IMMUNOCARD
Cod proiect: CF 148/15.11.2022
Contractul de finantare nr. 760061/23.05.2023
Titlul proiectului: Dezvoltarea unei noi terapii imunomodulatoare împotriva inflamației cardiace în infarctul miocardic, miocardită și sepsis
Project title: Development of a novel immunomodulatory therapy against cardiac inflammation in myocardial infarction, myocarditis and sepsis
Acronimul proiectului/Acronym: IMMUNOCARD
Autoritatea finanţatoare: Comisia Europeană, Ministerul Cercetării, Inovării şi Digitalizării, Planul Național de Redresare și Reziliență al României (PNRR)
Funding authority: The European Commission, Ministry of Research, Innovation and Digitization
Project duration: 01.07.2023 – 30.06.2026
Director de proiect/Project director: Alexandru Schiopu, M.D., Ph.D., Institute of Cellular Biology and Pathology "N. Simionescu", Bucharest, Romania (e-mail: Alexandru.Schiopu@med.lu.se)
Echipa proiectului/ Research team structure
1. Adrian Manea, Ph.D., Experienced researcher, Functional Genomics Department
2. Maya Simionescu, Acad., Ph.D., Experienced researcher, Director
3. Felicia Antohe, Ph.D., Experienced researcher, Proteomics Department
4. Simona-Adriana Manea, Ph.D., Experienced researcher, Functional Genomics Department
5. Mihaela-Loredana Vlad, Ph.D., Postdoc Researcher, Functional Genomics Department
6. Ioana Madalina Fenyo, Ph.D., Experienced researcher, Gene Regulation and Molecular Therapies Department
7. Bogdan Mihai Preda, Ph.D., Experienced researcher, Stem Cell Biology Department
8. Viorel Iulian Suica, Ph.D., Postdoc Researcher, Proteomics Department
9. Mirel Adrian Popa, Postdoc Researcher, Proteomics Department
10. Alexandra-Gela Lazar, Postdoc Researcher, Functional Genomics Department
11. Razvan-Gheorghita Mares, MD, Postdoc Researcher,Department of Functional and Complementary Sciences M2, University of Medicine and Pharmacy of Targu Mures, Targu Mures.
12. Mihaela-Isabela Serbanescu, Postdoc Researcher, Inflammation Department
13. Razvan-Daniel Macarie, Postdoc Researcher, Inflammation Department
14.Luminita - Felicia Dudu, Ph.D. Student Researcher, Functional Genomics Department
15.Razvan-Mihai Fueriu, Ph.D. Student Researcher, Functional Genomics Department
16. Gabriela Dumitrescu, Ph.D. Student Researcher, Functional Genomics Department
17. Ec. Doina Ghiorghiu, Responsible for financial coordination
18. Ec. Maria Tolbaru, Responsible for financial coordination
19. Ing. Paul Claus, Responsible for public acquisitions
20. Ref. sp. Liliana Zamfir, Responsible for human resources
Rezumatul proiectului:
Context. În prezent, nu sunt disponibile tratamente împotriva leziunilor miocardice induse de inflamaţia cardiacă excesiva din infarctul miocardic (IM), miocardita şi sepsis. Alarmina proinflamatoare S100A8/A9 este crescuta în toate aceste boli. Am demonstrat recent ca blocarea S100A8/A9 cu inhibitorul ABR-238901 (ABR) reduce inflamaţia şi îmbunataţeşte funcţia cardiacă la şoarecii cu IM. In studiile noastre preliminare, ABR a avut efecte similare la şoarecii cu miocardita şi sepsis.
Obiective. Ipoteza de baza a proiectului este că S100A8/A9 declansează mecanisme patogene comune in cardiomiopatiile inflamatorii. Scopul nostru experimental este de a caracteriza aceste mecanisme şi de a dezvolta strategii de tratament capabile să previna insuficienţa cardiacă. La pacienti cu IM, ne propunem sa identificăm efectele pe termen lung asupra sistemului imunitar si să definim un tipar imunologic specific pacienţilor cu risc de a dezvolta insuficienţa cardiacă.
Metode. Vom studia influenţa ABR asupra funcţiei cardiace, inflamaţiei, funcţiei mitocondriale, modificarilor epigenetice, apoptozei cardiomiocitare şi fibrozei în modele animale de IM, miocardita şi cardiomiopatie septică. In vitro, vom examina activarea cailor inflamatorii, disfuncţia mitocondrială şi apoptoza declanşata de S100A8/A9 în cardiomiocite, macrofage şi fibroblaşti.Într-o cohortă de pacienţi cu IM, vom analiza formarea autoanticorpilor cardiospecifici şi a markerilor epigenetici caracteristici pentru inducerea imunitaţii antrenate. Vom evalua un grup de mediatori cardiometabolici solubili pentru a detecta parametrii imunologici asociaţi cu o recuperare cardiacă nefavorabilă, masurată prin ecocardiografie la 6 luni post-IM.
