Professor Karlheinz Peter
Program Head: Atherothrombosis and Vascular
Head, Atherothrombosis and Vascular Laboratory
NHMRC Principal Research Fellow
Phone: +61 3 8532 1490
The Atherothrombosis and Vascular Biology Laboratory pursues a broad range of projects that have the common focus on improving diagnosis and therapy of thrombotic and inflammatory diseases such as myocardial infarction and atherosclerosis. A range of biotechnological methods are used, including recombinant protein design/production, generation of functionalised nanoparticles/ lipsomes/microbubbles, cell culture, flow cytometry, flow chamber, intravital microscopy, ultrasound, MRI, PET various fluorescence imaging systems and various animal models of thrombosis, atherosclerosis and inflammation. All of these projects have a strong translational orientation, which is facilitated by several laboratory members (physicians/cardiologists) treating patients with cardiovascular diseases. Several of the research projects resulted in patents that are currently being further developed to ultimately improve the health of patients.
Work in the laboratory is particularly attractive for students/post docs who are interested in the development of advanced biotechnological tools for molecular imaging and novel therapeutics (e.g. regenerative stem cell therapy and microRNA for plaque stabilisation). The translational direction of the laboratory and the inclusion of patients in studies such as for example the identification of vulnerable, rupture-prone atherosclerotic plaques of patients is highly attractive for physician scientists.
We introduced a novel concept of the functional role of CRP as a ‘pro-inflammatory system'. This concept is based on our findings that pentameric (p)CRP can undergo a conformational change to monomeric (m)CRP, which is highly pro-inflammatory and pro-coagulant, and induces a localised inflammatory reaction that aggravates many diseases. We have shown that pCRP to mCRP dissociation occurs on the surface of ‘stressed cells', such as activated, necrotic or apoptotic cells, and on microparticles (MPs) circulating in blood. For example, the surface of activated platelets causes a rapid dissociation of pCR to mCRP. We have also described mCRP formation induced by misfolded proteins such as Alzheimer plaques as a clearance mechanism that can ‘overshoot' in pathological situations. We will now develop inhibitors of CRP dissociation that can form the basis of a novel therapeutic approach for a range of protein misfolding disorders, such as Alzheimer disease.
The high morbidity and mortality of atherosclerosis is typically precipitated by plaque rupture, consequent thrombosis and myocardial infarction. However, research on underlying mechanisms and therapeutic approaches has been hampered by the lack of animal models that reproduce the plaque instability seen in human atherosclerosis. We developed a unique, reliable mouse model based on flow measurements and computational fluid dynamics that resembles human plaque characteristics most closely. We use this unique model now 1) as a discovery tool to identify messenger RNA and microRNA (miR) associated with plaque rupture, 2) for developing/testing of potential plaque-stabilising drugs, and 3) developing various approaches in molecular imaging (MRI, PET, ultrasound) that will allow the specific detection of unstable, rupture-prone plaques.
We use a highly versatile microfluidics system as a tool to study shear stress related induction of coagulation and platelet activation under physiological and pathological flow patterns. In addition, this system allows for systematic testing of anti-thrombotic drugs under flow conditions.
We have developed a range of recombinant antibodies that allow targeting of activated platelets, the activated coagulation system, and activated monocytes. Thereby we can specifically image thrombotic and inflammatory processes. We have tailored these antibodies to be used in advanced imaging technologies such as MRI, PET, ultrasound and fluorescence imaging (FLECT, IVIS). We are investigating diseases including atherosclerosis (particularly plaque instability), myocardial infarction and inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. The biotechnological development of these contrast reagents and particles are an important and highly translational focus in our group.
Using biotechnological tools, we are developing drugs that will be enriched at areas of thrombosis or inflammation without reaching a significant systemic circulating concentration. This allows for example to develop anti-thrombotic, anti-platelet or clot-busting drugs that are highly effective but do not cause bleeding complications. The transport and enrichment of these drugs is achieved by using nanoparticles, liposomes, microbubbles and other high end targeting particles. In addition to targeting drugs, we have also developed a recombinant antibody delivery system that allows to specifically deliver stem cells as a regenerative cell therapeutic approach, e.g. for the therapy of myocardial infarction.
Dr Jonathon Habersberger
Dr Nay Min Htun
Dr Jath Palasubramaniam
Visiting Scientist on Sabbatical
Professor Vibeke Videm, Norway