Fumito Ichinose, M.D., Ph.D.
Physician Investigator (Cl)
Anes. Research - Monthly, Research Institute
William Thomas Green Morton Professor of Anaesthesia
Harvard Medical School
Anesthesia & Crit. Care, Massachusetts General Hospital
|MD University of Tokyo 1988|
|PhD University of Tokyo 1996|
The overarching research goal of the Ichinose laboratory is to elucidate the molecular mechanisms responsible for the cardio-cerebral dysfunction and injury often found in patients suffering critical illness including sepsis, cardiac arrest and CPR, and neurodegenerative disorders. Objectives of our current research programs include characterization of the biological effects of nitrous oxide (NO) and hydrogen sulfide (H2S) in cellular function and to develop novel therapeutic strategies.
Role of sulfide catabolism in hypoxic brain injury and neurodegenerative diseases: In the first program, we are investigating the role of hydrogen sulfide catabolism in ischemic or hypoxic brain injury and neurodegeneration. We use multiple animal models including hibernating 13-lined ground squirrels, murine primary cortical neurons, and novel genetically-modified mice models. To characterize the effects of sulfide catabolism, we developed a series of new sulfide scavengers using a database of sulfide-specific chemical probes. We also use in vivo gene transfer techniques directly into murine brains using custom-made adeno-associate virus vectors. These studies are expected to illuminate the role of sulfide catabolism not only in hypoxia tolerance and neurodegenerative diseases but also in mammalian physiology in extreme environment.
Development of chemcial counter measures against hydrogen sulfide intoxication: Originally, hydrogen sulfide was discovered and studied as environmental hazard. Hydrogen sulfide intoxication is the second most common cause of gas-related death after carbon monoxide. Related to the first project, in the second program, we seek to develop countermeasures against H2S poisoning using the newly developed library of sulfide scavengers. We will develop and examine sulfonyl azide and selenium oxide based sulfide scavengers using established in vitro screening assays. Promising lead compounds will be tested in novel murine models of H2S intoxication and H2S-induced cardiopulmonary arrest developed in our laboratory. This project was recently funded by NIH CounterAct program.
Targeting hydrogen sulfide metabolism in microorganisms as a therapy: Hydrogen sulfide is considered as a gas that existed in ancient earth when life was born. Many micro-organisms retain the ability to use sulfide as an important energy source. In the third project, we are investigating the role of sulfide metabolism in micro-organisms including fungus and bacteria. Targeting sulfide metabolism may enable us to develop anti-microorganismal agents, which are based on novel mechanisms. Furthermore, because abundance of sulfide-producing bacteria is known to correlate with a number of bowel diseases including inflammatory bowel disease, manipulating sulfide metabolism may also prove to be therapeutic against diseases of host.
Role fo NO/cGMP-dependent mechanisms in blood-related disorders: In the fourth project, we are examining the role of NO/cGMP-dependent mechanisms in blood-related disorders including hypercoaguability after cardiac arrest and storage lesion of blood. In particular, we are studying the effects of NO/sGC-dependent signaling in a newly developed murine model of hemorrhagic shock-induced cardiac arrest resuscitated with stored blood. Insight gained from these studies may lay foundations to develop novel therapeutic approach to transfusion-related critical illness.
Role of post-cardiac arrest sedation on neurological outcomes after cardiac arrest: Although post cardiac arrest patients are routinely sedated with anesthetics (e.g., propofol), effects of post-arrest sedation on post-arrest outcomes are unknown. In the fifth program, we investigating the role of post-cardiac arrest sedation on brain injury and neurological recovery using a mouse model of cardiac arrest and CPR. Effects of post-arrest sedation with propofol and dexmedetomidine on neurological outcomes are examined using telemetric EEG, cerebral blood flow measurements with laser Doppler flowprobe, histological analysis, and neurological functional analysis using a well-established mouse model of cardiac arrest and CPR.