{"id":"https://openalex.org/G4805474792","display_name":"What are the pathomechanisms underlying cardiovascular anomalies in \u201cSMAD4pathies\u201d?","description":"The transcription factor SMAD4 is is the only shared partner of two signalling pathways (TGF\u00df and BMP), and as such, it will play a key role in the balance of these two pathways. SMAD4 mutations have been involved in three cardiovascular diseases that we will call SMAD4pathies: 1) Hereditary haemorrhagic telangiectasia (HHT), a vascular disorder with epitaxies and arteriovenous malformations, 2) the Myhre syndrome (MS), a developmental disorder with cardiomyopathy, septal defects, and aortic coarctation and 3) Thoracic aortic aneurysm and dissection (TAAD) which is a life-threatening disease characterized by an enlargement of the aortic wall. These SMAD4 mutations can either be found all over the gene in HHT or in a specific localization in MS. Our work suggests that MS SMAD4 mutations lead to a gain of function (GOF) through monoubiquitination. Conversely, the SMAD4 mutation described in TAAD has been proposed to lead to a loss of function (LOF) due to polyubiquitination. In HHT, our working hypothesis would be that of a LOF in accordance to the ACVRL1 and ENG mutations found in HHT. Together, these data support that SMAD4 mutations are directly linked to cardiovascular diseases, however the role of SMAD4 in the development of these diseases is not known. The aim of this ambitious project is to decipher the role of SMAD4 in these three diseases. Throughout the project, we will use state-of-the-art approaches to answer the following questions: 1) Can we identify new SMAD4 mutations using genomic approaches in HHT and TAAD? (task 1-2), 2) How does SMAD4 mediate distinct TGF\u00df/BMP signalling pathways? For this we will isolate/generate primary SMAD4 mutated cells from these 3 diseases (task3), identify their functional significance (task 4), define whether SMAD4 mutations are LOF or GOF in each disease (task 5), identify the specific cellular transcriptomic profile related to each disease (tasks 6-7), 3) How do SMAD4 mutations in vivo affect the cardiovascular system? for this, we will analyse the cardiac phenotype of the MS KI mouse model (CMVCre;Smad4I500/+) and challenge it with an aortic dissection model (tasks 8 and 9). This project is based on strong preliminary results: 1) We have identified in TAAD 3 new very rare variants of SMAD4. 2) We have identified 31 HHT cases with SMAD4 mutations among which, 9 unpublished SMAD4 mutations. 3) We have generated a CMVCre;Smad4+/ile500 KI mouse model for the MS. As expected this mutation leads to an increase in SMAD4 expression and our preliminary results support that this mouse model mimics the MS phenotype at the skeletal, ocular and heart levels. The deliverables of this project are: new SMAD4 mutations and new genes in a TAAD and HHT and analysis of the link between HHT and TAAD, generation of cells carrying SMAD4 mutations (vascular smooth muscle cells (VSMCs), endothelial cells (ECs) and CRISPR-Cas9 modified fibroblasts), functional characterization of SMAD4 mutations (GOF versus LOF), roles of the BMP versus TGF\u00df signalling in SMAD4pathies and in particular in MS, new direct and indirect target genes of SMAD4 in cells carrying SMAD4 mutations (RNA- and ChIP-Seq analyses) and characterization of the KI mouse model for MS and its susceptibility to develop TAAD. This collaborative research project involves two teams with highly complementary and synergistic skills pooled to reach the project\u2019s objectives. The team of C. Le Goff in Paris and of S. Bailly in Grenoble are internationally recognized for their genetic findings in TAAD and MS and in TGF\u00df/BMP signalling in vascular remodelling in HHT, respectively. In conclusion, our ambition is to generate three distinct SMAD4 related gene signatures and to understand the impaired biological functions in a disease specific context. A better knowledge of these SMAD4pathies will offer novel perspectives in the management and treatment of these patients.","funder_award_id":"ANR-20-CE14-0002","funder":{"id":"https://openalex.org/F4320320883","display_name":"Agence Nationale de la Recherche","doi":"10.13039/501100001665"},"funded_outputs":["https://openalex.org/W3179284246","https://openalex.org/W4200021203","https://openalex.org/W4365150372","https://openalex.org/W4378745514","https://openalex.org/W4391420568","https://openalex.org/W4391824273","https://openalex.org/W4393951018","https://openalex.org/W4403984010","https://openalex.org/W4413361476","https://openalex.org/W7218693156"],"funded_outputs_count":10,"parent_awards":[],"sub_awards":[],"sub_awards_count":0,"amount":479902.4,"currency":"EUR","amount_usd":588888.24,"amount_usd_basis":"daily_rate","recipients":[],"recipient_countries":[],"recipient_regions":[],"research_scope":{"is_research":true,"basis":"funder_default","tier":1},"funding_type":"research","funder_scheme":"AAPG2020","start_date":"2021-01-01","end_date":null,"start_year":2021,"end_year":null,"landing_page_url":"https://anr.fr/Projet-ANR-20-CE14-0002","doi":null,"provenance":"anr_opendata","lead_investigator":{"given_name":"Carine","family_name":"LE GOFF","orcid":"https://orcid.org/0000-0002-7788-708X","role_start":null,"affiliation":{"name":"Laboratoire de recherche vasculaire translationnelle","country":"France","ids":[{"id":"201420730B","type":"rnsr","asserted_by":"anr"}]},"author":null,"institutions":[]},"co_lead_investigator":null,"investigators":null,"works_api_url":"https://api.openalex.org/works?filter=awards.id:G4805474792","primary_topic":{"id":"https://openalex.org/T12199","display_name":"Vascular Anomalies and Treatments","score":0.9529,"subfield":{"id":"https://openalex.org/subfields/2716","display_name":"Genetics (clinical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T12199","display_name":"Vascular Anomalies and Treatments","score":0.9529,"subfield":{"id":"https://openalex.org/subfields/2716","display_name":"Genetics (clinical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}}],"institution_awarded":[],"updated_date":"2026-11-05T03:01:09.000Z","created_date":"2026-09-10T23:08:02.000Z"}