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Research Interests

Deciphering the role of somatic mutations in DNMT3A and TET2 during clonal hematopoiesis and their implications in inflammatory disease pathogenesis. 

1) Understanding the molecular basis of increased atherosclerosis in patients with gout.

Our laboratory is interested in deciphering the role of somatic mutations during clonal hematopoiesis to illuminate a crucial aspect of how these genetic alterations contribute to the pathogenesis of inflammatory diseases. Clonal hematopoiesis is a condition characterized by the expansion of blood cells from a single dominant clone, which occurs due to mutations in genes involved in cell regulation. DNMT3A and TET2 are the two most mutated genes. DNMT3A and TET2 are key epigenetic regulators involved in DNA methylation and demethylation, respectively, processes that are essential for controlling gene expression. Mutations in these genes disrupt these regulatory mechanisms, leading to altered gene expression profiles that can promote the survival and proliferation of the mutated cells over normal cells. This clonal expansion, while not malignant, has been associated with an increased risk of some inflammatory diseases, such as gout atherosclerosis.  Our data proves that local inflammation induced by MSUc in macrophages promotes atherosclerosis in murine models and is accompanied by systemic activation of Peripheral Blood Mononuclear Cells (PBMCs), Bone Marrow Cells (BMCs), and Kupffer Cells (KCs). Additionally, we discovered that MSUc disrupts DNMT3A and TET2 activity in macrophages to predispose to atherosclerosis by impairing lysosomal function and mitochondrial DNA integrity. Understanding the impact of DNMT3A and TET2 mutations in clonal hematopoiesis not only sheds light on the mechanisms underlying blood cancers but also opens new avenues for researching the molecular links between clonal hematopoiesis and chronic inflammatory diseases, potentially leading to targeted therapies.

2) Unravel the molecular transcriptional program governing trained immunity in macrophages during inflammation.

Our lab is also interested in unraveling the molecular transcriptional program that controls trained immunity in macrophages during inflammation. Our research focuses on understanding the complex set of genetic instructions that enable macrophages to show a long-term response to secondary inflammatory stimulations during inflammatory diseases. Our work demonstrates that this adaptive-like behavior is regulated by epigenetic and metabolic changes induced by the first stimulus, which alter gene expression patterns without changing the DNA sequence. The research into the transcriptional programs at play involves finding specific genes and regulatory networks activated or repressed in macrophages during the training process, how these genetic changes are preserved and recalled upon subsequent challenges, and their impact on the cells’ inflammatory response. By delineating these mechanisms, we aim to uncover new insights into how innate immunity can be harnessed or modulated to improve therapeutic interventions against chronic inflammatory diseases.

3) Investigating the Impact of Human Genetic Variation on Macrophage Responses in Inflammatory Diseases.

Numerous inflammatory conditions show varying prevalences across different ethnic and racial groups, underscoring the need to understand how genetic diversity influences disease susceptibility and progression. Our laboratory aims to explore how differences in human genetics influence the behavior and efficacy of macrophages, during the onset and progression of inflammatory diseases. These variations can affect how macrophages recognize threats, produce signaling molecules, and start the inflammation process. Therefore, understanding the specific genetic factors that contribute to these variations can shed light on why some individuals are more susceptible to certain inflammatory conditions than others, or why they respond differently to treatments. This knowledge could lead to personalized medicine approaches that tailor treatments to an individual’s genetic makeup, potentially improving the effectiveness of therapies for inflammatory diseases.

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Academic & Professional Education

• BSc degree in Biochemistry, University of Navarra, Spain, 2005-2010. 
• Master’s degree in Cell and Developmental Biology, University College London, United Kingdom, 2011-2013. 
• PhD in Molecular Biosciences, Spanish National Cancer Centre, Spain, 2013-2018. 
• Postdoctoral researcher, University of California San Diego, USA, 2019-2024. 
• Assistant Professor, Division of Clinical Immunology and Rheumatology, the University of Alabama at Birmingham, 2024-present.