Importanţă. O terapie imunomodulatoare eficientă impotriva leziunilor miocardice inflamatorii ar putea reduce riscul de insuficienţă cardiacă la acest grup mare de pacienţi. Sunt necesare metode noi pentru a identifica pacienţii cu risc ridicat care necesită tratamente imunomodulatoare.
Project summary:
Background. We currently have no treatments against the myocardial damage induced by excessive cardiac inflammation in myocardial infarction (MI), myocarditis and sepsis. The potent pro-inflammatory alarmin S100A8/A9 is highly elevated in all these diseases. We have recently shown that S100A8/A9 blockade with the small molecule ABR-238901 (ABR) reduces inflammation and improves cardiac function in mice with MI. In our preliminary studies, ABR had similar effects in mice with autoimmune myocarditis and sepsis.
Aims. We hypothesise that S100A8/A9 triggers common pathogenic mechanisms in inflammatory cardiomyopathies. Our experimental goal is to characterise these mechanisms and to design treatment strategies able to prevent heart failure. In the clinical arm, we aim to identify the long-term effects of MI on the immune system and to define an immunologic signature that identifies patients at risk to develop heart failure.
Methods. We will study the influence of ABR on cardiac function, inflammatory pathways, mitochondrial function, epigenetic modifications, cardiomyocyte apoptosis and fibrosis in animal models of MI, myocarditis and septic cardiomyopathy. In-vitro, we will examine the activation of inflammatory pathways, mitochondrial dysfunction and apoptosis triggered by S100A8/A9 in cardiomyocytes, macrophages and fibroblasts. In a prospective cohort of MI patients, we will analyse the formation of cardio-specific autoantibodies and epigenetic marks characteristic for the induction of trained immunity. We will also assess a panel of soluble cardiometabolic mediators in order to detect immunological patterns associated with a negative of positive cardiac recovery, measured by echocardiography at 6 months post-MI.
Importance. An effective immunomodulatory therapy against inflammatory myocardial damage could reduce the risk of heart failure in this large patient group. Novel methods are needed to identify the high-risk patients requiring immunomodulatory treatments.
Vizibilitatea proiectului
Prezentarea proiectului PNRR CF148 “Development of a novel immunomodulatory therapy against cardiac inflammation in myocardial infarction, myocarditis and sepsis ", în cadrul conferinţei „40th Annual Scientific Session of the Romanian Society for Cell Biology”, 16 Noiembrie 2023, Bucureşti, Academia Română
Comunicat de presa finalizarea proiectului IMMUNOCARD: contribuții la înțelegerea mecanismelor inflamatorii asociate afectării miocardice - „PNRR: Fonduri pentru România modernă și reformată!” - Anuntul Public
Publicaţii/Publications
Peer-review ISI articles:
1. Jakobsson G, Papareddy P, Andersson H, Mulholland M, Bhongir R, Ljungcrantz I, Engelbertsen D, Björkbacka H, Nilsson J, Manea A, Herwald H, Ruiz-Meana M, Rodríguez-Sinovas A, Chew M, Schiopu A. Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction. Critical Care. 2023; 27(1):374. doi: 10.1186/s13054-023-04652-x. Factor de impact: 8.8. https://pmc.ncbi.nlm.nih.gov/articles/PMC10540409/pdf/13054_2023_Article_4652.pdf
2. Ingrid Didriksson, Maria Lengquis, Martin Spångfors, Märta Lefer, Theodor Sievert1, Gisela Lilja, Attila Frigyesi, Hans Friberg, Alexandru Schiopu. Increasing plasma calprotectin (S100A8/ A9) is associated with 12-month mortality and unfavourable functional outcome in critically ill COVID-19 patients. Journal of Intensive Care (2024), 12(1):26, https://doi.org/10.1186/s40560-024-00740-4, Factor de impact: 3.8. https://pmc.ncbi.nlm.nih.gov/articles/PMC11232228/pdf/40560_2024_Article_740.pdf
3. Razvan Gheorghita Mares, Viorel Iulian Suica, Elena Uyy, Raluca Maria Boteanu, Luminita Ivan, Iuliu Gabriel Cocuz, Adrian Horatiu Sabau, Vikas Yadav, Istvan Adorjan Szabo, Ovidiu Simion Cotoi, Mihaela Elena Tomut, Gabriel Jakobsson, Maya Simionescu, Felicia Antohe, Alexandru Schiopu. Short-term S100A8/A9 blockade promotes cardiac neovascularization after myocardial infarction. J Cardiovasc Transl Res. (2024), doi: 10.1007/s12265-024-10542-6, Factor de impact: 2.4. https://pmc.ncbi.nlm.nih.gov/articles/PMC11634919/pdf/12265_2024_Article_10542.pdf
