脑发育不全 2a 的人类类器官模型再现了大脑特定区域的大小差异。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-22 DOI: 10.1242/dmm.050740

Theresa Kagermeier, Stefan Hauser, Kseniia Sarieva, Lucia Laugwitz, Samuel Groeschel, Wibke G Janzarik, Zeynep Yentür, Katharina Becker, Ludger Schöls, Ingeborg Krägeloh-Mann, Simone Mayer

{"title":"Human organoid model of pontocerebellar hypoplasia 2a recapitulates brain region-specific size differences.","authors":"Theresa Kagermeier, Stefan Hauser, Kseniia Sarieva, Lucia Laugwitz, Samuel Groeschel, Wibke G Janzarik, Zeynep Yentür, Katharina Becker, Ludger Schöls, Ingeborg Krägeloh-Mann, Simone Mayer","doi":"10.1242/dmm.050740","DOIUrl":"10.1242/dmm.050740","url":null,"abstract":"Pontocerebellar hypoplasia type 2a (PCH2a) is an ultra-rare, autosomal recessive pediatric disorder with limited treatment options. Its anatomical hallmark is hypoplasia of the cerebellum and pons accompanied by progressive microcephaly. A homozygous founder variant in TSEN54, which encodes a tRNA splicing endonuclease (TSEN) complex subunit, is causal. The pathological mechanism of PCH2a remains unknown due to the lack of a model system. Therefore, we developed human models of PCH2a using regionalized neural organoids. We generated induced pluripotent stem cell (iPSC) lines from three males with genetically confirmed PCH2a and subsequently differentiated cerebellar and neocortical organoids. Mirroring clinical neuroimaging findings, PCH2a cerebellar organoids were reduced in size compared to controls starting early in differentiation. Neocortical PCH2a organoids demonstrated milder growth deficits. Although PCH2a cerebellar organoids did not upregulate apoptosis, their stem cell zones showed altered proliferation kinetics, with increased proliferation at day 30 and reduced proliferation at day 50 compared to controls. In summary, we generated a human model of PCH2a, providing the foundation for deciphering brain region-specific disease mechanisms. Our first analyses suggest a neurodevelopmental aspect of PCH2a.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733665","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

Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus. 对糖尿病猪肺的多组学分析揭示了糖尿病肺部并发症的分子机理。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-23 DOI: 10.1242/dmm.050650

Bachuki Shashikadze, Florian Flenkenthaler, Elisabeth Kemter, Sophie Franzmeier, Jan B Stöckl, Mark Haid, Fabien Riols, Michael Rothe, Lisa Pichl, Simone Renner, Andreas Blutke, Eckhard Wolf, Thomas Fröhlich

{"title":"Multi-omics analysis of diabetic pig lungs reveals molecular derangements underlying pulmonary complications of diabetes mellitus.","authors":"Bachuki Shashikadze, Florian Flenkenthaler, Elisabeth Kemter, Sophie Franzmeier, Jan B Stöckl, Mark Haid, Fabien Riols, Michael Rothe, Lisa Pichl, Simone Renner, Andreas Blutke, Eckhard Wolf, Thomas Fröhlich","doi":"10.1242/dmm.050650","DOIUrl":"10.1242/dmm.050650","url":null,"abstract":"Growing evidence shows that the lung is an organ prone to injury by diabetes mellitus. However, the molecular mechanisms of these pulmonary complications have not yet been characterized comprehensively. To systematically study the effects of insulin deficiency and hyperglycaemia on the lung, we combined proteomics and lipidomics with quantitative histomorphological analyses to compare lung tissue samples from a clinically relevant pig model for mutant INS gene-induced diabetes of youth (MIDY) with samples from wild-type littermate controls. Among others, the level of pulmonary surfactant-associated protein A (SFTPA1), a biomarker of lung injury, was moderately elevated. Furthermore, key proteins related to humoral immune response and extracellular matrix organization were significantly altered in abundance. Importantly, a lipoxygenase pathway was dysregulated as indicated by 2.5-fold reduction of polyunsaturated fatty acid lipoxygenase ALOX15 levels, associated with corresponding changes in the levels of lipids influenced by this enzyme. Our multi-omics study points to an involvement of reduced ALOX15 levels and an associated lack of eicosanoid switching as mechanisms contributing to a proinflammatory milieu in the lungs of subjects with diabetes mellitus.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426582","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

