Research
Our lab has been just started from July 2008, and currently is under setting and recruiting people. 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. 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 areas (i.e.; ARDS, multiple organ failures, pressure overload heart failure, and long QT syndrome). 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.
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 as below;
1) Virus-host interaction in highly pathogenic influenza virus infection
- Role of endosomal phosphatidylinositols in influenza virus infection
- Lipidomics in influneza –phospholipids matabolome analysis -
2) Dissecting molecular pathogenesis and therapeutics of pulmonary and cardiovascular diseases
- Genome-wide screening of novel genes involved in the disease pathogenesis and generation of knockout mice
- Elucidation of mechanisms of the disease and translate them to new therapies
3) In vivo imaging of disease process in mice using two photon microscopy in mouse ICU (Figure 2)
Selected publications
- 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.
