JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.186344
Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau V Vo, Timothy Y Huang, Charles Spruck, Richard L Carpenter, Y Alan Wang, Q Richard Lu, Kenneth P Nephew, Jia Shen
{"title":"SUV39H1 maintains cancer stem cell chromatin state and properties in glioblastoma.","authors":"Chunying Li, Qiqi Xie, Sugata Ghosh, Bihui Cao, Yuanning Du, Giau V Vo, Timothy Y Huang, Charles Spruck, Richard L Carpenter, Y Alan Wang, Q Richard Lu, Kenneth P Nephew, Jia Shen","doi":"10.1172/jci.insight.186344","DOIUrl":"10.1172/jci.insight.186344","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most lethal brain cancer, with GBM stem cells (GSCs) driving therapeutic resistance and recurrence. Targeting GSCs offers a promising strategy for preventing tumor relapse and improving outcomes. We identify SUV39H1, a histone-3, lysine-9 methyltransferase, as critical for GSC maintenance and GBM progression. SUV39H1 is upregulated in GBM compared with normal brain tissues, with single-cell RNA-seq showing its expression predominantly in GSCs due to super-enhancer-mediated activation. Knockdown of SUV39H1 in GSCs impaired their proliferation and stemness. Whole-cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq data, we further demonstrated that knockdown of SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Chaetocin, an SUV39H1 inhibitor, mimics the effects of SUV39H1 knockdown, reducing GSC stemness and sensitizing cells to temozolomide, a standard GBM chemotherapy. In a patient-derived xenograft model, targeting SUV39H1 inhibits GSC-driven tumor growth. Clinically, high SUV39H1 expression correlates with poor glioma prognosis, supporting its relevance as a therapeutic target. This study identifies SUV39H1 as a crucial regulator of GSC maintenance and a promising therapeutic target to improve GBM treatment and patient outcomes.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.171783
Vasantha L Kolachala, Sushma Chowdary Maddipatla, Shanta Murthy, Yeonjoo Hwang, Anne F Dodd, Garima Sharma, Sachith Munasinghe, Ranjit Singh Pelia, Suresh Venkateswaran, Murugadas Anbazhagan, Tarun Koti, Navdeep Jhita, Gaurav N Joshi, Chrissy A Lopez, Duke Geem, Hong Yin, David J Cutler, Peng Qiu, Jason D Matthews, Subra Kugathasan
{"title":"Altered inflammatory mucosal signatures within their spatial and cellular context during active ileal Crohn's disease.","authors":"Vasantha L Kolachala, Sushma Chowdary Maddipatla, Shanta Murthy, Yeonjoo Hwang, Anne F Dodd, Garima Sharma, Sachith Munasinghe, Ranjit Singh Pelia, Suresh Venkateswaran, Murugadas Anbazhagan, Tarun Koti, Navdeep Jhita, Gaurav N Joshi, Chrissy A Lopez, Duke Geem, Hong Yin, David J Cutler, Peng Qiu, Jason D Matthews, Subra Kugathasan","doi":"10.1172/jci.insight.171783","DOIUrl":"10.1172/jci.insight.171783","url":null,"abstract":"<p><p>Crohn's disease (CD) involves a complex intestinal microenvironment driven by chronic inflammation. While single-cell RNA sequencing has provided valuable insights into this biology, the spatial context is lost during single-cell preparation of mucosal biopsies. To deepen our understanding of the distinct inflammatory signatures of CD and overcome the limitations of single-cell RNA sequencing, we combined spatial transcriptomics of frozen CD surgical tissue sections with single-cell transcriptomics of ileal CD mucosa. Coexpressed genes and cell-cell communication from single-cell analyses and factorized genes from spatial transcriptomics revealed overlapping pathways affected in inflamed CD, like antigen presentation, phagosome activity, cell adhesion, and extracellular matrix. Within the pathways, early epithelial cells showed evidence of significant changes in gene expression and subtype composition, while spatial mapping revealed the location of the events, particularly antigen presentation from epithelial cells in the base of the crypt. Furthermore, we identified early epithelial cells as a potential mediator of the MHC class II pathway during inflammation, which we validated by spatial transcriptomics cell subtype deconvolution. Therefore, the inflammation from CD appears to change the types of interactions detectable between epithelial cells with immune and mesenchymal cells, likely promoting the conditions for more macrophage infiltration into these inflammatory microdomains.