Uncovering the role of the protein DISC1 in cARDIAc ischemia (DISCARDIA)

Despite considerable efforts, effective strategies to prevent damage to the heart following myocardial infarction remain limited. Myocardial infarction is the first manifestation of ischemic heart disease and activates multiple signalling processes that can eventually lead to heart failure. DISCARDIA will answer this challenge by pursuing my novel scientific discovery of the scaffolding protein Disrupted in Schizophrenia 1 (DISC1), which hitherto remains completely unexplored in the heart. Our preliminary data suggest that DISC1 plays a major role in cardiac remodelling and function, as well as in protection against ischemic damage. The major aim of DISCARDIA is to determine if this multi-functional protein is a master regulator in the heart that orchestrates intracellular processes that protect against ischemic heart disease. DISCARDIA will characterize in detail the role of the DISC1 protein, using a range of experimental approaches with further verification in a line of proof-of-concept studies using clinically relevant patient populations. DISCARDIA aim to explore the full potential for this discovery and hopefully in the future lay the foundation for novel therapeutic strategies for ischemic heart disease.

Despite considerable efforts, effective strategies to prevent damage to the heart following myocardial infarction (MI) remain limited. MI is the first manifestation of ischemic heart disease (IHD) and activates multiple signalling processes that can eventually lead to heart failure. DISCARDIA will answer this challenge by pursuing my novel scientific discovery of the scaffolding protein Disrupted in Schizophrenia 1 (DISC1), which hitherto remains completely unexplored in the heart. My preliminary in vivo and in vitro data suggest that DISC1 plays a major role in cardiac remodelling and function, as well as in protection against ischemic damage. Reduced DISC1 expression is an established risk factor for schizophrenia (SZ), and SZ patients die 20 years earlier than the general population, largely due to IHD. SZ patients therefore offer a unique opportunity to provide evidence of causality between DISC1 deficiency and IHD in humans, while potentially also answering the question of why SZ patients are more susceptible to IHD. In DISCARDIA I will advance from a unique line of preliminary data, lean on existing knowledge on DISC1 from neuroscience and apply this to cardiology, with the overall aim to determine if this multi-functional protein is a master regulator in the heart that orchestrates intracellular processes that protect against IHD. We will characterise in detail the role of the DISC1 protein, using a range of in vitro and in vivo experimental approaches with further verification in a line of proof-of-concept studies using clinically relevant patient populations of IHD and SZ. I postulate that reduced DISC1 protein directly causes cardiac deterioration and especially renders the heart vulnerable to ischemic challenges such as myocardial infarction. This RCN grant will enable DISCARDIA to explore the full potential for this discovery and hopefully in the future lay the foundation for novel therapeutic strategies for IHD.