{"database":"BioModels","file_versions":[],"scores":null,"additional":{"submitter":["Erzsébet Ravasz Regan"],"curationStatus":["Non-curated"],"modellingApproach":["boolean model"],"levelVersion":["L3V1"],"full_dataset_link":["https://www.ebi.ac.uk/biomodels/MODEL2605070001"],"publication_pubmed":["42190016"],"isPrivate":["false"],"repository":["BioModels"],"modelFormat":["SBML"],"omics_type":["Models"],"tokenised_name":["Deritei2026   SHH driven EMT in COPD wound healing"],"publication_year":["2026"],"submissionId":["MODEL2605070001"],"publication_authors":["Dávid Deritei, Wardatul Jannat Anamika, Anny Xiaobo Zhou, Jeong H Yun, Maor Sauler, Michael H Cho, Edwin K Silverman, Erzsébet Ravasz Regan, Kimberly Glass"],"first_author":["Dávid Deritei"],"publication":["42190016,\n                            Genetic variants near Hedgehog interacting protein (<i>HHIP</i>) have been consistently associated with increased risk for chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. However, <i>HHIP</i>'s role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the Hedgehog pathway and downstream <i>GLI1</i> and <i>GLI2</i> activation. The Hedgehog pathway plays an important role in wound healing, specifically in activating transcription factors that drive the epithelial-mesenchymal transition (EMT), which in its intermediate state (partial EMT) is necessary for the collective movement of cells closing a wound. Herein, we use a systems biology approach to propose a mechanism to explain HHIP's role in faulty epithelial wound healing, which could contribute to the development of emphysema, a key feature of COPD. Using two different Boolean models, we show dysfunctional HHIP results in a lack of negative feedback on GLI, triggering a full EMT, where cells become mesenchymal and do not properly close the wound. We validate these Boolean models with experimental evidence gathered from published scientific literature. Finally, we show evidence supporting our hypothesis in single-cell and single-nucleus RNA-Seq data from different COPD cohorts and <i>Hhip</i> heterozygous knockout mice. Overall, our analyses suggest that aberrant wound healing due to dysfunctional HHIP, combined with chronic epithelial damage through cigarette smoke exposure, may be a primary cause of COPD-associated emphysema.. 22, 123.\n                            Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.\nBiochemistry and Molecular Biology Program, The College of Wooster, Wooster, OH, 44691"],"submitter_mail":["eregan@wooster.edu"],"submitter_affiliation":["Biochemistry and Molecular Biology, Department of Biology, The College of Wooster, Wooster, OH 44691."],"pubmed_abstract":["Genetic variants near Hedgehog interacting protein (<i>HHIP</i>) have been consistently associated with increased risk for chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. However, <i>HHIP</i>'s role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the Hedgehog pathway and downstream <i>GLI1</i> and <i>GLI2</i> activation. The Hedgehog pathway plays an important role in wound healing, specifically in activating transcription factors that drive the epithelial-mesenchymal transition (EMT), which in its intermediate state (partial EMT) is necessary for the collective movement of cells closing a wound. Herein, we use a systems biology approach to propose a mechanism to explain HHIP's role in faulty epithelial wound healing, which could contribute to the development of emphysema, a key feature of COPD. Using two different Boolean models, we show dysfunctional HHIP results in a lack of negative feedback on GLI, triggering a full EMT, where cells become mesenchymal and do not properly close the wound. We validate these Boolean models with experimental evidence gathered from published scientific literature. Finally, we show evidence supporting our hypothesis in single-cell and single-nucleus RNA-Seq data from different COPD cohorts and <i>Hhip</i> heterozygous knockout mice. Overall, our analyses suggest that aberrant wound healing due to dysfunctional HHIP, combined with chronic epithelial damage through cigarette smoke exposure, may be a primary cause of COPD-associated emphysema."],"pubmed_title":["HHIP's dynamic role in epithelial wound healing reveals a potential mechanism of COPD susceptibility."],"pubmed_authors":["Deritei Dávid D, Anamika Wardatul Jannat WJ, Zhou Anny Xiaobo AX, Yun Jeong H JH, Sauler Maor M, Cho Michael H MH, Silverman Edwin K EK, Ravasz Regan Erzsébet E, Glass Kimberly K"],"additional_accession":[]},"is_claimable":false,"name":"Deritei2026 - SHH-driven EMT in COPD wound healing","description":"We modeled the effects of altered Hedgehog signaling on the behavior of lung epithelial cells during the wounding of a cellular monolayer by examining the interplay between EMT, mechanosensing, and\nproliferation in response to icroenvironmental signals near the wound. To do this, we expanded a previously published model of mechanosensitive EMT (MODEL2312140001), which examined the synergistic effect of low cell density, stiff extracellular matrix (ECM), and strong mitogens in driving EMT in the absence of transforming signals such as\nTGFβ. The current expanded model includes a detailed cell cycle control circuit driven\nby growth signaling, integrated with adhesion, contact inhibition, control of EMT by TGFβ or growth signals, migration, as well as apoptosis. We added a Hedgehog signaling module such that it impacts the rest of the network by promoting EMT and survival. The rest of the network, in turn, modulates the SHH signal primarily via C/\nEBPα, a transcription factor required for lung maturation and known to reduce GLI1 expression in lung epithelia. To model the effect of EMT on the underlying ECM, we incorporated the feedback control of key lung alveolar ECM components by\nmatrix metalloproteinases MMP2/7/9. These MMPs lead to basement membrane destruction and interstitial ECM stiffening during EMT.","dates":{"last_modification":"2026-05-08","publication":"2026-07-25","submission":"2026-05-07"},"accession":"MODEL2605070001","cross_references":{"pubmed":["42190016"],"mamo":["MAMO:0000053"],"biomodels__db":["MODEL2605070001"]}}