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Involvement of lncRNA MIR205HG in idiopathic pulmonary fibrosis and IL-33 regulation via Alu elements.","authors":"Tsuyoshi Takashima, Chao Zeng, Eitaro Murakami, Naoko Fujiwara, Masaharu Kohara, Hideki Nagata, Zhaozu Feng, Ayako Sugai, Yasue Harada, Rika Ichijo, Daisuke Okuzaki, Satoshi Nojima, Takahiro Matsui, Yasushi Shintani, Gota Kawai, Michiaki Hamada, Tetsuro Hirose, Kazuhiko Nakatani, Eiichi Morii","doi":"10.1172/jci.insight.187172","DOIUrl":"10.1172/jci.insight.187172","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) causes remodeling of the distal lung. Pulmonary remodeling is histologically characterized by fibrosis, as well as appearance of basal cells; however, the involvement of basal cells in IPF remains unclear. Here, we focus on the long noncoding RNA MIR205HG, which is highly expressed in basal cells, using RNA sequencing. Through RNA sequencing of genetic manipulations using primary cells and organoids, we discovered that MIR205HG regulates IL-33 expression. Mechanistically, the AluJb element of MIR205HG plays a key role in IL-33 expression. Additionally, we identified a small molecule that targets the AluJb element, leading to decreased IL-33 expression. IL-33 is known to induce type 2 innate lymphoid cells (ILC2s), and we observed that MIR205HG expression was positively correlated with the number of ILC2s in patients with IPF. Collectively, these findings provide insights into the mechanisms by which basal cells contribute to IPF and suggest potential therapeutic targets.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Metabolic shifts in tryptophan pathways during acute pancreatitis infections.","authors":"Daosheng Wang, Silei Sun, Qianli Zhao, Bing Zhao, Li Ma, Tongxuan Su, Lili Xu, Menglu Gui, Dan Xu, Wei Chen, Yu Zeng, Yining Shen, Yiyue Liu, Cen Jiang, Qi Ni, Yingchao Cui, Yide Lu, Qiuya Lu, Danfeng Dong, Yibing Peng, Enqiang Mao","doi":"10.1172/jci.insight.186745","DOIUrl":"10.1172/jci.insight.186745","url":null,"abstract":"<p><p>Infectious complications (ICs) in acute pancreatitis (AP) are primarily driven by intestinal bacterial translocation, significantly increasing mortality and hospital stays. Despite this, the role of the gut microenvironment, particularly its metabolic aspects, in AP remains poorly understood. In this study, we investigated a cohort of patients with AP, and conducted supplemental murine studies, to explore the relationship between the gut metabolome and the development of ICs. Metabolomic analysis revealed that disruptions in gut tryptophan metabolism - especially reductions in serotonin and indole pathways - are key features associated with IC occurrence. Additionally, elevated plasma levels of tryptophan metabolites within the kynurenine pathway were identified as valuable predictive biomarkers for ICs. Mechanistic studies in murine models demonstrated that an impaired intestinal Th17 response, modulated by these tryptophan metabolites, plays a critical role in IC development. Serotonin supplementation enhanced Th17 responses, reducing IC incidence, while administration of kynurenic acid, a kynurenine metabolite, exacerbated pancreatic infections, potentially through immunosuppressive effects. These findings highlight the pivotal role of tryptophan metabolites in AP pathogenesis, emphasizing their potential as both predictive markers and therapeutic targets in IC management.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.177999