Honors & Awards

• 2023. CNIO Award for NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation.  
• 2022. Early career investigator grant from the Arthritis National Research Foundation. 
• 2022. Award for Select Presentations of Abstract Research Keynotes at the Gout, Hyperuricemia, and Crystal-Associated Disease network (GCAN).  
• 2022. Travel award to attend to the the Gout, Hyperuricemia, and Crystal-Associated Disease network (GCAN) meeting.  
• 2019–2020. Postdoctoral Fellowship, European Molecular Biology Organization, EMBO.  
• 2018. PhD degree awarded with high honors.  
• 2018. Agüera-Nieto award. Nr5a2 couples differentiation and inflammation in the pancreas.
• 2018. Constantes y vitals award. Nr5a2 couples differentiation and inflammation in the pancreas. 
• 2017. Travel grant to attend to the American Pancreas Association Meeting. NFIC is a novel NR5A2 interactor and regulator of the pancreatic acinar program.  
• 2017. Award of European Pancreatic Club for the best abstract submitted in basic science. NFIC is a novel NR5A2 interactor and regulator of the pancreatic acinar program.  
• 2017. Travel award to attend the European Pancreas Club meeting.  
• 2013-2016. PhD under the Formacion de Personal Investigador (FPI) fellowship granted to Dr. Francisco X. Real by the Spanish Government.  
• 2011-2012. Fundacion para la Juventud Scholarship for Master’s degree. Migration of neural crest cells as model for cancer metastasis.   
• 2009-2010. Beca de Colaboración scholarship for a research internship at the Applied Medical Research Center.  
• 2005-2010. Five consecutive Alumni Navarrensis scholarships for the BSc degree. 

