Disease Models & Mechanisms最新文献_第7页

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

The preclinical gap in pancreatic cancer and radiotherapy. 胰腺癌和放射治疗的临床前差距。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-09 DOI: 10.1242/dmm.050703

Mathias Tesson, Jennifer P Morton

引用次数: 0

Exploring host-pathogen interactions in the Dictyostelium discoideum-Mycobacterium marinum infection model of tuberculosis. 探索盘基竹荪-海洋分枝杆菌感染结核病模型中宿主-病原体之间的相互作用。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-07-01 Epub Date: 2024-07-22 DOI: 10.1242/dmm.050698

Sandra Guallar-Garrido, Thierry Soldati

引用次数: 0

Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered cranial neurogenesis. CHDFIDD 小鼠模型的早期胚胎发育显示出面部裂隙和颅神经发生改变。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-06-20 DOI: 10.1242/dmm.050261

Marek Hampl, Nela Jandová, Denisa Lusková, Monika Nováková, Tereza Szotkowská, Štěpán Čada, Jan Procházka, Jiri Kohoutek, Marcela Buchtová

{"title":"Early embryogenesis in CHDFIDD mouse model reveals facial clefts and altered cranial neurogenesis.","authors":"Marek Hampl, Nela Jandová, Denisa Lusková, Monika Nováková, Tereza Szotkowská, Štěpán Čada, Jan Procházka, Jiri Kohoutek, Marcela Buchtová","doi":"10.1242/dmm.050261","DOIUrl":"10.1242/dmm.050261","url":null,"abstract":"CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD) is associated with mutations in the CDK13 gene encoding transcription-regulating cyclin-dependent kinase 13 (CDK13). Here, we focused on the development of craniofacial structures and analyzed early embryonic stages in CHDFIDD mouse models, with one model comprising a hypomorphic mutation in Cdk13 and exhibiting cleft lip/palate, and another model comprising knockout of Cdk13, featuring a stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically expressed at high levels in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13 deficiency leads to development of hypoplastic branches of the trigeminal nerve including the maxillary branch. Additionally, we detected significant changes in the expression levels of genes involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes in the expression pattern of other key face-specific genes (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in the regulation of craniofacial morphogenesis.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11212636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174107","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 and therapeutic insights from animal modeling of fusion-driven pediatric soft tissue sarcomas. 从融合驱动的小儿软组织肉瘤动物模型中获得生物学和治疗学启示。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-06-25 DOI: 10.1242/dmm.050704

Jack P Kucinski, Delia Calderon, Genevieve C Kendall

{"title":"Biological and therapeutic insights from animal modeling of fusion-driven pediatric soft tissue sarcomas.","authors":"Jack P Kucinski, Delia Calderon, Genevieve C Kendall","doi":"10.1242/dmm.050704","DOIUrl":"10.1242/dmm.050704","url":null,"abstract":"Survival for children with cancer has primarily improved over the past decades due to refinements in surgery, radiation and chemotherapy. Although these general therapies are sometimes curative, the cancer often recurs, resulting in poor outcomes for patients. Fusion-driven pediatric soft tissue sarcomas are genetically defined by chromosomal translocations that create a chimeric oncogene. This distinctive, almost 'monogenic', genetic feature supports the generation of animal models to study the respective diseases in vivo. This Review focuses on a subset of fusion-driven pediatric soft tissue sarcomas that have transgenic animal tumor models, which includes fusion-positive and infantile rhabdomyosarcoma, synovial sarcoma, undifferentiated small round cell sarcoma, alveolar soft part sarcoma and clear cell sarcoma. Studies using the animal models of these sarcomas have highlighted that pediatric cancers require a specific cellular state or developmental stage to drive tumorigenesis, as the fusion oncogenes cause different outcomes depending on their lineage and timing of expression. Therefore, understanding these context-specific activities could identify targetable activities and mechanisms critical for tumorigenesis. Broadly, these cancers show dependencies on chromatin regulators to support oncogenic gene expression and co-opting of developmental pathways. Comparative analyses across lineages and tumor models will further provide biological and therapeutic insights to improve outcomes for these children.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141445875","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

