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Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation

English title Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation
Applicant Allam Ramanjaneyulu
Number 190073
Funding scheme SNSF Professorships
Research institution Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.04.2020 - 31.03.2021
Approved amount 394'978.00
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All Disciplines (3)

Discipline
Pathophysiology
Immunology, Immunopathology
Biochemistry

Keywords (7)

Haematopoiesis; Inflammation; HSCs function and cell cycle; Anemia; Inflammasomes; Erythropoiesis; Specific Translation

Lay Summary (German)

Lead
Ribonuclease Inhibitor (RNH1) regulates haematopoiesis and inflammation. Our project is to understand the detailed molecular mechanism of RNH1 in haematopoiesis and inflammation.
Lay summary

 

Die Hämatopoiese ist ein komplexer Prozess bei dem reife Blutzellen unterschiedlicher Differenzierung aus pluripotenten hämatopoietischen Stammzellen entstehen. Defekte in diesem Prozess können zu hämatologischen Neoplasien führen. Entzündung ist eine stark regulierte Antwort des Immunsystems auf Infektionen, Zellschaden oder exogene Noxen. Neuere Studien legen nahe, dass entzündliche Prozesse die Hämatopoiese beeinflussen, und dass eine chronische Entzündung zur Entstehung von hämatopoietischen Neoplasien beitragen kann. Es ist daher wichtig den Zusammenhang zwischen Hämatopoiese und Entzündung zu verstehen.

 

Der Ribonukleaseinhibitor (RNH1) ist ein zytosolisches Protein, welches Ribonukleasen inhibieren kann. Wir haben kürzlich publiziert, dass RNH1 ein Ribosom assoziiertes Protein ist, und dass es die Erythropoiese kontrolliert indem es die Translation von GATA1 reguliert. Zusätzlich haben wir herausgefunden, dass RNH1 den Zellzyklus von hämatopoietischen Stammzellen kontrolliert und Einfluss auf deren Differenzierung nimmt. RNH1 hemmt zudem Entzündungsprozesse, indem es die Aktivität des Inflammasoms reduziert. Unsere Daten belegen somit, dass RNH1 ein Regulator sowohl der Hämatopoiese als auch der Entzündung ist.

 

Dieser Antrag hat zum Ziel detaillierte molekular-mechanistische Kenntnisse über die Regulation der Inflammasom-Aktivierung, der Ribosomen und der Hämatopoiese durch RNH1 zu erwerben. Speziell soll auch die Rolle von RNH1 in der Diamond-Blackfan Anämie (DBA), eine angeborenes Knochenmarkversagen, und dem 5q- Syndrom, ein Subtyp der myelodysplastischen Syndrome (MDS), untersucht werden. Beide Krankheiten werden durch Mutationen in ribosomalen Proteinen verursacht.

 

Diese Forschung soll zu einem besseren Verständnis von RNH1 in der Hämatopoiese und Entzündung und dadurch zur Entwicklung von neuen therapeutischen Ansätzen in der Behandlung von hämatologischen und entzündlichen Leiden führen.

 

 

Direct link to Lay Summary Last update: 04.05.2020

Responsible applicant and co-applicants

Employees

Publications

Publication
Angiogenin (ANG)—Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease
Sarangdhar Mayuresh Anant, Allam Ramanjaneyulu (2021), Angiogenin (ANG)—Ribonuclease Inhibitor (RNH1) System in Protein Synthesis and Disease, in International Journal of Molecular Sciences, 1287.
LRR protein RNH1 inhibits inflammasome activation through proteasome-mediated degradation of Caspase-1 and is associated with adverse clinical outcomes in COVID-19 patients
BombaciGiuseppe, SarangdharMayuresh, AllamRamanjaneyulu (2021), LRR protein RNH1 inhibits inflammasome activation through proteasome-mediated degradation of Caspase-1 and is associated with adverse clinical outcomes in COVID-19 patients, 1.

Collaboration

Group / person Country
Types of collaboration
Trang Hoang/Institute of Research in Immunology and Cancer, University of Montreal, Canada Canada (North America)
- Publication
- Research Infrastructure
Fabio Martinon/Dept of Biochemistry-University of Lausanne Switzerland (Europe)
- Publication
- Research Infrastructure
Anne Angelillo-Scherre/Klinik für Hämatologie&Hämatologisches Zentrallabor,Inselspital, Bern Switzerland (Europe)
- Publication
- Research Infrastructure
- Exchange of personnel
Pascal Schneider/University of Lausanne Switzerland (Europe)
- Publication
- Research Infrastructure
Vijay G. Sankaran/Harvard Medical School/ USA United States of America (North America)
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
157486 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2015 SNSF Professorships
183721 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2019 SNSF Professorships

Abstract

Ribonuclease Inhibitor (RNH1) is an ubiquitously expressed 50-kDa leucine-rich repeat (LRR) protein. Interestingly, RNH1 gene is absent in lower vertebrates, evolved in amniotes via gene duplication and conserved among mammalian species. As suggested by its name, RNH1 binds to and inhibits pancreatic type ribonucleases. Further, RNH1 contains numerous cysteine residues whose sulfhydryl groups might play key structural roles and protect from oxidative damage. Despite of all these observations, the function of RNH1 in vivo remains unexplored. Recently, we have uncovered important role of RNH1 in erythropoiesis, adult haematopoietic stem cell (HSC) function, ribosomal proteins (RPs) genes translation and inflammasome activation. It is remarkable that, the higher vertebrate specific gene regulating such important functions in mammalian species. Further studies are necessary to understand the molecular mechanisms of RNH1 in these processes.We recently published that RNH1 is important for embryonic development and regulates erythropoiesis by specifically regulating GATA1 mRNA translation. Further work on RNH1 led us to uncover several other important functions. First, RNH1 is essential for HSCs cell cycle regulation and steady state hematopoiesis. Rnh1-deficiency in adult mouse HSCs resulted in an increased number of myeloid cells but decreased lymphoid and erythroid cells, resembling emergency myelopoiesis phenotype. Rnh1-deficiecy increased HSCs cell cycle and decreased their function. Second, we found that RNH1 regulates hematopoietic specific translation. RNH1-deficiency specifically decreased translation in hematopoietic origin cells but not in non-hematopoietic origin. Further, RNH1 binds to ribosomes and regulates RPs gene expression at translation level independent of mTOR signaling. Third, we found that RNH1 negatively regulates inflammasome activation by regulating expression of inflammasome proteins ASC and Caspase-1, suggesting that RNH1 inhibits inflammation. Collectively, these findings have introduced RNH1 as a novel player in hematopoiesis, translation and inflammation.The goal of this proposal is to understand how RNH1 regulates hematopoiesis, specific translation and inflammation. Three complementary research sub-projects were designed to elucidate molecular mechanisms of RNH1 action. The first sub-project will focus on how RNH1 regulates HSCs function and hematopoiesis. The second sub-project will investigate the role of RNH1 in hematopoietic specific translation by focusing on how RNH1 affects RPs gene expression and how it specifically regulates hematopoietic specific translation. We will also investigate a potential role of RNH1 in the pathology of DBA and 5q-syndrome. The third sub-project will study the molecular mechanism of RNH1 in the regulation of inflammasome activation and inflammation. Results from these studies will provide a better understanding of RNH1 in the regulation of hematopoiesis and inflammation. Moreover, our results will aid the development of therapies to treat patients with inflammatory disorders, hematopoietic malignancies and erythropoiesis disorders that are caused by ribosomal deficiency.
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