FUJIU Katsuhito, MD, PhD |The University of Tokyo, Department of Cardiovascular Medicine; NAKAYAMA Yukiteru, MD, PhD; SUGITA Junichi, MD, PhD; OSHIMA Tsukasa, MD, PhD
Competition Sponsor: Japan Agency for Medical Research and Development
Awardee Year: 2022
Heart failure is currently an incurable disease. I will try to clarify why it is not curable. So far, I have found that macrophages in the heart have cardioprotective effects, and their deficiency results in heart failure death (Nat Med 2017) and sudden cardiac death (Nat Commun 2021). We also found that the cardioprotective effect of cardiac macrophages is maintained by the inter-organ network among the heart, brain, and kidney via the immune and nervous system networks (Nat Med 2017). Based on the previous findings, we will examine how the cardiac homeostasis mechanism is disrupted and find new therapeutic targets for heart failure.
I hypothesized that “cardiovascular stress and aging accumulate somewhere as stress memory. Our preliminary data demonstrated new inter-organ coordination between heart-brain-several organs via the vagal afferent, brain, and sympathetic efferent provoke innate immune memory. Then, the stress memory impaired the differentiation of tissue macrophages in the heart and other organs. We believe that this mechanism is the cause of repeated heart failure once it develops.
In particular, we focus on the activation of afferent neurons. The neurons directly sense changes in the heart and integrate them within the neurons. Our findings suggest cardiovascular stress may be perceived as a specific substance. This project will identify molecular switches of heart failure as particular substances and their receptors by analyzing selectively activated afferent neurons. These experiments should provide a new heart failure-associated interorgan communication and find new heart failure-specific substances and receptors that provoke heart failure recurrence and comorbidities.
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