Face-valid phenotypes in a mouse model of the most common mutation in EEF1A2-related neurodevelopmental disorder. 与 EEF1A2 相关的神经发育障碍中最常见突变 E122K 小鼠模型的面部有效表型。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-02-02 DOI: 10.1242/dmm.050501

Grant F Marshall, Melissa Fasol, Faith C J Davies, Matthew Le Seelleur, Alejandra Fernandez Alvarez, Cavan Bennett-Ness, Alfredo Gonzalez-Sulser, Catherine M Abbott

{"title":"Face-valid phenotypes in a mouse model of the most common mutation in EEF1A2-related neurodevelopmental disorder.","authors":"Grant F Marshall, Melissa Fasol, Faith C J Davies, Matthew Le Seelleur, Alejandra Fernandez Alvarez, Cavan Bennett-Ness, Alfredo Gonzalez-Sulser, Catherine M Abbott","doi":"10.1242/dmm.050501","DOIUrl":"10.1242/dmm.050501","url":null,"abstract":"De novo heterozygous missense mutations in EEF1A2, encoding neuromuscular translation-elongation factor eEF1A2, are associated with developmental and epileptic encephalopathies. We used CRISPR/Cas9 to recapitulate the most common mutation, E122K, in mice. Although E122K heterozygotes were not observed to have convulsive seizures, they exhibited frequent electrographic seizures and EEG abnormalities, transient early motor deficits and growth defects. Both E122K homozygotes and Eef1a2-null mice developed progressive motor abnormalities, with E122K homozygotes reaching humane endpoints by P31. The null phenotype is driven by progressive spinal neurodegeneration; however, no signs of neurodegeneration were observed in E122K homozygotes. The E122K protein was relatively stable in neurons yet highly unstable in skeletal myocytes, suggesting that the E122K/E122K phenotype is instead driven by loss of function in muscle. Nevertheless, motor abnormalities emerged far earlier in E122K homozygotes than in nulls, suggesting a toxic gain of function and/or a possible dominant-negative effect. This mouse model represents the first animal model of an EEF1A2 missense mutation with face-valid phenotypes and has provided mechanistic insights needed to inform rational treatment design.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10855229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139097501","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

TANGO2 deficiency disease is predominantly caused by a lipid imbalance. TANGO2 缺乏症主要是由脂质失衡引起的。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-06-05 DOI: 10.1242/dmm.050662

Michael Sacher, Jay DeLoriea, Mahsa Mehranfar, Cody Casey, Aaliya Naaz, Chiara Gamberi

{"title":"TANGO2 deficiency disease is predominantly caused by a lipid imbalance.","authors":"Michael Sacher, Jay DeLoriea, Mahsa Mehranfar, Cody Casey, Aaliya Naaz, Chiara Gamberi","doi":"10.1242/dmm.050662","DOIUrl":"10.1242/dmm.050662","url":null,"abstract":"TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11179719/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247287","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

Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström syndrome cardiomyopathy. 雌性 Alms1 基因缺陷小鼠会出现成人阿尔斯特罗姆综合征心肌病的超声心动图特征，但不会出现婴儿阿尔斯特罗姆综合征心肌病的超声心动图特征。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-06-28 DOI: 10.1242/dmm.050561

Eleanor J McKay, Ineke Luijten, Sophie Broadway-Stringer, Adrian Thomson, Xiong Weng, Katya Gehmlich, Gillian A Gray, Robert K Semple

