Shingo Yasuhara, M.D.
|Title||Assistant Professor of Anaesthesia|
|Institution||Massachusetts General Hospital|
|Address||Shriners' Burn Institute|
Department of Anesthesia
51 Blossom St
Boston MA 02114
||Carl Moyer Award|
2005||Shriners Research Grant|
||Society for Pediatric Research Student Award (Mentor of Recipient A. Asai)|
||Eastern Society for Society for Pediatric Research Training Award (Mentor of Recipient A. Asai)|
2010||Shriners Research Grant|
Our research goal is to provide the detailed explanations of the pathophysiological mechanisms of, and thus find the effective therapeutic target of, various muscle diseases. For example, after severe burn injury or under sepsis, the patients show a whole body muscle atrophy - a pathological status called systemic muscle wasting whose mechanism still remains to be fully characterized. Muscle wasting affects patients prognosis. On the other hand, there is another disease entity of muscle dystrophies with elusive pathological mechanisms. We are trying to find out the common and uncommon mechanisms for these two different muscle diseases.
To study these muscle diseases, we first started several years ago, developing various new experimental methods of in vivo microscopy. We went further to construct our own in vivo confocal microscope from scratch. By using these new tools, we are investigating into the mechanisms of these diseases.
The list of the specific assays we can perform on skeletal muscles using in vivo microscopy includes; in vivo cell death quantification, in vivo microcirculation analyses (RBC flux, RBC velocity, plasma flow, & their automated analyses), visualization of in vivo NO production, in vivo ROS production, in vivo calcium signaling, in vivo autophagy turnover, in vivo transgene expression, etc. (Potential future collaborators are welcome to contact us).
One important thing we can never over-emphasize is that in vivo microscopy is NOT another merely "technologically difficult art" to show off scientific skills NOR is it just another tool that can be replaced by conventional methods of analysis. It provides fundamentally different levels of information that has not been usually obtained by conventional post-mortem histological analyses or MACRO-scopic measurement.
For example, if we take out a chunk of tissue from a patient or an animal model, there will no longer exist live microcirculation or calcium signaling once the tissue is fixed and processed for analysis. If these functional aspects are playing essential roles in the pathogenesis of a disease, one can be very well dismissing important pieces of the puzzle in the whole explanation of such a disease. Of course, conventional histology is important, but it provides more or less only "structural" information. In vivo microscopes can, however, show us "functional" changes of the tissue in a very lively fashion. Medical science is already at a stage where more and more disease are being explained by the "functional" changes of physiological regulations.
For example, if we want to diagnose and evaluate the complications of a diabetes mellitus, a.k.a. circulatory disturbances of the affected tissues, we can very well take out the tissue from the patient or an animal model, and study the histology -- or structure of the blood vessels. Such conventional method of analysis can detect traces of microcirculatory disturbances once the complication has advanced into a late phase where part of the blood vessels show signs of arteriosclerosis. In vivo microscopy can, on the other hand, detect functional alterations, or the responsiveness of the microvessels, and thus has the potential to detect the onset of the complications at a much earlier stage.
From a clinical side of view, however, one stereotypic opinion is like, we already have a whole variety of MACRO-scopic tools to evaluate the patients' blood flow status. Why bother to use microscopes and make it more complicated?
It is true that MACRO-scopic blood flow measurement can provide the functional aspect of tissue circulation. MACRO-scopic flow analysis tools, however, mostly rely on the flow velocity. On the other hand, in the microscopic world, there are a whole different gamut of parameters of microcirculation, including plasma flow velocity, RBC flux (or numbers of RBCs passing by), RBC velocity, functional capillary density, heterogeneity vs. homogenity of the distribution of microcirculation, to name a few. All these parameters represent different physiological roles of blood flow, and often show discrepancy in their regulation kinetics from those of others. If one is looking only at MACRO-scopic perfusion of blood flow, it may not easy to understand that there exist so many other important parameters. In order to precisely understand the circulation status of a tissue, however, one cannot ignore these different microscopic parameters. I will explain the reasons blow.
We all know from physiology text books that some human organs such as the lung, show an elusive pathological status called "functional AV shunt". Under pathological conditions, even without obvious arterio-venous anastomosis, it has been known that the arterial blood short-circuits into the vein. Very often, there is no major change in the MACRO-scopic blood flow dynamics except for the fact that there is poor oxygen exchange somehow. It has been mathematically well known that heterogeneity in the functional capillary density can dramatically decrease the tissue oxygen supply/exchange even if the MACRO-scopic blood flow remains the same. Thus, in vivo microscopy and the documentation of parameters of microcirculation can very well explain such pathological status.
This is as if Newtonian view of the behavior of matters cannot explain the physical law in detail when matters are divided into sub-atom levels, and all of a sudden, quantum physics becomes necessary to characterize the particles in the microscopic world. After all, we, who live in the 21st century, all know that modern electronics could not have flourished in its current status without the establishment of quantum physics in the 20th century.
In fact, we have already successfully demonstrated that in vivo microscopy can document functional changes in muscle diseases, and that such changes are essential in the cause of those diseases (see publication below, 2006 PLoS One). We would have never been able to discover such findings if we had been studying only at the MACRO-scopic level.
Inter-communications between myocytes and blood vessles, between nerve and blood vessels, between stroma cells and myocytes, the long-term turnover rate of tissue degeneration and regeneration, etc. These are other kinds of aspects that have been largely set aside or not thoroughly investigated in fully quantitative manners, when drawing the pathophysiological explanation of a disease by conventional research approaches. And such discussions go on and on to explain the growing demand for in vivo microscopical analyses.
All the discussions above are about more long-term impact of in vivo microscopy. Lastly, I will address more short-term, direct applications of of this technique potentially in the clinical setting.
In the field of cardiac surgery, there are two famous operations; Maze Operation for atrial fibrillation, and Batista Operation for dilated myopathy. Both operations are about dissecting out some unnecessary/harmful portion of the heart either to improve the cardiac output, or to treat arrhythmia. Both operations are, however, extremely difficult and requires skill, especially when we try to evaluate what part to dissect. Clearly, no one wants to remove too much of the healthy part of the heart. So, question has always been, how one can distinguish between the normal and abnormal portions?
If one can somehow "see" the focus of arrhythmia, it becomes so much easier to determine which part to cut out by Maze Operation, based on such information. If one can visualize which area of the left ventricle has poor contractility, has more fibrosis than other domain, or has poor shedding of blood vessels due to such fibrotic changes, it becomes easier for one to decide the dissection area by Batista's Operation.
In the experimental setting, we are already at the stage where we are, on the regular basis, observing calcium waves in detail, measuring practically all the different parameters of microcirculation, movement of the myofibers, detailed morphology, cell death, autophagy, extent of NO production, ROS production, etc, all in the muscles of live mice.
It would be beneficial to extrapolate these techniques in the future to serve to improve those difficult cardiac surgeries.
Finally, we are also trying to build more advanced and more unique microscopes to reach further beyond our current findings.
The fields of my expertise are: internal medicine, critical care medicine, cardiopulmonology, molecular biology, biochemistry & protein biology, signal transduction, cell & organelle biology, membrane & vesicle transport, animal studies, mechanical physiology, microcirculation, neuroscience, histology, microscopy & optics, electrical engineering & circuit designing, control system, mathematics, etc.
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