Publications

• M. Alishala., RL. Bryan, I. Cobo. (2024).  A protocol to prepare monosodium urate crystals for in vitro and in vivo studies in mouse and human cells. STAR protocols (accepted). 
• I. Cobo.*, J. Murillo., M. Alishala., S. Calderon., R. Coras., N. Spann., T. Prohaska., P. Alabarse., S. Yeong., CK. Nickl., T. Le., A. Chen., B. Le., A. Vogel., T. Weichhart., J. Fuster., T. Bradstreet., A. Webber., B. Edelson., B. Razani., B. Ebert., R. Taneja., R. Terkeltaub., R. Bryan., M. Guma., C. Glass., *co-corresponding author. (2024). Particle uptake by macrophages triggers bifurcated transcriptional pathways that differentially regulate inflammation and lysosomal gene expression. Immunity (under revision). 
• L. Antonucci., N. Li., A. Duran., I. Cobo., K. Watari., C. Nicoletti., S.P. Nandi., F. Zhu., Y. Zhao., I.  Riahi., M. Tsuda., V. M. Shah., T. Morgan., T. Waugh., L. Caputo., Y. Liu., A. R. Nilsson., H. Xian., J. Todoric., E. Sanchez-Lopez., G. Eibl., E. A. Vucic., M. Krawczyk., Q. Xu., A. M. Lowy., G. Hatzivassiliou., M. Roose-Girma., D. Skowronska-Krawczyk., D. Bar-Sagi., P. Tamayo., Y. Wu., T. C Sears., C. K. Glass, L. B. Alexandrov., P. L. Puri, D. W. Dawson., Y. Hu., M. T. Diaz-Meco., J. Moscat., and M. Karin. Nature Cancer, 2024 (under revision). 
• Y. Abe., E.R. Kofman., M. Almeida., Z. Ouyang., F. Ponte., J.R. Mueller., G. Cruz-Becerra., M. Sakai., T.A. Prohaska., N.J. Spann., (…), I. Cobo., et al. (2023). RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1beta- and RNA-dependent co-activator of osteoclast gene expression. Mol Cell. 10.1016/j.molcel.2023.08.029. 
• I. Cobo., J. Murillo., M. Alishala and M. Guma. ‘Epigenetic and metabolic regulation of macrophages during gout’. Gout Urate Cryst. Depos. Dis. 2023,1(3). 
• I. Cobo., S. Paliwal., C. Bodas., I. Felipe., J. Melia-Aloma., A. Torres., J. Martinez-Villarreal., M. Malumbres., F. Garcia., I. Millan., et al. (2023). NFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation. Nat Commun 14, 3761. 10.1038/s41467-023-39291-x. 
• B.R. Fixsen., C.Z. Han., Y. Zhou., N.J. Spann., P. Saisan., Z. Shen., C. Balak., M. Sakai., I. Cobo., I.R. Holtman., et al. (2023). SALL1 enforces microglia-specific DNA binding and function of SMADs to establish microglia identity. Nat Immunol 24, 1188-1199. 10.1038/s41590-023-01528-8. 
• K. Battis., J.B. Florio., M. Mante., A. Lana., I. Naumann., C. Gauer., V. Lambrecht., S.J. Muller., I. Cobo., B. Fixsen., et al. (2022). CSF1R-Mediated Myeloid Cell Depletion Prolongs Lifespan But Aggravates Distinct Motor Symptoms in a Model of Multiple System Atrophy. J Neurosci 42, 7673-7688. 10.1523/JNEUROSCI.0417-22.2022. 
• M.A. Hoeksema., Z. Shen., I.R. Holtman., A. Zheng., N.J. Spann., I. Cobo., M. Gymrek., and C.K. Glass. (2021). Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4. Sci Adv 7. 10.1126/sciadv.abf9808. 
• A. Torres., B. Pedersen., I. Cobo., R. Ai., R. Coras., J. Murillo-Saich., G. Nygaard., E. Sanchez-Lopez., A. Murphy., W. Wang., et al. (2022). Epigenetic Regulation of Nutrient Transporters in Rheumatoid Arthritis Fibroblast-like Synoviocytes. Arthritis Rheumatol 74, 1159-1171. 10.1002/art.42077. 
• I. Cobo., A. Cheng., J. Murillo-Saich., R. Coras., A. Torres., Y. Abe., A.J. Lana., J. Schlachetzki., R. Liu-Bryan., R. Terkeltaub., et al. (2022). Monosodium urate crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response. Cell Rep 38, 110489. 10.1016/j.celrep.2022.110489. 
• I. Cobo., T. Tanaka., C.K. Glass., and C. Yeang. (2021). Clonal hematopoiesis driven by DNMT3A and TET2 mutations: role in monocyte and macrophage biology and atherosclerotic cardiovascular disease. Curr Opin Hematol. 10.1097/MOH.0000000000000688. 
• I. Cobo., T.N. Tanaka., K. Chandra Mangalhara., A. Lana., C. Yeang., C. Han., J. Schlachetzki., J. Challcombe., B.R. Fixsen., M. Sakai., et al. (2022). DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages. Immunity 55, 1386-1401 e1310. 10.1016/j.immuni.2022.06.022. 
• I. Cobo., M. Iglesias., M. Flandez., C. Verbeke., N. Del Pozo., M. Llorente., R. Lawlor., C. Luchini., B. Rusev., A. Scarpa., and F.X. Real. (2021). Epithelial Nr5a2 heterozygosity cooperates with mutant Kras in the development of pancreatic cystic lesions. J Pathol 253, 174-185. 10.1002/path.5570. 
• V.J. Sanchez-Arevalo Lobo., L.C. Fernandez., E. Carrillo-de-Santa-Pau., L. Richart., I. Cobo., J. Cendrowski., U. Moreno., N. Del Pozo., D. Megias., B. Breant., et al. (2018). c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis. Gut 67, 707-718. 10.1136/gutjnl-2016-312306. 
• I. Cobo., P. Martinelli., M. Flandez., L. Bakiri., M. Zhang., E. Carrillo-de-Santa-Pau., J. Jia., V.J. Sanchez-Arevalo Lobo., D. Megias., I. Felipe., et al. (2018). Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554, 533-537. 10.1038/nature25751. 
• A. Szabo¹., I. Cobo¹., S. Omara., S. McLachlan., R. Keller., and R. Mayor. (2016). The Molecular Basis of Radial Intercalation during Tissue Spreading in Early Development. Dev Cell 37, 213-225. 10.1016/j.devcel.2016.04.008. ¹:equal contributors. 

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