{"title":"Female Alms1-deficient mice develop echocardiographic features of adult but not infantile Alström syndrome cardiomyopathy.","authors":"Eleanor J McKay, Ineke Luijten, Sophie Broadway-Stringer, Adrian Thomson, Xiong Weng, Katya Gehmlich, Gillian A Gray, Robert K Semple","doi":"10.1242/dmm.050561","DOIUrl":"10.1242/dmm.050561","url":null,"abstract":"Alström syndrome (AS), a multisystem disorder caused by biallelic ALMS1 mutations, features major early morbidity and mortality due to cardiac complications. The latter are biphasic, including infantile dilated cardiomyopathy and distinct adult-onset cardiomyopathy, and poorly understood. We assessed cardiac function of Alms1 knockout (KO) mice by echocardiography. Cardiac function was unaltered in Alms1 global KO mice of both sexes at postnatal day 15 (P15) and 8 weeks. At 23 weeks, female - but not male - KO mice showed increased left atrial area and decreased isovolumic relaxation time, consistent with early restrictive cardiomyopathy, as well as reduced ejection fraction. No histological or transcriptional changes were seen in myocardium of 23-week-old female Alms1 global KO mice. Female mice with Pdgfra-Cre-driven Alms1 deletion in cardiac fibroblasts and in a small proportion of cardiomyocytes did not recapitulate the phenotype of global KO at 23 weeks. In conclusion, only female Alms1-deficient adult mice show echocardiographic evidence of cardiac dysfunction, consistent with the cardiomyopathy of AS. The explanation for sexual dimorphism remains unclear but might involve metabolic or endocrine differences between sexes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956789","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

Computational identification of disease models through cross-species phenotype comparison. 通过跨物种表型比较计算识别疾病模型。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-07-01 DOI: 10.1242/dmm.050604

Pilar Cacheiro, Diego Pava, Helen Parkinson, Maya VanZanten, Robert Wilson, Osman Gunes, The International Mouse Phenotyping Consortium, Damian Smedley

{"title":"Computational identification of disease models through cross-species phenotype comparison.","authors":"Pilar Cacheiro, Diego Pava, Helen Parkinson, Maya VanZanten, Robert Wilson, Osman Gunes, The International Mouse Phenotyping Consortium, Damian Smedley","doi":"10.1242/dmm.050604","DOIUrl":"10.1242/dmm.050604","url":null,"abstract":"The use of standardised phenotyping screens to identify abnormal phenotypes in mouse knockouts, together with the use of ontologies to describe such phenotypic features, allows the implementation of an automated and unbiased pipeline to identify new models of disease by performing phenotype comparisons across species. Using data from the International Mouse Phenotyping Consortium (IMPC), approximately half of mouse mutants are able to mimic, at least partially, the human ortholog disease phenotypes as computed by the PhenoDigm algorithm. We found the number of phenotypic abnormalities in the mouse and the corresponding Mendelian disorder, the pleiotropy and severity of the disease, and the viability and zygosity status of the mouse knockout to be associated with the ability of mouse models to recapitulate the human disorder. An analysis of the IMPC impact on disease gene discovery through a publication-tracking system revealed that the resource has been implicated in at least 109 validated rare disease-gene associations over the last decade.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330579","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

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress. ATP1A3 调节蛋白质合成，以确保线粒体在热应激下的稳定性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-07-02 DOI: 10.1242/dmm.050574

Fumihiko Fujii, Hikaru Kanemasa, Sayaka Okuzono, Daiki Setoyama, Ryoji Taira, Kousuke Yonemoto, Yoshitomo Motomura, Hiroki Kato, Keiji Masuda, Takahiro A Kato, Shouichi Ohga, Yasunari Sakai

{"title":"ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.","authors":"Fumihiko Fujii, Hikaru Kanemasa, Sayaka Okuzono, Daiki Setoyama, Ryoji Taira, Kousuke Yonemoto, Yoshitomo Motomura, Hiroki Kato, Keiji Masuda, Takahiro A Kato, Shouichi Ohga, Yasunari Sakai","doi":"10.1242/dmm.050574","DOIUrl":"10.1242/dmm.050574","url":null,"abstract":"Pathogenic variants in ATP1A3, the gene encoding the α3 subunit of the Na+/K+-ATPase, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerated symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as Eif4g (encoded by Eif4g1), Pabpc1 and Fmrp (encoded by Fmr1), in mouse Neuro2a cells. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C variant of human ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 (encoded by Rps6) and increased susceptibility to heat stress. In agreement with these findings, induced pluripotent stem cells (iPSCs) from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient-derived iPSCs showed lower calcium influxes in responses to stimulation with ATP than those in control iPSCs. These data indicate that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes in patients with the p.R756C variant among a variety of ATP1A3-related disorders.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158162","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