International Circulation: Could you talk about your some of your personal experiences in translational research?
《国际循环》：请您谈谈您在转化医学研究中的个人经验？
Dr. Fisher: I have been doing this for a long time. The first memorable experience was in 1985. We did the first tPA experiment in an animal model and showed that it was effective in rabbits. I would like to say that translational research is a very rewarding experience. You start with a hypothesis and， through the process of experimentation， you can make a novel discovery. This is especially true for me， because I started doing animal modeling from the perspective of a clinician. For me there has been a few “ah-ha” moments over the course of the last 30 years， and the tPA was one of them.
Another was in the in the early 90s， when we started using MRI as an assessment tool to evaluate therapeutic responses. The first drug we tested was a neuroprotective agent and we demonstrated that it effected the evolution of the diffusion lesion in vivo. As there was one prior study， we were the second group to show the evolution of an ischemic lesion in a living animal. The first neuroprotective drug we tested worked.
In the early 2000s， we started combining the effusion and perfusion images to look at the evolution of the ischemic penumbra. We mapped the evolution of the penumbra over time and watched the mismatch of the two disappear. Then we tried various treatments. We tried a whole series of different agents and we could see that different drugs could slow down the diffusion lesion evolution and prolong the penumbra.
The most recent moment was a couple a years ago， when we published a paper on high flow oxygen treatment. We were able to extend the therapeutic time window of tPA in the animal model. I think an interesting future application of this research would be to give this as a pre-hospital treatment. This may allow for the extended survival of the penumbra. By having more penumbra， we will be able to treat with reperfusion.
Dr. Fisher: 我做转化医学研究已经有很长时间了。令人难忘的经历最早开始于1985年。我们首次在动物模型上进行了tPA实验并证实它在兔子体内是有效的。我认为转化医学研究是非常有意义的。你从一个假设开始，通过实验得到一个新的发现。对我而言尤其如此，因为我从临床医生的角度来设计并开展动物实验。对于我来说在过去的30年里有一些取得重大发现的时候，tPA就是其中之一。
另一个就是在90年代早期的时候，那时我们开始用MRI作为一种评估工具来评价治疗的反应。我们检测的第一个药物是一种神经保护剂，我们的研究显示这种药物影响了弥散性病变在体内的进展。在先前的一项研究中，我们是第二个显示在活体动物中缺血性病变进展的研究小组。我们检测的第一种神经保护药物在实验中是有效的。
在2000年早期，我们开始把渗出和灌注影像相结合来观察缺血的半暗带的进展。我们描绘出在一段时间内半暗带的变化并观察两种影像的差异。然后我们尝试了各种治疗方法。我们尝试了一系列不同的药物并且发现不同的药物能减缓弥散病灶的进展并延长半暗带。
最近的一次发现是在2年前，我们发表了一篇关于高流量氧治疗的文章。我们在动物实验中能延长tPA的治疗时间窗。我认为这项研究将来可能作为一种入院前的治疗方法而得到应用。这意味着半暗带处组织存活的几率增加。当存在更多的半暗带时，我们将可能进行再灌注治疗。
IC: Given your track record with MRI-based research， could you please tell our readers about your latest progress in this field?
《国际循环》：根据您以往在MRI方面的研究，您能跟读者谈谈您在这方面最近取得的成果吗？
We are currently performing imaging experiments where we inject labeled clots into our animals. These clots are radio-opaque and are obvious on T1 imaging， allowing us to perform serial imaging every 15 minutes for a couple of hours. In doing so， we could compare the rapidity and extent of clot lysis with different therapies. We compared tPA and tPA plus annexin II and we were able to show that the combination worked more rapidly and completely than tPA alone. We plan to continue this research. The first experiment will be to find a maximized dose of the combination. Basically， if you want new lytic， it has to be an improvement over tPA. An improvement would dissolve clots more completely and faster. Now， we have a new assessment tool to watch real time clot dissolution in vivo. Downstream from there， we are able to image the hypoperfuse plane and compare how much of that is restored to normal perfusion， as well as the ultimate effects of the reperfusion on the size of the infarct.
This research is part of a translational grant we have with Massachusetts General Hospital. The basic idea of this whole program is to investigate this combination treatment as a new drug application， so that it can undergo clinical trials. Funding translational research is a relatively new initiative of the NIH. Their goal is to bring new therapies， based on a complete data package from animals， to the point of clinical trials. This used to be in the domain of the drug companies， but the NIH is now funding some treatments that drug companies would be willing to develop for various reasons.
Dr. Fisher: 我们最近正在进行在动物体内注射标记凝块的影像学实验。这些凝块是X线不透明的并且在T1加权相下清晰可见，使我们能在几个小时内每隔15分钟采集一次并获得一系列影像。在这个过程中，我们能对比在不同治疗下凝块溶解的速度和程度。我们把tPA和tPA联合膜联蛋白II治疗进行了对比，我们的结果显示联合治疗比tPA单独治疗的起效更迅速作用更完全。我们计划继续进行这项实验。首先需要进行实验找到联合用药的最大剂量。从基本上来讲，如果你想要一种新的溶栓药物，它的作用就必须优于tPA。效果的增强会更快更有效的溶解血栓。现在我们有了一种新的评估工具来实时观察血栓在体内的溶解。接下来，我们就能通过影像显示低灌注阶段并对灌注恢复到正常水平的程度进行对比，同时还能观察梗死区域再灌注的最终效果。
这项研究是我们在马萨诸塞总医院转化医学基金的一部分。这项研究的主要目的是为了探索这种联合治疗作为一种新的药物治疗的应用，因此它还会继续进行临床试验。资助转化医学研究是NIH相对新的项目。转化医学的目的是通过从动物实验中获得的完整资料来探索新的治疗方法，并最终进行临床试验。这在以前都是药物公司的研究领域，但是NIH现在开始资助一些药物公司由于各种原因愿意开发的治疗方法。
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