Functional exploration of copy number alterations in a Drosophila model of triple-negative breast cancer. 果蝇三阴性乳腺癌模型拷贝数改变的功能探索。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-03 DOI: 10.1242/dmm.050191

Jennifer E L Diaz, Vanessa Barcessat, Christian Bahamon, Chana Hecht, Tirtha K Das, Ross L Cagan

{"title":"Functional exploration of copy number alterations in a Drosophila model of triple-negative breast cancer.","authors":"Jennifer E L Diaz, Vanessa Barcessat, Christian Bahamon, Chana Hecht, Tirtha K Das, Ross L Cagan","doi":"10.1242/dmm.050191","DOIUrl":"10.1242/dmm.050191","url":null,"abstract":"Accounting for 10-20% of breast cancer cases, triple-negative breast cancer (TNBC) is associated with a disproportionate number of breast cancer deaths. One challenge in studying TNBC is its genomic profile: with the exception of TP53 loss, most breast cancer tumors are characterized by a high number of copy number alterations (CNAs), making modeling the disease in whole animals challenging. We computationally analyzed 186 CNA regions previously identified in breast cancer tumors to rank genes within each region by likelihood of acting as a tumor driver. We then used a Drosophila p53-Myc TNBC model to identify 48 genes as functional drivers. To demonstrate the utility of this functional database, we established six 3-hit models; altering candidate genes led to increased aspects of transformation as well as resistance to the chemotherapeutic drug fluorouracil. Our work provides a functional database of CNA-associated TNBC drivers, and a template for an integrated computational/whole-animal approach to identify functional drivers of transformation and drug resistance within CNAs in other tumor types.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891809","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

An Irak1-Mecp2 tandem duplication mouse model for the study of MECP2 duplication syndrome. 基于Cas9融合的接近方法产生了一个Irak1-Mecp2串联重复小鼠模型，用于研究MeCP2重复综合征。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-23 DOI: 10.1242/dmm.050528

Eleonora Maino, Ori Scott, Samar Z Rizvi, Wing Suen Chan, Shagana Visuvanathan, Youssif Ben Zablah, Hongbin Li, Ameet S Sengar, Michael W Salter, Zhengping Jia, Janet Rossant, Ronald D Cohn, Bin Gu, Evgueni A Ivakine

{"title":"An Irak1-Mecp2 tandem duplication mouse model for the study of MECP2 duplication syndrome.","authors":"Eleonora Maino, Ori Scott, Samar Z Rizvi, Wing Suen Chan, Shagana Visuvanathan, Youssif Ben Zablah, Hongbin Li, Ameet S Sengar, Michael W Salter, Zhengping Jia, Janet Rossant, Ronald D Cohn, Bin Gu, Evgueni A Ivakine","doi":"10.1242/dmm.050528","DOIUrl":"10.1242/dmm.050528","url":null,"abstract":"MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of the MECP2 locus and its surrounding genes, including IRAK1. Current MDS mouse models involve transgenic expression of MECP2 only, limiting their applicability to the study of the disease. Herein, we show that an efficient and precise CRISPR/Cas9 fusion proximity-based approach can be utilized to generate an Irak1-Mecp2 tandem duplication mouse model ('Mecp2 Dup'). The Mecp2 Dup mouse model recapitulates the genomic landscape of human MDS by harboring a 160 kb tandem duplication encompassing Mecp2 and Irak1, representing the minimal disease-causing duplication, and the neighboring genes Opn1mw and Tex28. The Mecp2 Dup model exhibits neuro-behavioral abnormalities, and an abnormal immune response to infection not previously observed in other mouse models, possibly owing to Irak1 overexpression. The Mecp2 Dup model thus provides a tool to investigate MDS disease mechanisms and develop potential therapies applicable to patients.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330578","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

The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome. 在巨噬细胞活化综合征模型中，NLRP3 炎性体对 IL-18 的产生至关重要。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-30 DOI: 10.1242/dmm.050762

Tara A Gleeson, Christina Kaiser, Catherine B Lawrence, David Brough, Stuart M Allan, Jack P Green

