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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 Departament

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 Departament

5. Mihaela-Loredana Vlad, Ph.D., Postdoc Researcher, Functional Genomics Departament

6. Ioana Madalina Fenyo, Ph.D.,Experienced researcher,Gene Regulation and Molecular Therapies Departament

7. Bogdan Mihai Preda, Ph.D.,Experienced researcher, Stem Cell Biology Department

8. Viorel Iulian Suica, Ph.D., Postdoc Researcher,Proteomics Department

9. Razvan Gheorghita Mares, MD, Ph.D. Student,Department of Functional and Complementary Sciences M2, University of Medicine and Pharmacy of Targu Mures, Targu Mures.

10. Alexandra-Gela Lazar, Ph.D. Student, Functional Genomics Departament

11. Vacant position (Postdoc Researcher)

12.Luminita - Felicia Dudu,Ph.D. Student Researcher, Functional Genomics Departament

13.Razvan-Mihai Fueriu, Ph.D. Student Researcher, Functional Genomics Departament

14.Mirel Adrian Popa, Postdoc Researcher, Proteomics Department

15. Ec. Doina Ghiorghiu,Responsible forfinancial coordination

16. Ing. Paul Claus, Responsible forpublic acquisitions

17. Ref. sp. Liliana Zamfir, Responsible forhuman 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

Sesiunea de lansare a proiectului PNRR CF148 “Development of a novel immunomodulatory therapy against cardiac inflammation in myocardial infarction, myocarditis and sepsis ", 21 Septembrie 2023, ora 14, Aula Institutului de Biologie si Patologie Celulara “Nicolae Simionescu”.

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

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: 15.1 (Q1).