Projekt HRZZ: BMP1-IsoFor

This project is funded by the Croatian Science Foundation.

Newly discovered BMP1 circulating isoforms as biomarkers and therapeutic targets for human diseases

“BMP1-IsoFor”

In this Installation Research Project (IRP) we will further examine the mechanisms of BMP1 isoform function in animal model of chronic kidney disease and liver fibrosis. The primary research area will cover the discovery and establishment of a novel therapeutic target(s) in regenerative medicine. This IRP should also support foundation of a new independent scientific group by Dr. Lovorka Grgurević which will receive an appropriate laboratory space in the Center for Translational and Clinical Research. The entire project team is composed of experts from collaborative institutions and collaborative laboratories.

Figure: Discovery and characterization of Bmp1 gene isoforms in the plasma of healthy individuals and patients with CKD, AMI, LC and pancreatitis. The regions of identified peptides from Bmp1 gene isoforms are indicated by * in (A). Peptide sequence and the Mascot score (MS) are shown in (B). Proteins were identified by liquid chromatography – mass spectrometry (LC-MS) using the Mascot search engine. Peptides with a mass deviation <10 ppm were accepted, and at least two detected peptides were required for protein identification (Grgurevic et al, 2011).

PROJECT DETAILS

Project title: Newly discovered BMP1 circulating isoforms as biomarkers and therapeutic targets for human diseases

Acronim: BMP1-IsoFor

Project code: 3509

Project type: Installation Research Project

Scientific area: Biomedicine and Health Sciences

Scientific field: Basic Medical Sciences

Principal Investigator (PI): Lovorka Grgurević, MD, PhD

Institution: University of Zagreb School of Medicine

Project duration in months: 36 (1.1.2016. – 1.9.2018.)

Project funding: This project is funded by the Croatian Science Foundation

Total budget: 999.000,00 HRK

SUMMARY OF THE PROJECT

We sought to identify and characterize the structure of circulating bone morphogenetic proteins (BMPs) in the human plasma directly associated with organ specific pathology. Instead, we unexpectedly discovered circulating Bmp1 gene metalloproteinase isoforms: BMP1-3 (mTld) in healthy men and in patients with chronic kidney disease (CKD), BMP1-4 in liver cirrhosis (LC), BMP1-5 in acute myocardial infarction (AMI), and BMP1-7 in pancreatitis. We then showed that injections of BMP1-3 protein deteriorate, while BMP1-3 neutralizing polyclonal antibody improves the kidney function and prevents death in rats with CKD. In addition, inhibition of BMP1-3 alone and in combination with a BMP1-4 antibody improved the organ function in LC and AMI. We assume that BMP1-3 represents a core regulatory pathway molecule essential in fibrosis, and its targeting may be sufficient to limit fibrosis progression, while other BMP1 isoforms are involved in organ specific regulatory pathways.

In line with these findings, in this project we propose a new scientific concept in combating fibrosis using core and organ specific regulatory pathways, through pursuing the following objectives:

to produce recombinant BMP1 isoform proteins and related neutralizing isoform-specific monoclonal antibodies;
to determine specific BMP1 isoform substrates;
to develop new sensitive plasma bioassays for measuring BMP1 isoforms in different animal experimental models; and
to explore the role of BMP1 isoforms in the pathology and function of animals with CKD and LC.

The most efficacious monoclonal antibodies variable domain will be sequenced and then humanized for potential development of new diagnostic tools and therapeutic application. This novel approach aims to acquire the first candidate specific treatment for halting or reversing the progression of CKD and LC. We hypothesize that modulation and/or inhibition of BMP1 isoforms represents future of diagnostic and therapeutic interventions in the field of molecular and translational medicine of fibrosis.

TEAM MEMBERS

Project scientific leader:

Lovorka Grgurević, MD, PhD (Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia)

Project team:

Hermann Oppermann, MD, PhD (Genera Research Ltd., Kalinovica, Croatia)

Morana Jankolija, MSc (Genera Research Ltd., Kalinovica, Croatia)

Tatjana Bordukalo Nikšić, PhD (Laboratory for Mineralized Tissues, University of Zagreb School of Medicine, Zagreb, Croatia)

Vera Kufner, PhD (Laboratory for Mineralized Tissues, University of Zagreb School of Medicine, Zagreb, Croatia)

Mario Matijašić, PhD (Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia)

Ivo Dumić-Čule, MD, PhD (Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia)

Hana Čipčić Paljetak, PhD (Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia)

Ruđer Novak, PhD (Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia)