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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 183721
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 01.04.2019 - 31.03.2020
Approved amount 396'170.00
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All Disciplines (3)

Discipline
Pathophysiology
Immunology, Immunopathology
Biochemistry

Keywords (6)

Specific Translation; Erythropoiesis; Myelopoiesis; Inflammation; Haematopoiesis; Inflammasomes

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. Emphasis is also placed on the clinical use of the results.
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: 25.04.2019

Responsible applicant and co-applicants

Employees

Collaboration

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

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
The American Society of Hematology (ASH) annual meeting Talk given at a conference Higher Vertebrate Specific Gene Ribonuclease Inhibitor (RNH1) is Essential for Adult Hematopoietic Stem Cell function and Cell Cycle Regulation. 07.12.2019 Orlando, United States of America Allam Ramanjaneyulu; Sarngdhar Mayuresh Anant;
Protein Synthesis and Translational Control, EMBO Poster Ribonuclease Inhibitor (RNH1) regulates hematopoietic specific translation 04.09.2019 Heidelberg, Germany Allam Ramanjaneyulu; Stilinovic Martina; Sarngdhar Mayuresh Anant;
ISEH 48th Annual Scientific Meeting Talk given at a conference Ribonuclease Inhibitor (RNH1) regulates hematopoietic specific translation. 22.08.2019 Brisbane, Australia Sarngdhar Mayuresh Anant; Stilinovic Martina; Allam Ramanjaneyulu;
Swiss Society of Hematology Talk given at a conference Ribonuclease inhibitor (RNH1) mediated cell cycle regulation is essential for haematopoietic stem cell function and lineage choice 27.06.2019 Zurich, Switzerland Sarngdhar Mayuresh Anant; Allam Ramanjaneyulu;


Awards

Title Year
ISEH Travel grant award 2019

Associated projects

Number Title Start Funding scheme
157486 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2015 SNSF Professorships
157486 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2015 SNSF Professorships
190073 Role of Ribonuclease inhibitor (RNH1) in Hematopoiesis and Inflammation 01.04.2020 SNSF Professorships

Abstract

Ribonuclease Inhibitor (RNH1) is an ubiquitously expressed 50-kDa leucine-rich repeat (LRR) protein. It is mainly localized in the cytosol, but can also be found in the nucleus and mitochondria. The human RNH1 gene evolved via gene duplication and is 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. Interestingly, the LRRs of RNH1 are very similar to those of NLRP proteins. NLRP proteins belong to NOD-like receptors (NLRs) family and form inflammasome complexes. Inflammasomes are caspase-1 activating complexes and they process IL-1 members IL-1ß and IL-18 cytokines and induce pyroptosis. Whether RNH1 plays a role in inflammasome activation needs to be established.We recently published that RNH1 is a ribosomal associated protein, binds to ribosomal proteins and regulates erythropoiesis by specifically regulating GATA1 mRNA translation. Loss of RNH1 led to a severe decrease in erythroid cell maturation, resulting in the death of mice at embryonic day E8.5 to E10. Further, RNH1 knockdown in human CD34+ cells lead to decrease in erythroid differentiation. These findings have high translational relevance, since it is known that mutations in ribosomal proteins cause i) macrocytic anemia in Diamond-Blackfan anemia (DBA), a congenital bone marrow failure syndrome, and ii) 5q-syndrome, a subtype of myelodysplastic syndrome (MDS). Interestingly, it has been shown that ribosomal deficiency in DBA patients specifically cause decrease in GATA1 translation, similarly to what is observed in RNH1 deficient mice and human erythroid cells. Recently, it has been shown that RNH1 is translationally down regulated in DBA patients. Further, we also found a second important function of RNH1 that it negatively regulates inflammasome activation by direct binding to NLRP proteins, suggesting that RNH1 inhibits inflammation. Collectively, these findings have introduced RNH1 as a novel player in hematopoiesis and inflammation. The goal of this proposal is to understand how RNH1 regulates hematopoiesis and inflammation. Three complementary research sub-projects were designed to elucidate molecular mechanisms of RNH1 action. The first sub-project will investigate the role of RNH1 in erythropoiesis by focusing on how RNH1 affects ribosome biology, erythroid maturation and role in adult erythropoiesis. We will also investigate a potential role of RNH1 in the pathology of DBA and 5q-syndrome. The second sub-project will study the molecular mechanism of RNH1 in the regulation of inflammasome activation and inflammation. The third sub-project will focus on the role of RNH1 in hematopoietic stem cell (HSC) function, differentiation of other hematopoietic lineages and possibly malignancies of HSCs.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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