Jean-Michel Paumier, James Zewe, Chiranjit Panja, Melissa R Pergande, Meghana Venkatesan, Eitan Israeli, Shikha Prasad, Natasha Snider, Jeffrey N Savas, Puneet Opal
{"title":"Neurofilament accumulation disrupts autophagy in giant axonal neuropathy.","authors":"Jean-Michel Paumier, James Zewe, Chiranjit Panja, Melissa R Pergande, Meghana Venkatesan, Eitan Israeli, Shikha Prasad, Natasha Snider, Jeffrey N Savas, Puneet Opal","doi":"10.1172/jci.insight.177999","DOIUrl":"10.1172/jci.insight.177999","url":null,"abstract":"<p><p>Neurofilament accumulation is associated with many neurodegenerative diseases, but it is the primary pathology in giant axonal neuropathy (GAN). This childhood-onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that enables neurofilament degradation. Using a combination of genetic and RNA interference approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through 2 mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations attract the chaperone 14-3-3, which is responsible for the proper localization of the key autophagy regulator transcription factor EB (TFEB). We propose that this dual disruption of autophagy contributes to the pathogenesis of other neurodegenerative diseases involving neurofilament accumulations.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.185953
Miguel A Garcia-Knight, J Daniel Kelly, Scott Lu, Michel Tassetto, Sarah A Goldberg, Amethyst Zhang, Jesus Pineda-Ramirez, Khamal Anglin, Michelle C Davidson, Jessica Y Chen, Maya Fortes-Cobby, Sara Park, Ana Martinez, Matthew So, Aidan Donovan, Badri Viswanathan, Eugene T Richardson, David R McIlwain, Brice Gaudilliere, Rachel L Rutishauser, Ahmed Chenna, Christos Petropoulos, Terri Wrin, Steven G Deeks, Glen R Abedi, Sharon Saydah, Jeffrey N Martin, Melissa Briggs Hagen, Claire M Midgley, Michael J Peluso, Raul Andino
{"title":"Circulating neutralizing antibodies and SARS-CoV-2 variant replication following postvaccination infections.","authors":"Miguel A Garcia-Knight, J Daniel Kelly, Scott Lu, Michel Tassetto, Sarah A Goldberg, Amethyst Zhang, Jesus Pineda-Ramirez, Khamal Anglin, Michelle C Davidson, Jessica Y Chen, Maya Fortes-Cobby, Sara Park, Ana Martinez, Matthew So, Aidan Donovan, Badri Viswanathan, Eugene T Richardson, David R McIlwain, Brice Gaudilliere, Rachel L Rutishauser, Ahmed Chenna, Christos Petropoulos, Terri Wrin, Steven G Deeks, Glen R Abedi, Sharon Saydah, Jeffrey N Martin, Melissa Briggs Hagen, Claire M Midgley, Michael J Peluso, Raul Andino","doi":"10.1172/jci.insight.185953","DOIUrl":"10.1172/jci.insight.185953","url":null,"abstract":"<p><p>The effect of preexisting neutralizing antibodies (NAb) on SARS-CoV-2 shedding in postvaccination infection (PVI) is not well understood. We characterized viral shedding longitudinally in nasal specimens in relation to baseline (pre/periinfection) serum NAb titers in 125 participants infected with SARS-CoV-2 variants. Among 68 vaccinated participants, we quantified the effect of baseline NAb titers on maximum viral RNA titers and infectivity duration. Baseline NAbs were higher and targeted a broader range of variants in participants with monovalent ancestral booster vaccinations compared with those with a primary vaccine series. In Delta infections, baseline NAb titers targeting Delta or Wuhan-Hu-1 correlated negatively with maximum viral RNA. Per log10 increase in Delta-targeting baseline NAb IC50, maximum viral load was reduced -2.43 (95% CI: -3.76, -1.11) log10 nucleocapsid copies, and infectious viral shedding was reduced -2.79 (95% CI: -4.99, -0.60) days. Conversely, in Omicron infections (BA.1, BA.2, BA.4, or BA.5), baseline NAb titers against Omicron lineages or Wuhan-Hu-1 did not predict viral outcomes. Our results provide robust estimates of the effect of baseline NAbs on the magnitude and duration of nasal viral replication after PVI (albeit with an unclear effect on transmission) and show how immune escape variants efficiently evade these modulating effects.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.187145
