Research
How does a pathogen utilize our body system? Virus cannot survive by themselves but do need host to infect. We are interested in virus – host interaction and roles of host factors in disease pathogenesis evoked by virus infection. We focus the molecular mechanisms by which influenza viruses cause severe diseases (i.e.; acute respiratory distress syndrome [ARDS]) in humans, as well as the pathogenesis of the diseases in critical care medicine (i.e.; ARDS, multiple organ failures, pressure overload heart failure, and long QT syndrome). Our group’s basic approach is to genetically manipulate genes in mice and to examine the effect of the modification on the biology of whole organism. Using in vivo mouse disease model systems combined with mouse genetics, molecular biology, cardiopulmonary physiology and in vivo imaging, we are trying to clarify the basic principles of physiology and disease pathogenesis, and to seek the novel therapeutic targets for the diseases.
1) Virus-host interaction in highly pathogenic influenza virus infection
Since April 2009, a novel swine-origin influenza A (H1N1) virus has emerged, and is spreading rapidly among humans on a worldwide scale. Also, H5N1 avian influenza virus continues to cause outbreaks in poultry and sporadic infections in humans. The mortality rate of H5N1 avian influenza in humans has been as high as 60%. Most patients who died of the influenza developed the ARDS, which is characterized by an extremely severe inflammatory response, diffuse alveolar damage and pulmonary edema, resulting in severe respiratory failure. Such patients with ARDS require critical cares including mechanical ventilation in the intensive care units (ICUs). Although initial analyses suggest that the clinical severity associated with the 2009 H1N1 virus is less than that seen in 1918 Spanish flu or H5N1 avian virus, preparedness for the current as well as future pandemics will require a better understanding of disease pathogenesis of influenza, including mechanisms of viral pathogenesis and interactions with the host machinery. Using mouse ICU model system (Figure 1), 
we found that the oxidative stress upon highly pathogenic H5N1 virus infection generates oxidative phospholipids which can trigger the over response of innate immune system resulting in hyper-production of proinflammatory cytokines, so called “cytokine storm”. Furthermore, we recently identified angiotensin converting enzyme 2 (ACE2), a newly identified ACE family molecule as an in vivo SARS-coronavirus receptor and demonstrated that ACE2 plays a crucial role in SARS pathogenesis. To further extend the study, using genetically modified mice and in vivo disease model systems, we are trying to elucidate molecular pathogenesis of the diseases and seek the therapeutic targets.
2) Dissecting mechanisms for global gene regulation by CCR4-NOT complex
By exploiting Genome-wide RNAi fly library (collaboration with IMBA), we conducted global in vivo heart failure screening, and subsequent in silico analyses for mammalian ortholog of screening hits first built a system map of heart genes controlling functions (Figure 2). As a result, we identified CCR4-NOT complex as a novel regulator of heart functions. CCR4-NOT was originally isolated as a global transcription regulator from yeast mutants, and it has recently been suggested as a crucial deadenylase for mRNA poly-A tail shortening, which is also implicated important for micro RNA-mediated mRNA decay. In our latest study analyzing the heart failure phenotype of CNOT3 knockout mice, we first elucidated CCR4-NOT is critically involved in histone modifications and epigenetic gene regulation for controlling heart function (Figure 3) (Cell, 2010). Accordingly, we hypothesize that CCR4-NOT complex is a global regulator of gene expression linking metabolism of mRNA and epigenetic gene regulation. In this project, we try to dissect the physiological role of CCR4-NOT complex in controlling heart and lung functions and will further investigate the significance of CCR4-NOT in disease pathogenesis of heart & respiratory failure, arrhythmia, ARDS, and COPD.
Selected publications
- Neely G#, Kuba K#*, Imai Y, Penninger JM*, et al. A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function. Cell. 2010, 141(1): 142-153. (#; equal contribution, *; shared correspondence)
- Imai Y, Kuba K et al. Identification of oxidative stress and toll like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008, 18;133(2):235-49.
- Kuba K, Zhang L, Imai Y et al. Impaired Heart Contractility in Apelin Gene–Deficient Mice Associated With Aging and Pressure Overload. Circulation Research. 2007, 101:32-42.
- Imai Y, Kuba K et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005 Jul 7;436(7047):112-6.
- Kuba K, Imai Y et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9.
- Goggel R, Winoto-Morbach S, Vielhaber G, Imai Y et al. PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med. 2004 Feb;10(2):155-60.
- Imai Y, Parodo J, Kajikawa O et al. Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA. 2003 Apr 23-30;289(16):2104-12.