{"title":"The NLRP3 inflammasome is essential for IL-18 production in a murine model of macrophage activation syndrome.","authors":"Tara A Gleeson, Christina Kaiser, Catherine B Lawrence, David Brough, Stuart M Allan, Jack P Green","doi":"10.1242/dmm.050762","DOIUrl":"10.1242/dmm.050762","url":null,"abstract":"Hyperinflammatory disease is associated with an aberrant immune response resulting in cytokine storm. One such instance of hyperinflammatory disease is known as macrophage activation syndrome (MAS). The pathology of MAS can be characterised by significantly elevated serum levels of interleukin-18 (IL-18) and interferon gamma (IFNγ). Given the role for IL-18 in MAS, we sought to establish the role of inflammasomes in the disease process. Using a murine model of CpG-oligonucleotide-induced MAS, we discovered that the expression of the NLRP3 inflammasome was increased and correlated with IL-18 production. Inhibition of the NLRP3 inflammasome or the downstream caspase-1 prevented MAS-mediated upregulation of IL-18 in the plasma but, interestingly, did not alleviate key features of hyperinflammatory disease including hyperferritinaemia and splenomegaly. Furthermore blockade of IL-1 receptor with its antagonist IL-1Ra did not prevent the development of CpG-induced MAS, despite being clinically effective in the treatment of MAS. These data demonstrate that, during the development of MAS, the NLRP3 inflammasome was essential for the elevation in plasma IL-18 - a key cytokine in clinical cases of MAS - but was not a driving factor in the pathogenesis of CpG-induced MAS.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11317095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075521","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

Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders. Taf1 基因敲除对胚胎雄性小鼠是致命的，杂合子雌性小鼠表现出体重和运动障碍。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-10 DOI: 10.1242/dmm.050741

Elisa M Crombie, Andrea J Korecki, Karen Cleverley, Bethany A Adair, Thomas J Cunningham, Weaverly Colleen Lee, Tess C Lengyell, Cheryl Maduro, Victor Mo, Liam M Slade, Ines Zouhair, Elizabeth M C Fisher, Elizabeth M Simpson

{"title":"Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.","authors":"Elisa M Crombie, Andrea J Korecki, Karen Cleverley, Bethany A Adair, Thomas J Cunningham, Weaverly Colleen Lee, Tess C Lengyell, Cheryl Maduro, Victor Mo, Liam M Slade, Ines Zouhair, Elizabeth M C Fisher, Elizabeth M Simpson","doi":"10.1242/dmm.050741","DOIUrl":"10.1242/dmm.050741","url":null,"abstract":"The TATA box-binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of the basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in human males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked dystonia-parkinsonism, a neurodegenerative disorder. However, this field has lacked a genetic mouse model of TAF1 disease to explore its mechanism in mammals and treatments. Here, we generated and validated a conditional cre-lox allele and the first ubiquitous Taf1 knockout mouse. We discovered that Taf1 deletion in male mice was embryonically lethal, which may explain why no null variants have been identified in humans. In the brains of Taf1 heterozygous female mice, no differences were found in gross structure, overall expression and protein localisation, suggesting extreme skewed X inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting that a small subset of neurons was negatively impacted by Taf1 loss. Finally, this new mouse model may be a future platform for the development of TAF1 disease therapeutics.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11261634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158163","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

Biological resilience in health and disease. 健康和疾病中的生物复原力。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-25 DOI: 10.1242/dmm.050799

Helen Weavers

引用次数: 0

The value of slow-burning science: an interview with Peter Friedl and Bettina Weigelin. 慢热科学的价值：彼得-弗里德尔和贝蒂娜-魏格林访谈录。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-31 DOI: 10.1242/dmm.052037

Peter Friedl, Bettina Weigelin

引用次数: 0

Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma. YES驱动的转移性和增殖性肝细胞癌的合成小鼠模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-25 DOI: 10.1242/dmm.050553

Laure Voisin, Marjorie Lapouge, Marc K Saba-El-Leil, Melania Gombos, Joaquim Javary, Vincent Q Trinh, Sylvain Meloche

{"title":"Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.","authors":"Laure Voisin, Marjorie Lapouge, Marc K Saba-El-Leil, Melania Gombos, Joaquim Javary, Vincent Q Trinh, Sylvain Meloche","doi":"10.1242/dmm.050553","DOIUrl":"10.1242/dmm.050553","url":null,"abstract":"Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 7","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757732","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