Juliane Schwanbeck, Max Stahnke, Anna Eberlein, Madeleine Goeritzer, Arndt Schulze, Dominique Pernitsch, Dagmar Kolb, Gernot F Grabner, Theda Up Bartolomaeus, Sofia K Forslund, Holger Gerhardt, Gabriele G Schiattarella, Lucia Cocera Ortega, Natalia López-Anguita, Erin E Kershaw, Henrike Maatz, Norbert Hübner, Rudolf Zechner, Anna Foryst-Ludwig, Ulrich Kintscher
{"title":"Endothelial deletion of adipose triglyceride lipase protects against heart failure with preserved ejection fraction.","authors":"Juliane Schwanbeck, Max Stahnke, Anna Eberlein, Madeleine Goeritzer, Arndt Schulze, Dominique Pernitsch, Dagmar Kolb, Gernot F Grabner, Theda Up Bartolomaeus, Sofia K Forslund, Holger Gerhardt, Gabriele G Schiattarella, Lucia Cocera Ortega, Natalia López-Anguita, Erin E Kershaw, Henrike Maatz, Norbert Hübner, Rudolf Zechner, Anna Foryst-Ludwig, Ulrich Kintscher","doi":"10.1172/jci.insight.187145","DOIUrl":"10.1172/jci.insight.187145","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.178631
QiQi Zhou, Liuqing Yang, Zachary T Verne, Benjamin B Zhang, Jeremy Z Fields, Amber T Thacker, G Nicholas Verne
{"title":"Human colonic EVs induce murine enteric neuroplasticity via the lncRNA GAS5/miR-23/NMDA NR2B axis.","authors":"QiQi Zhou, Liuqing Yang, Zachary T Verne, Benjamin B Zhang, Jeremy Z Fields, Amber T Thacker, G Nicholas Verne","doi":"10.1172/jci.insight.178631","DOIUrl":"10.1172/jci.insight.178631","url":null,"abstract":"<p><p>Postinfectious, diarrhea-predominant, irritable bowel syndrome (PI-IBS-D) is difficult to treat owing to its unknown pathophysiology. Extracellular vesicles (EVs) derived from human colon tissue and long noncoding RNAs (lncRNAs), such as growth arrest-specific 5 (GAS5), may play key roles in the pathophysiology of PI-IBS-D. To determine whether altered colonic EV lncRNA signaling leads to gastrointestinal dysfunction and heightened visceral nociception in patients with PI-IBS-D via the GAS5/miR-23ab/NMDA NR2B axis, we conducted translational studies, including those on (a) the role of colonic EV lncRNAs in patients with PI-IBS-D, human colonoids, and PI-IBS-D tissues; (b) i.p. injection of colonic EVs from patients with PI-IBS-D into Rab27a/b-/- mice (P-EV mice) to investigate whether colonic EVs drive visceral hypersensitivity in vivo via the GAS5/miR-23ab/NMDA NR2B axis; and (c) treatment of mice with oligo-miR-23 precursors and anti-GAS5 Vivo-Morpholinos for GAS5/miR-23ab/NMDA NR2B axis mechanisms. Colonic EVs from patients with PI-IBS-D, but not from control participants, demonstrated reduced miR-23a/b expression caused by enhanced GAS5 expression, which drives increased NR2B expression. Intraperitoneal injection of anti-GAS5-Vivo-Morpholino into P-EV mice increased miR-23 levels and decreased NR2B expression and VMR to CD. EVs are internal messengers that alter gastrointestinal function and increase visceral nociception in patients with PI-IBS-D. Strategies to deliver EVs to modulate GAS5/miR-23ab/NMDA NR2B axis signaling may lead to new and innovative treatments for patients with PI-IBS-D.