Forsøksdyr: Lumican's role in hypertrophic cardiomyopathy - studies of the aMHC R403Q/LUM-KO mouse

Godkjenningsdato 19.08.2020

Godkjenningsperiode 01.09.2020-31.08.2024

Heart failure is a major cause of severe disease and death globally, with 100,000-200,000 patients in Norway. The most common form of inherited heart failure is hypertrophic cardiomyopathy (HCM), occurring in 1:500 people. Heterozygous mutations in genes in the heart (such as myosin heavy chain (a-MHC)) cause HCM. Cardiac fibrosis cause arrhythmias in HCM, and HCM is the most common cause of sudden cardiac death among young people, including many athletes.

Our group has studied the role of lumican in cardiac fibrosis over many years. Lumican is a proteoglycan located in the extracellular matrix (ECM), the space between the contractile cells of the heart (the cardiomyocytes). We have shown that lumican levels are upregulated in hearts of patients and mice (a-MHC R403Q) with HCM. Lumican binds to collagen fibers, and our main hypothesis is that it regulates fibrosis, and thereby arrhythmogenesis, in HCM.

To understand the role of lumican in the heart, we rely on continued use of an existing in vivo lumican knockout model, the LUM-KO mouse (C57BL/6J background. FOTS ID 11669), in combination with our HCM mouse model, the aMHC R403Q mouse (129S6/SVEv background. FOTS IDs 7466, 14962 & 17235). By crossing these two mouse lines to make the aMHC R403Q/LUM-KO mouse (mixed background, this application), we will gain invaluable insight into the mechanistic role lumican has in fibrosis in HCM.

HCM will be induced by administration of Cyclosporine A (CsA) (ref. FOTS IDs 7466, 14962 & 17235). The aMHC R403Q mouse is a well-established HCM model made in the Seidman lab, Harvard Medical School, along with the use of CsA to induce HCM.

The purpose of this experiment is to investigate the importance of lumican in HCM and fibrosis. By researching this topic, we provide a better understanding of the underlying causes of heart failure, which, in the long run, contributes to development of new therapies. Such experiments therefore have great scientific and societal value.

We plan to study mice with HCM induced by age or CsA. CsA is administered by feeding, and other methods are undertaken while mice are anaesthetised, including echocardiography and MRI. These methods are well-established at our research institute (IEMF).

A total of 2344 mice are planned for this project, which has been calculated based on experience with similar previous projects, statistical assessment and good staff training. The majority of these mice are used for breeding.

The best experimental models of heart failure in patients is achieved only with in vivo animal models and cannot be replaced by cell culture experiments or tissue biopsies. The 3Rs are safeguarded by use of well-established models, which limits numbers of animals used for experiments. Tissue collected from one animal will be used for multiple molecular analyses, thus reducing numbers further. By isolating cells from these animals, we will also conduct follow-up work on disease mechanisms without the need for further animal experimentation.