4. Helena Grauen Larsen, Jiangming Sun, Marketa Sjögren, Yan Borné, Gunnar Engström, Peter Nilsson, Marju Orho-Melander, Isabel Goncalves, Jan Nilsson, Olle Melander, Alexandru Schiopu. The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population. Sci Rep. (2024), 14(1):11567, doi: 10.1038/s41598-024-62385-5, Factor de impact: 3.8. https://pmc.ncbi.nlm.nih.gov/articles/PMC11109115/pdf/41598_2024_Article_62385.pdf
5. Troels Yndigegn, Thomas Gu, Helena Grufman, David Erlinge, Arash Mokhtari, Ulf Ekelund, Martin Magnusson, Emma Gustafsson, Jan Nilsson, Isabel Goncalves, Alexandru Schiopu. Elevated carbohydrate antigen 125 (CA125) is associated with incident heart failure and mortality in acute coronary syndrome. ESC Heart Failure (2024), 1-10, doi: 10.1002/ehf2.15037, Factor de impact: 3.2. https://pmc.ncbi.nlm.nih.gov/articles/PMC11631263/pdf/EHF2-11-4325.pdf
6. Baojun Zhong, Ben King, Homa Waziri, Troels Yndigegn, Daniel Engelbertsen, Harry Björkbacka, Jan Nilsson, Isabel Goncalves, Anna M Blom, Alexandru Schiopu. Shedding of membrane complement inhibitors CD59 and CD46 into the circulation is associated with poor prognosis in acute coronary syndrome patients: a cohort study. J Transl Med (2024), Nov 10; 22(1):1011, doi: 10.1186/s12967-024-05781-9, Factor de impact: 7.5. https://pmc.ncbi.nlm.nih.gov/articles/PMC11550518/pdf/12967_2024_Article_5781.pdf
7. Simona-Adriana Manea, Mihaela-Loredana Vlad, Alexandra-Gela Lazar, Horia Muresian, Maya Simionescu, Adrian Manea. SET7 lysine methyltransferase mediates the up-regulation of NADPH oxidase expression, oxidative stress, and NLRP3 inflammasome priming in atherosclerosis. J Transl Med. 2025; 23(1):339. doi: 10.1186/s12967-025-06338-0. Factor de impact: 9.7.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11912627/pdf/12967_2025_Article_6338.pdf
8. Mihaela-Loredana Vlad, Razvan-Gheorghita Mares, Gabriel Jakobsson, Simona-Adriana Manea, Alexandra-Gela Lazar, Mihai Bogdan Preda, Mirel Adrian Popa, Maya Simionescu, Alexandru Schiopu, Adrian Manea. Therapeutic S100A8/A9 inhibition reduces NADPH oxidase expression, reactive oxygen species production and NLRP3 inflammasome priming in the ischemic myocardium. Eur J Pharmacol. 2025; 996:177575. doi: 10.1016/j.ejphar.2025.177575, Factor de impact: 5.7. https://www.sciencedirect.com/science/article/pii/S0014299925003292?via%3Dihub
9. Maria Lengquist, Vera Sundén-Cullberg, Sofie Hyllner1, Hazem Koozi, Anders Larsson, Lisa Mellhammar, Hans Friberg, Alexandru Schiopu, Attila Frigyesi. Calprotectin as a sepsis diagnostic marker in critical care: a retrospective observational study. Sci Rep. 2025; 15(1):15529. doi: 10.1038/s41598-025-95420-0. Factor de impact: 4.08 https://pmc.ncbi.nlm.nih.gov/articles/PMC12049440/pdf/41598_2025_Article_95420.pdf
10. Alexandru Schiopu, Troels Yndigegn, Sara Svedlund, Gayathri Narasimhan, Bi Juin Loong, Vijayalakshmi Varma, Emily L Ongstad, Isabel Goncalves, Anna Collén, Jan Nilsson, Li-Ming Gan. Circulating soluble LOX-1 and patient prognosis after an acute coronary syndrome. Heart. 2025; 0:1–8, heartjnl-2025-326315. doi: 10.1136/heartjnl-2025-326315, Factor de impact: 4.4. https://heart.bmj.com/content/heartjnl/early/2025/09/16/heartjnl-2025-326315.full.pdf
11. Elena Uyy, Viorel-Iulian Suica, Luminita Ivan, Raluca Maria Boteanu, Diana alentina Uta, Elena Georgiana Bernea, Dragos¸ Eugen Georgescu, Ovidiu Chiriac, Maya Simionescu and Felicia Antohe. Dysregulation of circulating damage-associated molecular patterns in diabetic foot syndrome. Front. Immunol., 2026, Volume 17 - 2026, doi.org/10.3389/fimmu.2026.1849387, Factor de impact: 7.
12. Felicia-Luminita Dudu, Razvan-Mihai Fueriu, Gabriel Jakobsson, Mihaela-Loredana Vlad, Alexandra-Gela Lazar, Simona-Adriana Manea, Adrian Manea, Alexandru Schiopu. Induction of murine experimental autoimmune myocarditis - Technical details, implementation and evaluation. Romanian Journal of Cardiology, 2025. 35(3). p.194-204. doi: 10.2478/rjc-2025-0026.
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