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.","authors":"Takao Ukaji, Daisuke Arai, Harumi Tsutsumi, Ryoya Nakagawa, Fumihiko Matsumoto, Katsuhisa Ikeda, Osamu Nureki, Kazusaku Kamiya","doi":"10.1172/jci.insight.185193","DOIUrl":"10.1172/jci.insight.185193","url":null,"abstract":"<p><p>Mutations in the gap junction β2 (GJB2) gene, which encodes connexin 26, are the leading cause of genetic deafness. These mutations are characterized by the degeneration and fragmentation of gap junctions and gap junction plaques (GJPs) composed of connexin 26. Dominant-negative mutations of GJB2, such as R75W, cause syndromic hearing loss and palmoplantar keratoderma. We previously reported that the R75W mutation, a single-base substitution where C is replaced by T, causes fragmentation of GJPs. Therefore, an adenine base editor (ABE), which enables A-to-G base conversions, can potentially be useful for the treatment of this genetic disease. Here, we report that an all-in-one adeno-associated virus (AAV) vector, which includes a compact ABE (SaCas9-NNG-ABE8e) with broad targeting range, and a sgRNA targeting the R75W mutation in GJB2 corrected this pathogenic mutation and facilitated the recovery of the gap junction intercellular communication network of GJPs. In a transgenic mouse model with the GJB2 R75W mutation, AAV-mediated base editing also restored the fragmented GJPs to orderly outlines in cochlear supporting cells. Our findings suggest that an ABE-based base-editing strategy could be an optimal treatment for the dominant form of GJB2-related hearing loss, GJB2-related skin diseases, and other deafness-related mutations, especially single-base substitutions.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
JCI insightPub Date : 2025-03-10DOI: 10.1172/jci.insight.186070
Fadhl Alakwaa, Vivek Das, Arindam Majumdar, Viji Nair, Damian Fermin, Asim B Dey, Timothy Slidel, Dermot F Reilly, Eugene Myshkin, Kevin L Duffin, Yu Chen, Markus Bitzer, Subramaniam Pennathur, Frank C Brosius, Matthias Kretzler, Wenjun Ju, Anil Karihaloo, Sean Eddy
{"title":"Leveraging complementary multi-omics data integration methods for mechanistic insights in kidney diseases.","authors":"Fadhl Alakwaa, Vivek Das, Arindam Majumdar, Viji Nair, Damian Fermin, Asim B Dey, Timothy Slidel, Dermot F Reilly, Eugene Myshkin, Kevin L Duffin, Yu Chen, Markus Bitzer, Subramaniam Pennathur, Frank C Brosius, Matthias Kretzler, Wenjun Ju, Anil Karihaloo, Sean Eddy","doi":"10.1172/jci.insight.186070","DOIUrl":"10.1172/jci.insight.186070","url":null,"abstract":"<p><p>Chronic kidney diseases (CKDs) are a global health concern, necessitating a comprehensive understanding of their complex pathophysiology. This study explores the use of 2 complementary multidimensional -omics data integration methods to elucidate mechanisms of CKD progression as a proof of concept. Baseline biosamples from 37 participants with CKD in the Clinical Phenotyping and Resource Biobank Core (C-PROBE) cohort with prospective longitudinal outcome data ascertained over 5 years were used to generate molecular profiles. Tissue transcriptomic, urine and plasma proteomic, and targeted urine metabolomic profiling were integrated using 2 orthogonal multi-omics data integration approaches, one unsupervised and the other supervised. Both integration methods identified 8 urinary proteins significantly associated with long-term outcomes, which were replicated in an adjusted survival model using 94 samples from an independent validation group in the same cohort. The 2 methods also identified 3 shared enriched pathways: the complement and coagulation cascades, cytokine-cytokine receptor interaction pathway, and the JAK/STAT signaling pathway. Use of different multiscalar data integration strategies on the same data enabled identification and prioritization of disease mechanisms associated with CKD progression. Approaches like this will be invaluable with the expansion of high-dimension data in kidney diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 5","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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